All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

After completing this application-based continuing education activity, pharmacists will be able to

Describe the different types of prescription drug coverage available to Medicare patients
Explain the patient costs associated with Medicare Part D prescription drug coverage
Demonstrate use of a patient’s Medicare Part D formulary to determine the appropriate type of coverage determination
Identify prescriptions that Medicare Part D does not cover

After completing this application-based continuing education activity, pharmacy technicians will be able to:

Describe the different types of prescription drug coverage available to Medicare patients
Explain the patient costs associated with Medicare Part D prescription drug coverage
Identify the types of coverage determinations available for Medicare Part D prescriptions
Outline the timeframes involved in Medicare Part D coverage determination and appeal decisions

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Millions of Americans are enrolled in Medicare Part D, with hundreds of specific Part D plans available across the country. The Centers for Medicare & Medicaid Services (CMS) regulates Part D coverage. Part D plans must submit their plan costs and formularies, including formulary restrictions, to CMS for annual approval. Patient costs for Part D coverage vary based on the specific choice of plan and the benefit phase. All Part D plans must provide a process for requesting coverage of prescription medications that are not on the formulary or on the formulary with restrictions. Pharmacists and pharmacy technicians are valuable resources and can advise Part D patients and prescribers about prescription costs and the options available for non-covered medications.

INTRODUCTION

As of April 2023, more than 51 million Americans were enrolled in prescription drug coverage through Medicare, with the number of enrollees steadily increasing every year.¹Private insurance companies contracted by the Centers for Medicare & Medicaid Services (CMS) provide Medicare prescription drug coverage. Although specific plans’ details differ, CMS requires that all plans offer certain features.

Pharmacists and pharmacy technicians can assist patients in navigating these features to maximize their prescription benefits. This continuing education activity will review the types of Medicare prescription drug coverage, associated patient costs, formulary structure, and the options available when a patient’s Part D plan does not cover a medication.

MEDICARE AND PRESCRIPTION DRUG COVERAGE

CMS provides “Original Medicare” to most Americans aged 65 and older. Original Medicare includes²:

Part A: Most Americans are eligible for Medicare Part A at no additional cost, as long as they or their spouses have paid sufficient Medicare taxes. Medicare Part A includes coverage for inpatient hospital stays, hospice, and skilled nursing facility care.
Part B: Medicare Part B is optional and usually requires additional fees. Part B coverage includes outpatient and home health care, preventive services, and durable medical equipment.

CMS contracts with private insurance companies to provide prescription drug coverage. Individuals enrolled in Original Medicare may purchase a standalone Part D Prescription Drug plan (PDP) for outpatient prescription drug coverage.

Rather than using CMS coverage, individuals may purchase Medicare-approved private insurance called Medicare Advantage (MA), also known as Part C. With this arrangement, the MA Plan supersedes Medicare Part A and Part B for most coverage. MA plans often have lower patient costs and extra benefits compared to Original Medicare but may have fewer covered hospitals and physicians.² Medicare Advantage Prescription Drug (MAPD) plans are MA plans that include prescription drug coverage and eliminate the need for a separate PDP.

SIDEBAR: Patient Costs Defined

Monthly Premium: a monthly payment that maintains enrollment in the plan; not impacted by deductible, copay, or coinsurance amounts

Annual Deductible: a yearly dollar amount the patient pays before insurance starts to contribute

Copayment (or Copay): a specific, pre-determined dollar amount the patient pays for each prescription, office visit, or other type of care after satisfying the deductible

Coinsurance: an alternative to a copay, the percentage of the total cost the patient pays for each prescription, office visit, or other type of care after satisfying the deductible

Medicare plans are associated with various costs to the enrollee (see SIDEBAR: Patient Costs Defined). Individuals with income higher than a predefined threshold pay a higher premium for their Part B coverage due to Medicare’s Income Related Monthly Adjustment Amount (IRMAA). IRMAA does not change any of the other costs associated with Medicare coverage. CMS may also issue a late enrollment penalty (LEP) to people who do not sign up for Part D (from either a PDP or MAPD) as soon as they become eligible for Medicare. Once assigned, CMS adds the LEP to the patient’s monthly Part D premium for the remainder of their enrollment in Part D, regardless of which Part D plan they choose. Even people not actively taking prescription medications should consider choosing a Part D plan with a low monthly premium and/or no annual deductible to avoid incurring LEP.²

Individuals and couples with incomes and assets less than an annual threshold set by CMS may qualify for a Low Income Subsidy (LIS), also known as “extra help.” For people who qualify, the LIS reduces or eliminates the Part D monthly premium, deductible, and copay/coinsurance. CMS automatically enrolls most qualified patients into extra help, but a manual application process is also available. Pharmacy personnel should refer patients to 1-800-MEDICARE or https://www.medicare.gov/basics/costs/help/drug-costs to see if they qualify for LIS.³

Once a patient decides between Original Medicare or MAPD coverage, the next step is choosing a specific plan. CMS provides a comprehensive platform, called Medicare Plan Finder (MPF) for patients to shop and compare costs for PDP and MAPD plans. Patients can enter their medication list and see detailed cost information for each prescription. MPF also includes information about participating pharmacies and Star Ratings, a system CMS uses to measure each Part D plan’s performance in the areas of customer service, member experience, drug safety, and drug pricing accuracy. CMS rates plans on a scale of one to five stars, with five stars indicating the highest level of performance.⁴

The MPF tool is located at www.medicare.gov/plan-compare.

It is not necessary for pharmacy personnel to distinguish between MAPD and PDP coverage before processing prescription claims. The member’s prescription drug card provides the details needed to submit pharmacy claims to either type of Part D plan. If the member’s prescription drug card is not available, CMS provides a process known as an E1 transaction that returns Part D coverage information using basic demographic information. Pharmacists and technicians should consult their employer’s training materials for specific instructions on submitting an E1 transaction.⁵

The Part D Coverage Cycle

The Part D coverage cycle runs January to December each year. Regardless of when an individual reaches each phase of coverage, summarized in Figure 1, they start over in the deductible phase each year on January 1^st. Only “True Out-of-Pocket” (TrOOP) costs as defined by CMS go toward the thresholds to move patients through each of the four coverage phases. Patient costs excluded from TrOOP are⁶

Medications not covered by the Part D plan
Prescriptions obtained at non-participating (i.e., out-of-network [OON]) pharmacies, except those specifically allowed under the Part D plan’s rules
Costs reimbursed by an organization other than the Part D plan

PAUSE AND PONDER: Some patients with lower prescription costs do not complete their annual deductible until November or December. They are surprised when their out-of-pocket costs increase again in January. How would you explain the increase?

Patients with higher prescription costs may also be subject to the coverage gap, commonly known as the “Donut Hole” (see SIDEBAR: Explaining the Donut Hole). The coverage gap occurs when a patient’s prescription drug costs exceed a defined threshold under Medicare Part D. In the coverage gap, a patient’s out-of-pocket cost for brand name prescriptions may increase.⁷ Patients with very high prescription drug costs may reach the end of the coverage gap to enter catastrophic coverage, where they pay nothing out of pocket. The Inflation Reduction Act of 2022 removed patient costs from the catastrophic phase starting in 2024 and eliminated the coverage gap starting in 2025.⁸

SIDEBAR: Explaining the Donut Hole

Have you ever wondered why the Medicare Part D coverage gap is called the “Donut Hole?”

Imagine a giant donut, a circle with a hole in the middle, big enough to drive through. Half of the donut is plain, but the other half has frosting and sprinkles. In January, you start driving in a straight line through the plain half of the donut, toward the frosted half. Your drug costs determine your speed.

The plain half of the donut represents the annual deductible and initial coverage phases where you are subject to normal coverage amounts.

If high drug costs cause you to drive faster, you exit the plain half of the donut and enter the donut’s hole before the end of the year. You are now driving where there is no donut, and you must pay more than the normal amount for brand name drugs.

If your drug costs are high enough that you speed to the other side of the hole before the end of the year, then you enter the frosting and sprinkles half of the donut. Frosting and sprinkles represent the additional Part D contributions in the catastrophic phase and you pay nothing out of pocket.

Unfortunately, your car has only a 365-day warranty, so when January comes, you must start all over at the plain side of the donut.

An annual bidding process determines the specific costs for each Part D plan. Each year, CMS sets limits and thresholds for certain aspects of Part D coverage but allows flexibility within these parameters for both PDP and MAPD plans. Insurance companies submit bids that demonstrate how their plans comply with CMS’s annual limits and thresholds. The financial information that contributes to each plan’s annual bid is highly complex, and CMS can either accept or reject each bid.

As part of the annual bidding process, CMS defines standard prescription drug coverage. For a “basic” Part D plan, a bid must either match or be financially equivalent to the CMS definition of standard coverage. Table 1 provides the 2023 and 2024 standard benefit parameters, as defined by CMS.⁹

Table 1. Limits and Thresholds for 2023 and 2024 Medicare Part D Plans⁹

	2023	2024
Annual Deductible Limit	$505	$545
Initial Coverage Limit (starts the coverage gap)	$4660 total drug costs	$5030 total drug costs
Out-of-Pocket Limit (ends the coverage gap and starts catastrophic phase)	$7400 patient cost	$8000 patient cost

Insurance companies may also offer “enhanced” Part D plans with coverage that is more robust than the defined standard. Most plans with enhanced coverage have higher monthly premiums compared to basic plans but offer corresponding advantages such as reduced deductibles, lower copays/coinsurance, and lower costs in the coverage gap.

Individuals should choose their Part D plans carefully because they can only sign up or change Part D plans during certain periods²:

During the 3-month initial enrollment period that starts 1 month before and ends 1 month after an individual’s 65^th birthday; coverage starts the month after initial enrollment
During the annual open enrollment period that runs from mid-October to early December each year; coverage starts on January 1 of the following year for people who enroll during annual open enrollment
During the Medicare Advantage open enrollment period that runs from January through March each year; during this time, CMS only allows certain types of changes
During special enrollment periods for qualifying events such as relocation or the loss of employer or Medicaid coverage. Natural disasters that disrupt the initial or annual enrollment period may also create special enrollment periods

Prescription Coverage Under Medicare Parts A and B

Original Medicare provides prescription drug coverage under very limited circumstances and CMS prohibits Part D from covering anything covered under Medicare Parts A or B.

Medicare Part A covers hospice care, including medications related to the hospice diagnosis. Hospice providers receive payment for these medications from CMS and are responsible for paying the pharmacy. Medicare Part D is prohibited from covering medications related to any hospice diagnosis.¹⁰

Medicare Part B provides the only coverage options for some items, such as diabetic testing supplies and certain vaccines. Coverage for other items may fall under Part B or Part D, depending on the specific circumstances. Table 2 compares Part B and Part D coverage for the most common examples.¹⁰

Table 2. Medicare Part B and Part D Coverage of Common Products

Product(s)	Part B Coverage	Part D Coverage^a
Nebulizer Solutions (such as albuterol sulfate and ipratropium bromide)	For patients residing at home.	For patients residing in a long-term care facility.
Influenza, Hepatitis B, Pneumonia, and Coronavirus (COVID-19) Vaccines	Yes	No
Immunosuppressants (such as cyclosporine and mycophenolate mofetil)	When used to prevent rejection of a Medicare-covered transplant.	When used for a medically accepted indication other than a Medicare-covered transplant.
Oral Anti-Cancer Drugs (such as cyclophosphamide and methotrexate)	When used to treat cancer.	When used to treat a medically accepted indication other than cancer.
Oral Anti-Emetic Drugs (such as ondansetron and promethazine)	When used to treat or prevent chemotherapy-related nausea and vomiting.	When used to treat or prevent medically accepted indications other than chemotherapy-related nausea and vomiting.
Insulin	When used in an insulin pump.	When not used in an insulin pump.
Diabetic Testing Supplies (such as test strips and lancets)	Yes	No
Insulin Injection Supplies (such as needles and alcohol swabs)	No	Yes
^aCoverage may be subject to formulary restrictions.

Part D plans are responsible for rejecting pharmacy claims for medications that may be covered under Part A or Part B. Pharmacy personnel should refer to claim reject messaging and redirect the claim appropriately.

Other Prescription Drug Coverage

Most people who qualify for Medicare are covered by some combination of Parts A, B, C, and D as described above. However, other prescription drug coverage options are available under special circumstances:

Employer Group Waiver plans (EGWPs): Employers may choose to provide prescription drug coverage for their retirees by contracting with a Part D plan for EGWP coverage. Retirees with EGWP plans that start as soon as they become eligible for Medicare are exempt from LEP. When providing an EGWP plan for their retirees, employers may also add additional benefits paid either through Part D or by the employer themselves.¹¹
Medicare Supplemental Insurance (Medigap): Medigap coverage helps with costs not covered by Medicare Parts A and B, such as copays and deductibles. Certain Medigap plans also help with skilled nursing facility or hospice costs and emergency care while traveling outside of the United States. Individuals who enrolled in Medigap prior to 2006 may have prescription drug coverage included, but those who are newer to Medigap should purchase separate Part D coverage to avoid LEP.¹²
Employer Coverage: Individuals who are actively employed (not retired) may have coverage through their employer to replace Medicare or use Medicare as secondary coverage. Covered employees are exempt from the LEP if the employer coverage is equivalent to at least a basic Part D plan.²
Consolidated Omnibus Budget Reconciliation Act (COBRA): People who have recently separated from an employer may be eligible for COBRA. Individuals enrolled in COBRA may still be subject to LEP because COBRA is usually not equivalent to Medicare coverage.²
Medicaid: People with low incomes who qualify for both Medicaid and Medicare receive the LIS and have Part D coverage with reduced patient costs. In most cases, Medicare pays first and Medicaid helps with remaining costs.²
Manufacturer Discount Programs: Many drug manufacturers provide coupons, discount cards, and patient assistance programs to help cover their products’ cost. Federal law prohibits using these manufacturer payments in combination with Medicare prescription drug coverage.¹³ Medicare patients may choose manufacturer coupons or patient assistance programs for certain prescriptions only when they do not use their Part D coverage.
Prescription Discount Cards: Unlike manufacturer discounts, which are limited to products produced by that manufacturer, prescription discount cards offer discounts on a wide range of medications. Also known as “cash cards”, prescription discount cards reduce the cash price of prescriptions, but are not used in combination with insurance, including Medicare.¹⁴ Patients who choose a prescription discount card cannot use it in combination with their Part D coverage for the same medication.

MEDICARE PART D FORMULARIES

CMS requires Part D plans to maintain a list of covered drugs, called a formulary. CMS reviews each Part D formulary to ensure sufficient coverage under each drug class. The copay or coinsurance for each medication on the formulary is determined by its “tier.” Medications on lower tiers generally cost less than drugs on higher tiers.¹⁵ CMS allows some flexibility on how Part D plans define their formulary tiers, so tier structure differs between plans. Figure 2 provides an example of a formulary tier arrangement.

Drug Placement and Formulary Restrictions

Specialty medications are high-cost prescription products used to treat complicated medical conditions. CMS limits the patient cost portion for these medications and Part D plans typically place all specialty mediations into designated formulary tiers.¹⁰

CMS requires that Part D plans cover adult vaccines (excluding those covered under Part B) recommended by The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices at no cost to the patient, regardless of formulary tier or benefit phase.¹⁶

In 2023, CMS began setting a maximum copay for insulin products covered under Part D. Currently, the maximum copay is $35 for a one-month supply and is subject to change on an annual basis. Insulin copays may be lower if a Part D plan includes specific insulin products on a formulary tier where the monthly copay is lower than the CMS maximum. A similar program exists for insulin used in an insulin pump and covered under Part B.¹⁶

Part D plans may put restrictions on formulary medications to ensure appropriate coverage and to control costs. CMS reviews the restrictions and will not allow overly restrictive formularies. Plans may place four types of restrictions on formulary medications¹⁰:

Quantity Limit: Quantity limit restrictions define the maximum number of dosage units allowed for a specific time period.
Step Therapy: Step therapy restrictions require patients to first try a different medication, usually a lower cost alternative, before the prescribed medication.
Prior Authorization: Prior authorizations require patients to meet specific criteria, which may be as simple as providing the diagnosis or more complicated (e.g., specific lab tests, involvement of a specialist physician).
Drug Utilization Review (DUR): May be “hard edits” that require a coverage determination or “soft edits” that require the dispensing pharmacist to obtain clinical information and enter a set of codes into the prescription claim.

CMS defines six drug classes—those used to treat disorders where changes or interruptions in therapy involve higher risk—as “protected class.” CMS requires that Part D formularies include most medications within these classes with at least one medication on a preferred tier and no restrictions. Plans are not, however, required to include all variations of each medication (i.e., brand name and generic or immediate and extended-release versions). The six protected classes are¹⁰

immunosuppressants (used to prevent organ transplant rejection)
antidepressants (used to treat depression)
antipsychotics (used to treat mental health disorders)
anticonvulsants (used to treat seizure disorders)
antiretrovirals (used to treat human immunodeficiency virus)
antineoplastics (used to treat cancer)

CMS allows plans to add medications and make other positive changes to their formulary throughout the year but restricts medication removal and other negative changes until the following January. This restriction protects patients from losing coverage for their prescriptions during the time when they cannot switch to a different Part D plan. Marketplace removal, safety concerns, and the availability of a new generic are examples of situations when CMS would allow removal of a medication from a Part D formulary during the year.

Part D plans must provide patients with ongoing access to their formulary information. Most Part D plans post formularies online and only provide paper copies upon request. Patients can also see the formulary status for their specific medications when comparing Part D plans using the MPF website.

COVERAGE DETERMINATIONS AND APPEALS

Patients and pharmacy personnel commonly generalize the term “prior authorization” to describe any situation that requires insurance approval before insurance covers a prescription. Under Medicare Part D, this is known as the coverage determination process. Part D patients may use the coverage determination process to request approval for a non-formulary medication or a formulary medication with restrictions.

Who hasn’t been frustrated after contacting a prescriber to change a non-formulary prescription to a formulary medication, only to have the formulary medication require prior authorization? Part D plans usually include messaging within rejected claims to help determine which type of coverage determination is needed. When faced with a prescription rejection, pharmacists and pharmacy technicians who understand the nuances of the coverage determination process are equipped to advise their Part D patients on the best course of action.

Several specific types of coverage determinations are available and each type of coverage determination has specific criteria for approval.^16,17 Table 3 provides a summary of coverage determination types, their uses, and the information required for approval.

Table 3. Types of Coverage Determinations and Their Uses^16,17

Medication Status	Coverage Determination	Requirements for Approval
On the formulary, but dosing regimen requires more than the formulary allowance or requires tablet splitting	Quantity Limit Exception	The quantity allowed by the plan’s formulary is not effective in treating the patient’s condition or requires tablet-splitting to achieve the prescribed dosing regimen.
On the formulary with step therapy restrictions	Step Therapy Exception	The patient tried the step medication and either did not achieve therapeutic effect or experienced an adverse outcome.
On the formulary with step therapy restrictions	Step Therapy	The patient is likely to experience an adverse outcome if they must first try the step medication.
On the formulary with prior authorization or “hard” DUR restrictions	Prior Authorization	The patient meets the Part D plan’s specific criteria for the prescribed medication.
On the formulary with a “soft” DUR restriction	None	DUR “soft edits” may require dispensing pharmacists to contact prescribers and obtain clinical information, but do not require a coverage determination.
Sometimes by Medicare Part B	Prior Authorization	Why the patient’s situation warrants coverage under Part D for the prescribed medication.
On the formulary, but the patient cannot afford the copay/coinsurance	Tier Exception	The required number^† of lower tier drugs for the same condition are less effective or likely to result in an adverse outcome. Not available for specialty or non-formulary medications and cannot provide a brand name medication at the generic cost.
Not on the formulary	Non-formulary Exception	The required number^† of formulary alternative medication(s) were ineffective or likely to result in an adverse outcome.

^†Patients should consult their specific plan information to find out how many alternatives are required for tier or non-formulary exceptions.

Part D plans will only approve a coverage determination request if the product is medically necessary and if the information submitted by the prescriber meets the plan’s criteria. Prescribers may submit information over the phone, by fax, or by mail. Most Part D plans also have an electronic portal to accept information from prescribers. Dispensing pharmacists are only permitted to supply information in place of the prescriber under limited circumstances, such as prior authorizations to determine Part B versus Part D coverage.

Approval and Denial Parameters

For exception requests that meet approval criteria, CMS requires Part D plans to maintain the approval at least through the end of the year. Part D plans may approve prior authorizations for a shorter time only if clinically appropriate and approved by CMS as part of the annual formulary approval process.

Part D plans will deny requests with incomplete information and requests that do not meet approval criteria. Part D plans will also deny any type of coverage determination if the medication is being used for a non-medically accepted indication. Medically accepted indications are uses approved by the United States Food and Drug Administration or listed in one of the references that CMS defines as approved compendia¹⁰:

American Hospital Formulary Service Drug Information
DRUGDEX Information System
Peer-reviewed medical literature (only allowed for biologics and anti-cancer chemotherapy medications)

Common examples of medications prescribed for non-medically accepted indications include the use of fentanyl lollipops/lozenges for non-cancer pain and hydroxychloroquine for coronavirus disease 2019 (COVID-19). Federal and state laws may allow prescriptions for non-medically accepted indications, but patients cannot use their Part D coverage to pay for them. Part D plans must block medication coverage if the determination process reveals a non-medically accepted indication, even for previously covered medications, quantities less than the predetermined limit, and any tier cost after a tier exception request.¹⁰ Pharmacists are not required to confirm medically accepted indications before dispensing prescriptions because CMS considers this a plan responsibility. As a result, Part D plans will often reject claims and require a prior authorization for medications commonly prescribed for non-medically accepted indications. Pharmacists and pharmacy technicians can assist patients and prescribers by communicating rejected claim information and explaining the CMS requirement for medically accepted indications. ¹⁰

In addition to medications covered under Part A or B, CMS specifically excludes certain types of medications from Part D coverage¹⁰:

Products used for weight loss or weight gain
Fertility medications
Cosmetic and hair growth products
Treatments for the symptomatic relief of cough and colds
Non-prescription medications
Prescription vitamins, except prenatal and fluoride products
Erectile dysfunction treatments

Bulk powders and inert excipients used for compounded prescriptions are also excluded from Part D coverage. Compounds may contain other ingredients that are covered with or without restrictions under Part D. When pharmacies bill some of a compound’s ingredients to Part D, CMS prohibits them from charging patients for the non-Part D portion.¹⁰

Patients cannot obtain Part D coverage for excluded medications using the coverage determination process. Employers may cover some of these medications and manufacturer coupons or prescription discount cards may help make these products more affordable for individuals without employer coverage.

PAUSE AND PONDER: Generic sildenafil is prescribed for both erectile dysfunction (excluded from Part D coverage) and pulmonary hypertension (eligible for Part D coverage). Can a dispensing pharmacist distinguish between the two to bill Part D for the appropriate product?

Part D plans may dismiss requests that are inappropriate, unnecessary, or filed incorrectly. CMS requires Part D plans to provide written notification and a reason for the dismissal to the patient and prescriber.¹⁷

If the patient or prescriber decides that a request is unnecessary, they can withdraw the request before a decision is issued. Withdrawing a request does not prevent the patient or prescriber from submitting a later request for the same medication.¹⁷

When a Part D plan denies a coverage determination, CMS requires them to send the specific reason(s) for the denial to the patient and the prescriber. Part D plans may choose to also send a copy of this information to the dispensing pharmacy.¹⁷ Depending on the reason for the denial, the patient or prescriber may choose to appeal the Part D plan’s decision.

Appeal requests must be within 60 days of the denial, unless good cause is established for missing the 60-day deadline. If the Part D plan denies the appeal, beneficiaries have up to four additional opportunities to appeal through entities outside of their Part D plan. After the second level, higher levels of appeal are only available if the drug cost meets a specific threshold set by CMS.¹⁸ Figure 3 outlines the five levels of appeal available to Part D patients.

A patient or prescriber can request a re-opening instead of the next level appeal if they feel that a coverage determination or appeal decision is in error. Part D plans may also initiate a re-opening if they identify a decision error.

Direct Member Reimbursements

Patients who pay for a covered Part D prescription without using their Part D Insurance may be eligible for reimbursement from their Part D plan through a process called Direct Member Reimbursement (DMR). To qualify for DMR, the prescription must meet the Part D plan’s coverage requirements and not be covered by any other type of insurance or discount card. Prescriptions obtained at an OON pharmacy must meet the Part D plan’s OON rules to qualify for reimbursement.¹⁹

Pharmacies should submit Part D prescriptions to the patient’s Part D plan whenever possible because a DMR reimbursement may not result in a full refund of the cash price.

Timeframes

Part D plans must offer both standard and expedited timeframes for coverage determination and appeal requests (listed in Table 4). Expedited requests are available when the standard timeframe could result in a significant adverse outcome. DMR requests do not qualify for expedited timeframes because the patient has already received the medication.¹⁷

Table 4. Plan Timeframes for Medicare Part D Requests¹⁶

Request Level	Request Urgency	Request Type	Required Timeframe
Initial Coverage Determination	Standard	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception	72 hours from supporting statement but no longer than 14 days from request received
Initial Coverage Determination	Expedited	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception	24 hours from supporting statement but no longer than 14 days from request received
Initial Coverage Determination	Standard	Prior Authorization Step Therapy (non-exception)	72 hours from request received
Initial Coverage Determination	Expedited	Prior Authorization Step Therapy (non-exception)	24 hours from request received
Initial Coverage Determination	N/A	Direct Member Reimbursement	14 days from request received
First Level Appeal	Standard	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception Prior Authorization	7 days from request received
First Level Appeal	Expedited	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception Prior Authorization	72 hours from request received
First Level Appeal	N/A	Direct Member Reimbursement	Notification of Decision: 14 days from request received Payment (if approved): 30 days from request received

Part D plans may automatically apply the expedited timeframe if the clinical information submitted for the coverage determination indicates that waiting may harm the patient’s health. Alternatively, Part D plans may downgrade an expedited request if they determine that the patient’s health will not be harmed by using the standard timeframe. CMS requires Part D plans to notify the patient if a request is downgraded from expedited to standard.¹⁷

All Part D timeframes are based on calendar hours/days and include weekends and holidays. Timeframes start as soon as the Part D plan receives a non-exception coverage determination or any type of valid appeal request, regardless of how much clinical information is included with the request. For exception requests, the timeframe starts as soon as the Part D plan receives clinical information from the prescriber to support the request (known as the prescriber’s supporting statement). When a supporting statement is missing from an exception request, CMS allows up to 14 days for plans to obtain it.¹⁷The following examples demonstrate Part D timeframes over weekends and holidays:

A patient requests a standard prior authorization on Friday afternoon, December 23. The prescriber’s office is closed for the three-day holiday weekend. The plan must deny the request in 72 hours (on Monday afternoon), even though the prescriber’s office was not available to provide information during that timeframe.
A different patient requests a standard non-formulary exception the same day. Their prescriber’s office is also closed for the three-day holiday weekend but contacts the plan with the supporting information on Tuesday morning. Since this is an exception request, 72 hour timeframe starts on Tuesday morning and the plan has until Friday morning to complete the request.

When clinical information is incomplete, CMS requires that Part D plans make reasonable efforts to contact the prescriber and obtain the missing information. Once the timeframe has started, making outreach attempts and waiting for additional information does not extend the request timeframe. The Part D plan will deny the request if they do not receive sufficient clinical information by the end of the allotted timeframe.¹⁷

PAUSE AND PONDER: It’s late Friday afternoon and your patient is anxious to request a prior authorization for her medication. The physician’s office is closed for the weekend. Could requesting an expedited coverage determination at this point cause more of a delay?

When a Part D plan does not process a request within the required timeframe, they must send the request to the IRE as an “auto-forward.” This is the same IRE that processes Part D second-level appeals. Part D plans must notify patients in the event of an auto-forward. CMS monitors Part D plans’ timeliness and issues penalties for excessive numbers of auto-forwards.

How to Submit Requests

CMS requires that Part D plans accept coverage determination requests via phone, fax, or mail. For appeals, plans must accept both standard and expedited requests via fax or mail. Verbal requests by phone are required for expedited appeals but optional for standard appeals.¹⁷ Many plans also choose to accept electronic requests via an online portal.

Patients should follow the instructions from their specific Part D plan for requesting a DMR. Part D plans usually require hard copies of payment receipts, so most patients file DMR requests by mail.

CMS does not permit Part D plans to require a specific form to submit a coverage determination, appeal, or DMR request.¹⁷ Although optional, using a form provided by the plan usually streamlines the process and reduces the risk of submitting incomplete information.

CMS does not allow dispensing pharmacists or pharmacy technicians to request a Part D coverage determination or appeal on behalf of the patient. Only the patient, the patient’s appointed representative, the prescriber, or the prescriber’s staff can request a coverage determination or appeal. Only patients or their appointed representative can request a DMR.¹⁷

The handout entitled “Medicare Prescription Drug Coverage and Your Rights” that dispensing pharmacies supply to patients when prescriptions cannot be filled under their Part D plan provides additional instructions for submitting requests.^17,20

CONCLUSION

Medicare patients have many choices available for their prescription drug coverage. CMS requires that all Part D plans conform to a set of common standards while allowing specific plans to offer a wide range of benefit options.

Pharmacists and pharmacy technicians with a basic understanding of Part D coverage options, patient costs, formulary structure, and the coverage determination and appeals process can help patients maximize the benefit from their Part D plan. Although CMS does not allow them to initiate coverage determinations and appeals, pharmacy personnel can advise Part D patients and their physicians on the most effective next steps when faced with a non-covered prescription.

All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

Pharmacists Post-test

After completing this continuing education activity, pharmacists will be able to
1. Describe the different types of prescription drug coverage available to Medicare patients.
2. Explain the patient costs associated with Medicare Part D prescription drug coverage.
3. Demonstrate use of a patient’s Medicare Part D formulary to determine the appropriate type of coverage determination.
4. Identify prescriptions that Medicare Part D does not cover.

1. Which of the following is the correct description for the type of Medicare coverage?
A. Medicare Part A: Covers outpatient and home health care, preventative services, and durable medical equipment.
B. Medicare Part B: Offered by private insurance companies for prescription drug coverage.
C. Medicare Part C: Offered by private insurance companies to provide Part A and Part B coverage.

2. What is an appropriate combination of coverage?
A. Medicare Part A + Medicare Part B + Medicare Part D
B. Medicare Part A + Medicare Part B + MAPD
C. Employer Coverage + Medigap + MAPD

3. A patient who is turning 65 next month asks you about delaying Part D coverage because she only takes two prescriptions that are very low cost using a prescription discount card. What is the possible risk of this approach when she eventually signs up for Part D coverage at a later date?
A. She may pay higher monthly premiums due to the coverage gap.
B. She may pay higher annual deductibles due to the late enrollment penalty.
C. She may pay higher monthly premiums due to the late enrollment penalty.

4. It’s January and a patient who paid a $10 copay for his prescription last month now has to pay 100% of the cost. What is the most likely explanation?
A. He is paying the annual deductible
B. He is in the coverage gap
C. His Part D plan doesn’t cover his medication

5. A patient who takes several expensive medications experiences a sharp increase in her out-of-pocket costs around midyear. What is the most likely explanation?
A. She has entered the deductible phase
B. She has entered the coverage gap phase
C. She has entered the catastrophic coverage phase

6. A patient’s Part D Plan is rejecting a prescription for apixaban. You locate its formulary online and find that dabigatran is listed, but not apixaban. What type of coverage determination does this patient need from this Part D Plan?
A. Step Therapy
B. Non-formulary
C. Prior Authorization

7. A patient’s Part D Plans is rejecting a prescription for alirocumab. You locate the formulary online and find that alirocumab is on the formulary but is not covered unless simvastatin has been tried first. What type of coverage determination does this patient need from this Part D Plan?
A. Step Therapy
B. Prior Authorization
C. Tier Exception

8. A Part D patient is struggling to afford his medication, even after the Part D Plan approved a non-formulary exception. What is their best option for lowering costs?
A. Talk to the prescriber about switching to an alternative on a lower formulary tier.
B. Ask their Part D Plan for a tier exception.
C. Find a manufacturer discount coupon to cover their Part D copay.

9. A Part D patient presents a prescription for a highly advertised diabetic medication and confides in you that she is not diabetic but hoping the medication will help with weight loss. Her Part D Plan requires prior authorization to establish medically accepted indication. What coverage option is available to them?
A. Part D after prior authorization approval
B. Manufacturer discount program
C. Medicare Advantage

10. A Medicare Part D Plan is rejecting claims for your patient’s diabetic test strips and lancets. What do you recommend as the next course of action?
A. Call the Part D Plan and request a coverage determination.
B. Pay out of pocket and ask the Part D Plan for direct member reimbursement.
C. Compile the documentation required to submit the claims to Part B.

All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to
1. Describe the different types of prescription drug coverage available to Medicare patients.
2. Explain the patient costs associated with Medicare Part D prescription drug coverage.
3. Identify the types of coverage determinations available for Medicare Part D prescriptions.
4. Outline the timeframes involved in Medicare Part D coverage determination and appeal decisions.

2. What is an appropriate combination of coverage?
A. Medicare Part A + Medicare Part B + Medicare Part D
B. Medicare Part A + Medicare Part B + MAPD
C. Employer Coverage + MAPD

5. A patient who takes several expensive medications experiences a sharp increase in her out-of-pocket costs around midyear. What is the most likely explanation?
A. She has entered the deductible phase.
B. She has entered the coverage gap phase.
C. She has entered the catastrophic coverage phase.

6. Which of the following combinations of coverage determinations may be required for a single prescription?
A. Non-formulary + Quantity Limit
B. Quantity Limit + Prior Authorization
C. Tier Exception + Non-formulary

7. Which type of reject requires a Part D coverage determination?
A. Non-formulary
B. Refill too soon
C. DUR soft edit

8. Which of the following is the correct description for a type of coverage determination under Medicare Part D?
A. Non-formulary exceptions: Used to request larger quantities of a medication
B. Tier Exceptions: Used to request a lower copay for a medication
C. Prior Authorization: Used to request a non-formulary medication

9. A patient called her Part D plan yesterday morning to request an urgent appeal for their medication. This afternoon, she has not received a response and the claim is still rejecting. How much longer might she have to wait for a response?
A. The appeal is already out of timeframe because it has been longer than 24 hours
B. 6 more days, for a total of 7 days
C. 2 more days, for a total of 3 days

10. You are working on a prescription that the Part D Plan is rejecting due to a quantity limit. The patient is not out of medication, so you advise him to call and ask for a standard quantity limit exception. How long should the patient expect to wait for the Part D Plan to make a decision?
A. 24 hours after the patient calls their Part D Plan to request the coverage determination
B. 24 hours after their prescriber provides clinical information to the Part D Plan
C. 72 hours after their prescriber provides clinical information to the Part D Plan

References

1. Centers for Medicare & Medicaid Services. Medicare Enrollment Dashboard. Accessed August 28, 2023. https://data.cms.gov/tools/medicare-enrollment-dashboard
2. Centers for Medicare & Medicaid Services. Medicare & You Handbook. Accessed September 5, 2023. https://www.medicare.gov/medicare-and-you
3. Centers for Medicare & Medicaid Services. Help with Drug Costs. Accessed September 6, 2023. https://www.medicare.gov/basics/costs/help/drug-costs
4. Centers for Medicare & Medicaid Services. Explore Your Medicare Coverage Options. Accessed September 13, 2023. www.medicare.gov/plan-compare
5. RelayHealth. Medicare Eligibility Verification Transaction. Accessed December 28, 2023. https://medifacd.mckesson.com/e1/
6. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 5: Benefits and Beneficiary Protections. September 20, 2011. Accessed September 5, 2023. https://www.cms.gov/medicare/prescription-drug-coverage/prescriptiondrugcovcontra/downloads/memopdbmanualchapter5_093011.pdf
7. Centers for Medicare & Medicaid Services. Costs in the Coverage Gap. Accessed September 6, 2023. https://www.medicare.gov/drug-coverage-part-d/costs-for-medicare-drug-coverage/costs-in-the-coverage-gap
8. Kaiser Family Foundation. Changes to Medicare Part D in 2024 and 2025 Under the Inflation Reduction Act and How Enrollees Will Benefit. Accessed December 27, 2023. https://www.kff.org/medicare/issue-brief/changes-to-medicare-part-d-in-2024-and-2025-under-the-inflation-reduction-act-and-how-enrollees-will-benefit
9. Centers for Medicare & Medicaid Services. Announcement of Calendar Year (CY) 2024 Medicare Advantage (MA) Capitation Rates and Part C and Part D Payment Policies. March 31, 2023. Accessed September 6, 2023. https://www.cms.gov/files/document/2024-announcement-pdf.pdf
10. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 6 – Part D Drugs and Formulary Requirements. January 15, 2026. Accessed August 23, 2023. https://www.cms.gov/medicare/prescription-drug-coverage/prescriptiondrugcovcontra/downloads/part-d-benefits-manual-chapter-6.pdf
11. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 12 – Employer/Union Sponsored Group Health plans. November 7, 2008. Accessed September 5, 2023. https://www.cms.gov/regulations-and-guidance/guidance/transmittals/downloads/dwnlds/r6pdbpdfpdf
12. Centers for Medicare & Medicaid Services. Learn How Medigap Works. Accessed October 25, 2023. https://www.medicare.gov/health-drug-plans/medigap/basics/how-medigap-works
13. Office of Inspector General. Special Advisory Bulletin, Pharmaceutical Manufacturer Copayment Coupons. September 2014. Accessed September 5, 2023. https://oig.hhs.gov/documents/special-advisory-bulletins/878/SAB_Copayment_Coupons.pdf
14. Dr Christina Polomoff discusses the complex world of medication discount cards. Am J Manag Care. April 13, 2021. Accessed September 5, 2023. www.ajmc.com/view/dr-christina-polomoff-discusses-the-complex-world-of-medication-discount-cards
15. Centers for Medicare & Medicaid Services. What Medicare Pat D plans Cover. Accessed September 7, 2023. https://www.medicare.gov/drug-coverage-part-d/what-medicare-part-d-drug-plans-cover
16. Centers for Medicare & Medicaid Services. Final Contract Year (CY) 2024 Part D Bidding Instructions. April 4, 2023. Accessed September 6, 2023. https://www.cms.gov/files/document/final-cy-2024-part-d-bidding-instructions.pdf
17. Centers for Medicare & Medicaid Services. Parts C&D Enrollee Grievances, Organization/Coverage Determinations, and Appeals Guidance. August 3, 2022. Accessed September 10, 2023. https://www.cms.gov/medicare/appeals-and-grievances/mmcag/downloads/parts-c-and-d-enrollee-grievances-organization-coverage-determinations-and-appeals-guidance.pdf
18. Centers for Medicare & Medicaid Services. Medicare Appeals. Accessed August 23, 2023. https://www.medicare.gov/Pubs/pdf/11525-Medicare-Appeals.pdf
19. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 14 – Coordination of Benefits. September 17, 2018. Accessed September 11, 2023. https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Chapter-14-Coordination-of-Benefits-v09-14-2018.pdf
20. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Coverage and Your Rights. Accessed September 12, 2023. https://www.cms.gov/outreach-and-education/outreach/partnerships/downloads/yourrightsfactsheet.pdf

Antipsychotic Utilization in a Pediatric Population-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-043-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Antipsychotic Utilization in a Pediatric Population

Megan Ehret, PharmD

1. Which medication is a first-line treatment option for a 14-year-old patient with newly diagnosed schizophrenia?
a. Divalproex Sodium
b. Haloperidol
C. Risperidone

2. Which medication is a first-line treatment option for a 16-year-old patient with bipolar disorder, most recent episode depressed?
A. Aripiprazole
B. Divalproex Sodium
C. Lurasidone

3. Which medication can cause the most substantial weight gain?
A. Cariprazine
B. Lumateperone
C. Olanzapine

4. Which rating scale should be used to screen patients for tardive dyskinesia?

A. Extrapyramidal Symptom Rating Scale
B. Barnes Akathisia Rating Scale
C. Abnormal Involuntary Movement Scale

5. In which disease state would it be appropriate to initiate an antipsychotic medication in a pediatric patient?
A. Autism
B. Conduct Disorder
C. Intellectual Disability

Indication Deviation in Women’s Health: Off-Label Drug Use from Conception to Menopause-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-040-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Pharmacist Post-test

Learning Objectives
After completing this continuing education activity, pharmacists will be able to
• RECOGNIZE diverse instances of off-label drug use in women's health, spanning pre-conception to menopause
• DISCUSS risks and advantages associated with off-label drug utilization during various reproductive stages
• IDENTIFY the pharmacist's role in advocating for safe and informed off-label drug use for women’s health

1. Which of the following can be treated through off-label use of metformin?
A. Hirsutism of PCOS
B. PCOS with BMI ≥ 25 kg/m2
C. Endometriosis

2. Which of the following medications is used off-label to induce ovulation in women experiencing infertility and trying to conceive?
A. Letrozole
B. Clomiphene citrate
C. Cetrorelix

3. Which of the following drugs is used off-label to treat menopausal hot flashes?
A. Clonidine
B. Paroxetine
C. Fezolinetant

4. Which of the following is TRUE about off-label medication use during pregnancy?
A. All drugs have sufficient efficacy and safety data to support their use during pregnancy
B. Providers should use the letter-based FDA rating system to aid in shared clinical decision-making
C. About three-quarters of pregnant women use medications for off-label uses during pregnancy

5. A patient comes to your pharmacy experiencing frequent hot flashes. She states that a friend suggested she try taking black cohosh. She takes lisinopril for hypertension and metformin for prediabetes, and she is otherwise healthy. Which of the following is the BEST response?
A. Black cohosh will interact with your blood pressure medication, so you should not take it. Ask your doctor about clonidine instead.
B. Black cohosh shows some benefit, but clinical trials are inconsistent and available data is insufficient. You can try taking 20 mg daily for a few weeks to see if your symptoms improve.
C. Black cohosh shows no benefit whatsoever for VMS of menopause. Ask your doctor about letrozole instead.

6. Which of the following is TRUE about Pregnancy Exposure Registries?
A. They steal data about women’s babies and sell it on the black market
B. They are FDA-sponsored registries that collect health information
C. Pregnant women volunteer to share their experiences with off-label drug use

The ABCD of Off-Label Medications for Weight Management-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-038-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

The ABCD of Off-Label Medications for Weight Management
Post Test
1. When working with a patient to manage ABCD, what is the first goal?

A. prevent weight regain
B. stop further weight gain
C. achieve weight reduction

2. Which of the following is the correct order of weight reduction efficacy (highest to lowest)?

A. tirzepatide > semaglutide > phentermine
B. semaglutide > SGLT2 inhibitors > phentermine
C. metformin = semaglutide > topiramate

3. What did the SELECT RCT report about patients 45 years and older with ABCD and existing cardiovascular disease who did not have diabetes?

A. The placebo-subtracted weight reduction for weekly semaglutide 2.4 mg was 15% of baseline body weight.
B. Subcutaneous semaglutide 2.4 mg once weekly reduced major adverse cardiovascular events in ABCD.
C. Subcutaneous semaglutide 2.4 mg once weekly significantly reduced weight but did not prevent cardiovascular events.

4. What is the most common adverse reaction for GLP-1 receptor agonist-based medications?

A. nausea and other gastrointestinal adverse effects
B. hypoglycemia
C. sleep disturbance

5. With which drug class can tirzepatide interact ?

A. beta blockers
B. ACE inhibitors
C. oral hormonal contraceptives

TOP 10 Cardiovascular Drugs Used Off Label!!!-RECORDED WEBINAR

Upon completion of this application based CE Activity, a pharmacist will be able to:

Identify how an FDA approved and off label indication differ and the implications of that differential designation

Identify which 10 FDA approved cardiovascular drugs have the most promising off label uses for treating other cardiac or noncardiac disorders

Describe the mechanisms of action for the purported off label uses of these drugs

Identify which national guidelines or consensus statements recommend the off-label use of drugs

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-039-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Post Test “TOP 10 Cardiovascular Drugs Used Off Label!!!”

1. Which of the following drugs has been used to enhance the chances of delivering a baby in patients with Factor 5 Leiden and what is the mechanism of benefit?
a) Thiazide diuretics; reduced placental calcium that stops crystalline umbilical cord blockage
b) LMWH; preventing placental thrombosis in patients who are hypercoagulable
c) Disopyramide – decreasing the inotropic effect in hypertrophic cardiomyopathy that leads to placental detachment

2. Which of the following drugs is effective for treating anal fissures and what is the mechanism of action?
a) IV iron; iron deficiency anemia promotes fissure formation so treating it reverses fissure
b) Amiodarone; overactive potassium channels in the anus lead to apoptosis of anal mucosal cells
c) CCBs; Blood vessel dilation enhancing blood flow to targeted areas in the body

3. Which of the following drugs is properly linked to the off-label indication it is commonly used for?
a) Beta-blockers – Raynaud’s phenomenon
b) Prazosin – Nightmares in PTSD patients
c) Clonidine – Stage fright

4. Which of the following drugs is used off label for the treatment of abnormal face and body hair growth in patients and what is the mechanism of action?
a) Spironolactone – blocking the effects of testosterone in several ways
b) Beta-blockers – blocking epinephrine induced follicular stimulation
c) Clonidine – central outflow of norepinephrine causes abnormal hair growth

5. Sally Sue has had atrial fibrillation for several months. Her cardiologist has prescribed several therapies that have been ineffective, and one that is on the drug shortage list and hard to find. Which of the following might the cardiologist use off-label according to the AHA/ACC Guideline?

a) Calcium channel blockers
b) Prazocin
c) Amiodarone

Long Acting Injectables LIVE Workshop-May 16, 2024

Pharmacists possess the training and skills necessary to administer certain long-acting injectable (LAI) medications used in the management of mental illnesses and substance use disorders. Through collaborative practice agreements, pharmacists can administer Long Acting Injectables in almost every state. In some states, including the state of Connecticut, this occurs via collaborative agreements, and necessary injection and disease state training. Administration of these medications by pharmacists can increase accessibility of care for patients.

UConn has developed web-based and LIVE continuing pharmacy education activities to enhance pharmacists’ skills and help them make sound clinical decisions about long acting injectables administration. This course includes eight hours of CPE (or eight hours of credit), required by the State of Connecticut. Successful completion of these eight hours (with four activities consisting of three hours online pre-requisite work and five hours of LIVE CE) will earn the pharmacist a Certificate in Long-Acting Injectables of Psychotropic Medication.

The LIVE Workshop listed below is required to earn the Long-Acting Injectable Psychotropic Medication Pharmacist certificate. The Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program costs $299 and includes both the 3 online prerequisites and this full day of LIVE training.

Thursday, May 16, 2024
8:30 am - 3:15 pm
Room Pharmacy Biology Bldg-Room 229
Storrs, CT

A light breakfast and lunch will be served.

At the end of this application and practice-based continuing education activity, the learner will be able to:

Describe the impact of stigma within the healthcare system and utilize non-stigmatizing terminology when talking to and about patients with psychiatric and/or substance use disorders

Identify patient barriers to obtaining appropriate treatment for psychiatric and/or substance use disorders

Explain the potential impact of LAI medications on patient health outcomes

Identify the key components of the Collaborative Practice Agreement associated with LAI medications.

Describe the key components of the Notes on Injection Clinical Encounter (NICE) documentation form.

Apply different best practices for documentation, maintenance of files, and communications with

prescribers.

Describe the steps in the safe and effective use of different LAI medications for schizophrenia, bipolar

disorder,and substance use disorder.

Compare and contrast how the administration techniques are similar or different for the different LAI

medications.

Demonstrate the use sterile injection techniques and best practices in the administration of different LAI

If desired, pharmacists can register for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program
or for the individual online activities. The Certificate consists of three activities in our online selection, and a 5 hour LIVE activity.

You may register for individual online topics at $17/CE Credit Hour, or for the Entire LAIA Certificate at $299.00 which includes 5 hours of LIVE CE and the 3 online pre-requisites listed below.

You must register for ALL 4 activities to receive the bundled pricing of $299.00

The University of Connecticut, School of Pharmacy, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Statements of credit will be issued for 5.0 hours (or 0.5 CEUS) for activity ACPE UAN 0009-0000-24-008-L01-P. UConn will be award credits once learner attends the full 5 hours, successfully passes the injection assessment and submits their evaluation. Your CE credits will be uploaded to your CPE monitor profile within 24 hours of your submitting the evaluation.

Kristin Waters, PharmD, BCPS, BCPP,
Assistant Clinical Professor
UConn School of Pharmacy
Storrs, CT

Nathaniel Rickles, PharmD, PhD, BCPP, FAPhA
Professor of Pharmacy Practice
UConn School of Pharmacy
Storrs, CT

Sindu Sahadevan, PharmD, BCGP
Medical Science Liaison-CNS Psychiatry
Teva Pharmaceuticals
New York, NY

Sharon Spicer, BSRN
Director of Quality Assurance and Customer Success
Connecticut Pharmacy & Long Term Care
Wallingford, CT

Jehan Marino, PharmD, BCPP
Medical Science Liaison Director-Neuroscience Field Medical Affairs
Otsuka Pharmaceutical Development & Commercialization, Inc.
New York, NY

Yasmin Togun, PhD, MPH
Medical Science Liaison
Otsuka Pharmaceutical Development & Commercialization, Inc.
New York, NY

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Dr. Waters is a consultant with Janssen Pharmaceuticals. She will discuss all drugs without bias. All financial interests with ineligible companies (as noted) have been mitigated.

Dr. Sahadevan is a medical Science liaison with Teva Pharmaceuticals

Drs. Marino and Togen are medical science liaisons with Otsuka Pharmaceuticals

Dr. Rickles and Sharon Spicer have no relationships with ineligible companies.

Treating Gout without Doubt

After completing this application-based continuing education activity, pharmacists will be able to

1. Describe gout's pathogenesis, relationship to hyperuricemia, and complications of untreated gout
2. Describe the diagnosis and goals of therapy for gout
3. Recall nonpharmacologic therapy for the management of gout and medications that can increase serum uric acid level
4. Discuss the appropriate approach to gout therapy (acute attack treatment, prevention of future gout attacks, "medication-in-pocket," and "treat-to-target") and its timing

After completing this application-based continuing education activity, pharmacy technicians will be able to:

1. Describe gout's pathogenesis, relationship to hyperuricemia, and complications of untreated gout
2. Recall nonpharmacologic therapy for the management of gout and medications that can increase serum uric acid level
3. Recognize different pharmacological classes and regimens for urate-lowering therapy (ULT) and target serum uric acid level
4. Define the "treat-to-target" and "medication-in-pocket" approaches in gout therapy

Gout is the most common form of inflammatory arthritis affecting about 9.2 million adults in the United States (US) and is the result of hyperurice-mia. Gout results from the chronic deposition and crystallization of urate in the joints and tissues. Although gout can affect any joint, initial attacks usually in-volve the big toe joint. The most recent guideline for the management of gout recommends colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids (oral, intraarticular, intramuscular) as first-line agents for the treatment of gout flares. Patient-specific factors guide the drug choice among the first-line agents. Interleukin-1 inhibitors or adrenocorticotropic hormone are alternative agents. Pharmacists are well-positioned to assess adherence to ULT and educate patients about the importance of urate lowering therapy. Pharmacy technicians can ensure that patients have refills on their medication-in-pocket prescription to facilitate early initiation.

INTRODUCTION

“I’ve been shot, and I’ve been stabbed; nothing compares to gout pain.”

This is how Jim, a 77 year old man, describes his pain as he hobbles into the pharmacy to refill his prescription for colchicine. Jim complains that colchicine is not controlling his gout. He is wearing slippers that show his red swollen joint around his right big toe that is warm and painful to touch. Jim says his physician explained that these symptoms are due to podagra, uric acid crystallization and settling in the joint between his foot and big toe.¹ As Jim speaks, his breath projects a strong alcohol smell.

Gout is the most common form of inflammatory arthritis affecting about 9.2 million adults in the United States (US) and is the result of hyperuricemia.^2,3Men are at higher risk of developing gout than women.⁴ Other risk factors include post-menopause, genetics, end-stage renal disease, and major organ transplant.

Uric acid overproduction, under-excretion, or both, elevate serum uric acid levels.⁵ Underexcretion of uric acid accounts for about 90% of gout cases.⁶ Human bodies produce uric acid as they break down dying tissues.⁴ Other sources of uric acid are foods high in purines, such as meats, seafood, and alcoholic beverages.^{7, 8} Ancient Greek history states that only rich people, who could afford these expensive foods, experience gout.⁹Therefore, in the 5^th century before Christmas (B.C.), people referred to gout as “the disease of kings.”¹⁰

PATHOGENESIS

Uric acid circulates in the blood as monosodium urate.¹¹ In the kidneys, uric acid and urate undergo filtration and secretion into the filtrate followed by about 90% reabsorption into the blood.¹² The American College of Rheumatology (ACR) guideline defines hyperuricemia as serum uric acid of 6.8 mg/dL or greater, the level above which urate becomes insoluble in the blood.⁴

Gout results from the chronic deposition and crystallization of urate in the joints and tissues.^4,13Insoluble monosodium urate crystals form stone-like deposits, known as tophi, in soft tissues, synovial tissues, or bones.^14,15 Tophi trigger an inflammatory response, which presents as an acute gout attack.^15,16 However, hyperuricemia does not always result in gout.⁴

Although gout can affect any joint, initial attacks usually involve the big toe joint. Gout attacks are sudden and very painful.¹⁷ Acute gout attacks reach maximum pain level in 12 to 24 hours and may last 3 to 14 days if patients do not seek therapy.¹⁸ For this reason, all healthcare providers including those on pharmacy teams need to educate patients to seek medical care. Effective gout management reduces the risk of long-term complications like degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement.¹⁹

DIAGNOSIS OF GOUT

Clinicians diagnose gout by collecting patient history, examining the patient, laboratory workup, and imaging.¹⁹ Uric acid crystals in the synovial fluid or tophi in tissues and/or bones confirm gout diagnosis regardless of the uric acid level.⁴

TREATMENT OF GOUT

The ACR guideline describes 3 treatment goals for patients with gout²⁰:

Terminating the acute gout attack
Preventing future attacks
Lowering the serum uric acid level

Terminating the Acute Gout Attack

The ACR published the most recent guideline for the management of gout in 2020. The ACR guideline recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids (oral, intraarticular, intramuscular) as first-line agents for the treatment of gout flares.²⁰Patient-specific factors guide the drug choice among the first-line agents. Interleukin-1 (IL-1) inhibitors or adrenocorticotropic hormone (ACTH) are alternative agents.²⁰If a first-line agent is ineffective, intolerable, or contraindicated, the ACR guideline recommends switching to another first-line agent before trying alternative agents. Topical ice is an adjunct to pharmacologic therapy. The severity of the gout flare guides the treatment duration.

Colchicine

Colchicine exerts its anti-inflammatory effects by binding to free tubulin dimers leading to microtubule polymerization inhibition, which affects cellular function.^{21, 22} Colchine has had an interesting history, as the SIDEBAR explains. Common side effects of colchicine are dose-dependent and include diarrhea, nausea, and vomiting.Because of its mechanism of action, toxic levels of colchicine inhibit cellular division leading to failure of multiple organs .²² Colchicine doses of 0.8 mg/kg are lethal.²³ Colchicine undergoes extensive tissue distribution and therefore, a lower dose can be toxic in patients with liver or renal failure. Some unchanged colchicine undergoes renal excretion through glomerular filtration and therefore, requires dosage adjustment for renal dysfunction.^{21, 24} Cytochrome P450 3A4 hepatic enzymes metabolize colchicine.²¹^{, 25} P-glycoprotein facilitates colchicine removal from the body.²⁶Co-administration of medications that inhibit CYP3A4 enzyme activity (example: grapefruit juice, azole antifungals, erythromycin, verapamil) increase the risk of colchicine toxicity.²¹^{, 25} In addition, co-administration of colchicine with P-glycoprotein inhibitors (example: digoxin) increases the risk of colchicine toxicity.²⁶ Toxic symptoms are dose-dependent with increasing severity.²⁷Patients with toxicity may present with gastrointestinal symptoms (nausea, vomiting, diarrhea), hypotension, lactic acidosis, or acute kidney injury.^{22, 27} To decrease the risk of toxicity, colchicine’s prescribing information recommends avoiding its co-administration with P-glycoprotein inhibitors or CYP3A4 inhibitors in patients with renal or hepatic impairment.²⁸ For other patients, the prescribing information recommends weighing risks versus benefits before co-administering colchicine with medications that pose a significant drug interaction.

SIDEBAR: HISTORY OF COLCHICINE

Colchicine is derived from a plant, Colchicum automnale.²⁹ Other names for this plant include Autumn Crocus, meadow saffron, naked lady, and colchicum.³⁰ Ebers Papyrus, an Egyptian medical document on herbs dating back to 1500 BC, indicates the use of C. automnale for joint pain.³¹ In 1833, a German pharmacist analyzed the substance and gave it the name colchicine.²⁹ In France, in 1819, a chemist and a pharmacist isolated colchicine from the plant. In 1884, a French pharmacist produced and sold colchicine as 1 mg granules, which is still available in some countries.^29,32 Colchicine accounts for about 0.1-0.6% of the plant content.³³ Non-surprisingly, the C. automnale plant is poisonous. Humans should not ingest the plant. Symptoms of C. automnale toxicity resemble the side effects or toxicity of colchicine.³⁴ These symptoms range from diarrhea, nausea, and vomiting to organ failure and death.

Colchicine was available for decades in the US without a U.S. Food and Drug Administration (FDA) approved labeling.³⁵Despite the Food, Drug, and Cosmetics Act requiring the FDA to approve medications based on efficacy and safety data, colchicine was grandfathered in. Grandfathered drugs were medications available on market before the Food, Drug, and Cosmetics Act of 1938 or its amendments in 1962.

In 2006, the FDA initiated the unapproved drug initiative (UDI).³⁶ The goal of the UDI program was to decrease the number of medications in the United States that do not carry FDA approval. Under the UDI program, the FDA allowed exclusive marketing to manufacturers who obtain FDA approval. Some pharmacists and pharmacy technicians may recall colchicine shortage as manufacturers of colchicine received warning letters from the FDA to stop selling colchicine.³⁷ Mutual Pharmaceutical Company submitted a new drug application (NDA) for colchicine in November 2008.³⁸ The UDI did not require manufacturers to conduct new clinical trials to obtain FDA approval. Mutual Pharmaceutical Company’s NDA included data from randomized controlled trials in 1974 and 2004 that proved the safety and efficacy of colchicine. As a result, in July 2009 the FDA approved colchicine for the treatment of gout and familial Mediterranean fever. Colchicine came back to the US market under brand name Colcrys.³⁹

Colchicine is light sensitive. Pharmacies should protect colchicine from light and dispense it in a light-resistant container.²⁸ The FDA requires pharmacies to distribute a medication guide to patients when dispensing colchicine.⁴⁰ Medication guides inform patients of potential serious adverse reactions and harm mitigation strategies. The Institute for Safe Medical Practices (ISMP) lists colchicine on the look-alike sound-alike (LASA) list due to potential for confusion with Cortrosyn, which is the brand name for cosyntropin.⁴¹Of note, cosyntropin is a synthetic adrenocorticotropin hormone that has anti-inflammatory properties and is an alternative agent for gout attacks.⁴²In patients with a history of gout, the ACR guideline recommends a “medication-in-pocket” (discussed below) approach to allow early initiation of an anti-inflammatory drug at the onset of a gout flare.²⁰ Since colchicine has anti-inflammatory properties, it is an option for the “medication-in-pocket” approach.

The pharmacist takes a close look at Jim’s prescription refill history to figure out why colchicine is not working for Jim. The pharmacist explores several possibilities:

Is Jim adhering to his urate-lowering therapy (ULT)?
Is Jim refilling his colchicine as part of a gout flare prophylactic therapy upon initiating ULT?
Is Jim asking for colchicine as a “medication-in-pocket” approach?
Is Jim consuming excessive alcohol?
Is Jim eating foods rich in purines?
Is Jim taking any prescription or over-the-counter medications that may increase his uric acid level?

NSAIDs

The FDA has approved indomethacin, naproxen, and sulindac for the treatment of acute gout flare.^{43,44, 45} However, the guideline does not recommend a specific NSAID.²⁰ Choice of agent depends on patient-specific factors including cardiovascular (CV) risk, gastrointestinal (GI) risk, cost, and availability without a prescription.⁴⁶ Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor and therefore carries a low GI risk but is associated with a dose-dependent increase in CV risk.^{47, 48} Ibuprofen carries a low GI risk. Indomethacin, naproxen, diclofenac, and sulindac carry a moderate GI risk.^{49, 50} Among the nonselective NSAIDs, CV risk is highest with diclofenac and lowest with naproxen.⁵¹ Despite differences in CV risk among nonselective NSAIDs, the FDA mandates a boxed warning for all NSAIDs about increased risk of thrombosis, myocardial infarction (MI), and stroke.^{52, 53} In addition, the FDA requires pharmacies to distribute a medication guide to patients when dispensing a prescription for NSAIDs.⁵⁴ Any NSAID is an option for the “medication-in-pocket” approach.²⁰

Glucocorticoids

The ACR guideline does not recommend a specific oral glucocorticoid.²⁰ Parenteral glucocorticoids (intramuscular, intravenous, or intraarticular) are alternative options for patients who cannot tolerate oral therapy. Glucocorticoids (example: prednisone, methylprednisolone) are an attractive option for patients with chronic kidney disease (CKD) or those who cannot tolerate colchicine or NSAIDs.^1,55Short-term glucocorticoids do not cause significant side effects.^{56, 57} Glucocorticoids are an additional option for the “medication-in-pocket” approach, including injectable formulations for patients who cannot take oral medications.²⁰Methylprednisolone is available in different dosage forms such as oral, intramuscular (as acetate or succinate), intravenous (as acetate), and intraarticular (as acetate).⁵⁸

Anakinra

Anakinra is an IL-1 receptor antagonist.⁵⁹ It blocks the activity of the inflammatory mediatory IL-1. Anakinra has an off-label indication for gout attacks at a dose of 100 mg subcutaneously daily for 3 to 5 days.^{60, 61} The ACR guideline classifies anakinra as an alternative agent, particularly due to cost.²⁰ The manufacturer recommends storing anakinra in the refrigerator and protecting from light until ready for administration.⁶²Patients can self-administer anakinra after demonstrating proper administration technique.⁵⁹

ACTH

Adrenocorticotropic hormone (ACTH) binds to melanocortin receptors, which triggers the release of endogenous steroids, thus decreasing inflammation.⁶³ The ACR guideline recommends ACTH as an alternative agent.^20,63 ACTH is available as an intramuscular or subcutaneous injection.⁶⁴ The purified cortrophin formulation carries an indication for acute gouty arthritis.⁶⁵ The manufacturer does not provide a dosing recommendation specific for gout and recommends caution in patients with renal insufficiency.^64-66 The manufacturer recommends storing ACTH in the refrigerator until ready for administration and warming to room temperature before injecting.⁶⁷

Table 1 summarizes the first-line agents for the treatment of gout flares.

Table 1. First-line Agents for the Treatment of Gout Flares^{20, 24, 44-46, 56, 68-71}
Therapy	Dose	Comment	Monitoring parameters
Colchicine	· Day 1 of therapy: Use treatment dose of 1.2 mg by mouth (PO) as soon as possible then 0.6 mg after one hour. Maximum dose 1.8 mg/day. · Day 2 and until flare resolves, use prophylactic dose of 0.6 mg PO once or twice daily.	If creatinine clearance (CrCl) < 30 mL/min: · Use 1.2 mg PO as soon as possible then single dose of 0.6 mg after one hour. Avoid repeating therapy within a 14-day period. · Alternatively, use 0.3 mg PO as soon as possible as a single dose. Avoid repeating therapy within 3-7 days. If patient is on dialysis: · Use 0.6 mg PO as a single dose. Avoid repeating therapy within a 14-day period.	Monitor patients with CrCl ≤ 80 mL/min closely for adverse effects.
NSAIDs	· Indomethacin: 50 mg three time daily until pain is tolerable (usually, 3 to 5 days). · Sulindac: 200 mg twice daily until attack resolves (usually, 7 days). · Naproxen: 750 mg x 1 dose then 250 mg every 8 hours until attack resolves (usually, 2 days).	· The manufacturer does not provide recommendations for renal dosage adjustment. · The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommends avoiding use of NSAIDs If CrCl < 30 mL/minute.	Monitor GI, renal, and CV toxicity in elderly patients. Prescribe lowest effective dose for the shortest duration possible.
Glucocorticoids	· Follow specific glucocorticoid dosing recommendation.	Safest option in patients with CKD.	Monitor serum glucose, blood pressure, electrolytes, mood changes, and recurrent infections.

Interestingly, a panel consisting of eight patients with gout participated in the development of the 2020 ACR guidelines.²⁰ The patient panel provided valuable input from a patient perspective regarding therapy preference for patients with an established gout diagnosis. The patient panel strongly favored a medication-in-pocket approach for the treatment of acute gout flares. With this approach, the clinician prescribes an anti-inflammatory medication that the patient keeps on hand for use as needed.⁷² Moreover, the patient panel favored an injectable dosage form for the medication-in-pocket to control the pain faster in patients who can take nothing by mouth. The medication-in-pocket approach ensures that patients have quick access to an anti-inflammatory medication at the first onset of gout attack symptoms.²⁰

Jim’s colchicine regimen is consistent with the “medication-in-pocket” to treat an acute gout flare.

MANAGEMENT OF CHRONIC GOUT

The goal of chronic gout management is to lower the serum uric acid level with ULT, if indicated, and to prevent future attacks.²⁰ ULT includes medications that decrease uric acid production or promote uric acid excretion.⁷³ The ACR 2020 guideline recommends a “treat-to-target” approach that guides ULT dose titration and maintenance to achieve serum uric acid of less than 6 mg/dL.²⁰ Lower ULT initial dosing with subsequent titration decreases the risk of gout flare associated with ULT initiation.²⁰

Pause and Ponder: What patient factors determine eligibility for urate lowering therapy (ULT)?

Table 2 provides recommendation on initiation of ULT based on patient-specific factors.

Table 2 - Indication for ULT²⁰
Patient factors	2020 ACR guideline recommendation	Comment
≥1 subcutaneous tophi	ACR guideline strongly recommends initiating ULT	Moderate or high certainty of evidence that benefits of ULT consistently outweigh the risks
Gout-attributable radiographic damage
≥2 gout flares per year
> 1 flare but < 2 flares per year	ACR guideline conditionally recommends initiating ULT	Low certainty of evidence or no data available and/or benefits and risks closely balanced
First flare and any of the following: · Chronic kidney disease (CKD) stage ≥ 3 · Serum uric acid > 9 mg/dL · Urolithiasis
First gout flare	ACR guideline conditionally recommends against initiating ULT
Asymptomatic hyperuricemia*

*Serum uric acid > 6.8 mg/dL

Pause and Ponder: Which urate-lowering agent is first-line therapy?

Table 3 summarizes urate-lowering medications.

Table 3 - Urate Lowering Medications ^20,74-76
Pharmacological class	Mechanism of action	Medication	Comments
Xanthine Oxidase Inhibitors	Inhibition of xanthine oxidase resulting in decreased conversion of hypoxanthine to xanthine and xanthine to uric acid.	Allopurinol Febuxostat	· Allopurinol is first-line agent. · Start allopurinol at ≤ 100 mg/day in normal kidney function and ≤ 50 mg/day in CKD stage ≥ 3 then titrate. · Start febuxostat at ≤ 40 mg/day then titrate.
Uricosuric Agents	Inhibition of urate reabsorption in the renal tubules resulting in increased excretion of uric acid in the urine.	Probenecid	· ACR guideline strongly recommends XOI over probenecid for patients with CKD stage ≥ 3 · Start probenecid at 500 mg PO once or twice daily then titrate.
Urate Oxidase Enzyme	Catalysis of uric acid oxidation to water-soluble allantoin resulting in increased excretion of the allantoin in the urine.	Pegloticase	· ACR guideline strongly recommends against use of pegloticase as a first-line agent · Administer pegloticase 8 mg IV infusion every 2 weeks along with methotrexate 15 mg PO once a week with a folic acid supplement. · Start weekly methotrexate and folic acid supplementation 4 weeks before initiating pegloticase and continue while on pegloticase.

Clinicians usually determine eligibility for ULT when patients present with an acute gout attack.²⁰ Some experts favor initiating ULT two to four weeks after the resolution of a gout attack.⁷⁷ One reason for this practice stems from the fear of gout attack worsening with ULT initiation. The other reason is the perception that during a gout attack, patients are in too much pain to process information regarding chronic therapy. However, the ACR guideline favors initiating ULT during a gout flare as patients may not return for a follow-up visit to initiate ULT after the flare resolves.²⁰

XANTHINE OXIDASE INHIBITORS (XOIs)

XOI include allopurinol and febuxostat.²⁰ XOI are first-line among urate-lowering agents, and the guideline recommends allopurinol as a first-line agent for all patients with gout, unless contraindicated.

Allopurinol

Allopurinol is associated with an increased risk of allopurinol hypersensitivity syndrome (AHS), a rare but severe, and potentially life-threatening adverse reaction.⁷⁸ AHS presents as fever, severe rash, eosinophilia, hepatitis, and acute kidney injury.⁷⁹ AHS is more common in patients who are African Americans or of Southeast Asian descent.⁷⁸ Pharmacogenetic studies show that these patients have a gene on their human leukocyte antigen (HLA) system that increases the risk of developing AHS. This gene is the HLA-B*5801 allele.⁸⁰ The interaction of allopurinol with the HLA-B*5801 allele triggers an immune reaction characterized by T-cell activation.⁸¹ Not all patients who are positive for HLA-B*5801 allele develop AHS.⁸² Risk of AHS increases in HLA-B*5801 allele positive patients who have elevated allopurinol serum level due to dose increase or renal dysfunction.⁸¹

In the US, testing for HLA-B*5801 in Caucasians or Hispanics is not cost-effective.⁸³ The 2020 ACR guideline recommends genetic testing for the HLA-B*5801 allele before starting allopurinol for patients who are African Americans or of Southeast Asian descent.²⁰ The guideline recommends starting allopurinol at a low dose of 100 mg daily for normal renal function and a lower dose in case of renal dysfunction.

The prescribing information recommends protecting allopurinol from light.⁷⁴ ISMP lists the brand name of allopurinol, Zyloprim, on the look-alike sound-alike (LASA) list due to potential for confusion with zolpidem.⁴²

SIDEBAR: DID YOU KNOW THAT THE DISCOVERY OF ALLOPURINOL LED TO A NOBEL PRIZE AWARD?

Gertrude Elion, who earned a master’s degree in chemistry from New York University in 1941, worked as a lab assistant for George Hitchings. Up until the 1950s, scientists produced medications by screening and modifying naturally existing substances.⁸⁴ However, Elion and Hitchings’ contribution to medicine was groundbreaking to drug development as they introduced drug therapy that was targeted to specific cells. In 1963, Elion and Hutchings discovered that allopurinol blocked the synthesis of uric acid. In 1988, the Nobel Prize Committee awarded Gertrude Elion and George Hitchings the Nobel Prize in Physiology or Medicine for the discovery of allopurinol and other medications.⁸⁵

Febuxostat

Febuxostat carries a boxed warning for increased risk of CV death in patients with cardiovascular disease (CVD), when compared to allopurinol.⁸⁶ Therefore, the 2020 ACR guideline recommends selecting another ULT medication in patients with established CVD.²⁰ For patients who experience a CV event while on febuxostat, the ACR guideline recommends switching to a different ULT medication.²⁰ The FDA requires pharmacies to distribute a medication guide when dispensing febuxostat to patients.⁸⁶

URICOSURICS

Probenecid

Probenecid is the only uricosuric drug approved in the United States.^87,88 Probenecid may cause nephrolithiasis (uric acid stones in the kidneys).⁸⁹ These uric acid stones form as the uric acid crystallizes in an acidic urine. The prescribing information for probenecid recommends adequate hydration and adjunct urine alkalinizing agents (example: sodium bicarbonate or potassium citrate).⁸⁹ However, the 2020 ACR guideline determined insufficient evidence to recommend the routine use of alkalinizing agents with probenecid.²⁰ Probenecid is usually an add-on therapy in patients with partial response to an XOI. Remember to counsel patients on adequate hydration to decrease the risk of nephrolithiasis.

ISMP lists probenecid on the LASA list due to potential for confusion with Procanbid, the brand name for procainamide, an antiarrhythmic drug.⁴² Probenecid also has some interesting abuse potential (see the SIDEBAR).

SIDEBAR: CAN PROBENECID HELP ATHLETES IMPROVE PERFORMANCE?

Random drug testing in sports led athletes to misuse probenecid to mask the unlawful use of performance-enhancing drugs such as anabolic-androgenic steroids.⁹⁰ Probenecid inhibits the tubular secretion of anabolic-androgenic steroids in the kidneys, thus inhibiting their excretion in the urine. As a result, urine drug testing will not detect the use of these illegal substance, and athletes can pass the random drug testing successfully. In 1986, a doping control officer traveled from Norway and collected 6 urine samples from 6 Norwegian athletes who were training in the US. The athletes showed up at least 1.5 hours late probably to allow time for onset of action of the masking agent. Five of the samples showed an unusually dilute urine with low specific gravity. In addition, the concentration of endogenous androgenic-anabolic steroids in the urine samples was at least 100 times below normal.⁹⁰ These unusual findings along with suspicious behaviors projected by the athletes during the testing process, triggered further analysis of the urine samples. The lab identified a “new masking agent”, probenecid and its metabolite, in these urine samples. Today, probenecid appears on the World Anti Doping Agency (WADA) prohibited list.⁹¹ The WADA list serves as a standard for identifying substances that athletes may illegally use to enhance performance in sports.⁹¹

URATE OXIDASE ENZYME

Pegloticase

The FDA approved pegloticase for adults with chronic gout refractory to conventional therapy.⁹² The 2020 ACR guidelines recommends switching to pegloticase when XOIs, probenecid, and other interventions fail.²⁰ In clinical trials, administering methotrexate with pegloticase increased the chance of tophi resolution by 22.8% compared to pegloticase monotherapy.⁷⁶ Therefore, pegloticase’s prescribing information recommends co-administration with methotrexate, unless contraindicated. Folic acid supplementation decreases the risk of hepatotoxicity and GI side effects associated with methotrexate.⁹³ Pharmacists should counsel patients about the importance of adherence to folic acid while on methotrexate.

The manufacturer recommends storing pegloticase in the refrigerator and protecting it from light before dispensing.⁷⁶ After diluting pegloticase for IV infusion in an institutional setting, healthcare workers should protect the solution from light.

Pause and Ponder: When does the guideline recommend switching urate-lowering agents?

The 2020 ACR guideline recommends using the maximum tolerated or recommended dose of a ULT.²⁰ Figure 1 outlines the management of patients taking a XOI requiring adjustment to therapy:

Figure 1. Switching ULT

Jim’s medication profile reveals that he has been taking allopurinol for little over a year now.

DURATION OF THERAPY

For patients tolerating ULT, the 2020 ACR guideline recommends indefinite therapy to avoid worsening gout and its associated complications.²⁰ Patients may not adhere to therapy due to cost, pill burden, and low health literacy.⁹⁴ Remember to counsel patient on adherence and goals of ULT as patients may think they do not need to take ULT if they have no symptoms.

PREVENTING GOUT FLARE UPON INITIATION OF ULT

Initiation of ULT may trigger a gout flare due to activation of crystals precipitated in joints.^{95, 96} The risk of gout flare increases with higher reduction in serum uric acid levels. Studies suggest that gout attacks associated with ULT may decrease patient adherence to ULT.⁹⁷ Prophylaxis with anti-inflammatory medications decreases the risk of gout flare upon ULT initiation. The 2020 ACR guideline recommends prophylactic therapy upon initiating ULT and for at least three to six months. Patients who continue to experience flares may require a longer duration of prophylactic therapy.²⁰ Experts recommend colchicine or NSAIDs as first-line prophylactic therapy.⁹⁸ Table 4 summarizes prophylactic medications and recommendations.

Table 4 – Medications that Prevent Gout Attack with ULT Initiation
Medication	Recommendation
Low-dose colchicine	Use 0.6 mg once or twice daily
Low-dose NSAIDs	Use naproxen 250 mg or equivalent dose of different NSAID Add proton pump inhibitor if indicated
Low-dose prednisone or prednisolone	Use less than or equal to 10 mg per day Reserve corticosteroids for patients who cannot tolerate colchicine and NSAIDs

NONPHARMACOLOGIC THERAPY AND LIFESTYLE MODIFICATIONS

Serum uric acid levels decrease only slightly with dietary modifications.²⁰ In addition, certain diets may trigger a gout flare. To decrease the risk of flares, the 2020 ACR guideline conditionally recommends the following approaches:

Limiting alcohol intake
Limiting purine intake. Some examples of high-purine foods include seafood like sardines, tuna, haddock, and meats like bacon, turkey, veal, and liver.^{99, 100}
Limiting high-fructose corn syrup intake
Following a weight loss program if the patient is overweight or obese

Jim projected an alcohol breath when speaking. Jim may be consuming excessive amounts of alcohol. He may be consuming a non-gout friendly diet.

DIGITAL HEALTH AND GOUT MANAGEMENT

Digitalization of health care is rapidly evolving and involves the use of technology to manage health conditions, ameliorate modifiable risk factors, and promote health and wellness.¹⁰¹ Wearable devices such as fitness trackers, patient portals, and mobile apps are only few examples of digital health tools. Investigators suggest that gout mobile health apps may improve patient perception of the disease, clarify beliefs, and benefit self-care.¹⁰²However, further studies are essential to prove these mobile applications beneficial. As of this writing, several gout-related mobile health applications are available. Target users for these applications can be clinicians or patients. For example, a physician developed a mobile application called Gout Diagnosis. The application includes an evidence-based algorithm to facilitate an accurate diagnosis of gout.¹⁰³ On the other hand, patients can download from a variety of existing gout mobile applications at little or no cost.¹⁰⁴ The National Kidney Foundation developed a mobile application called Gout Central. This application comes from a reputable foundation and provides patient education on symptoms and risk factors for gout, nonpharmacologic recommendations such as diet and lifestyle modifications, and medications to treat gout and prevent flares.¹⁰⁴ The FDA does not regulate mobile medical applications.¹⁰⁵ Therefore, the choice of mobile health application depends on patient preference such as cost, ease of use, compatibility, security, and type of content.¹⁰⁶

A mobile application may help Jim learn about foods and drinks that may trigger gout attacks.

PHARMACY TEAM IMPACT ON GOUT MANAGEMENT

Pharmacists are the most accessible healthcare professionals. Patients with a gout flare may seek pharmacists for recommendations on pain management. When patients without a previous gout diagnosis present to the pharmacy, pharmacists may recognize signs of gout and refer them to their primary care clinician. Pharmacists can educate patients who have a diagnosis for gout about the phases and goals of gout therapy, including the likelihood that ULT will be a lifelong therapy.

Pharmacists are well-positioned to assess adherence to ULT and educate patients about the importance of ULT.¹⁰⁷ Pharmacists can assess patient understanding of various therapies and remind them that anti-inflammatory medications treat acute gout attack or prevent gout flare upon initiating ULT. Pharmacists should empower patients to request from their clinician a medication-in-pocket prescription. Pharmacists should counsel patients on the proper use of medication-in-pocket by reminding them to take the anti-inflammatory medication as soon as possible, ideally within 12 hours of onset of a gout attack.¹⁰⁸In addition, patients may need a reminder about continuing their ULT while taking the medication-in-pocket for acute flares.¹⁰⁹

Pharmacy technicians can ensure that patients have refills on their medication-in-pocket prescription to facilitate early initiation. Updating the patient’s records in the pharmacy software with the gout diagnosis can facilitate this continuity of care. The pharmacy team should encourage patients to fill all their prescriptions at the same pharmacy. Through access to all the patient’s medications, pharmacists and pharmacy technicians can play a crucial role in optimizing gout management by identifying medications that increase serum uric acid levels.¹¹⁰

In addition, the pharmacy team can identify potential drug-drug interactions. This is particularly important with colchicine as it is a substrate for CYP3A4 and P-gp and has a narrow therapeutic window.¹¹¹In addition, some medications are known to increase serum uric acid levels.²⁰ Advising patients to check with the pharmacy team before purchasing an over-the-counter (OTC) medication can decrease the use of inappropriate medications. When completing transactions at the register, pharmacy technicians are well positioned to identify OTC products that can worsen gout, such as vitamin A or niacin.¹¹² On the other hand, frequent purchase of OTC anti-inflammatory medications like naproxen or ibuprofen may imply uncontrolled gout.

Patients can find educational videos on YouTube to learn more about gout therapy and appropriate diet.¹¹³ Additional resources are available to patients on goutalliance.org. These include videos, podcasts, guides, and awareness events.¹¹⁴ Some patients may like to learn about their condition using gout-related mobile applications.

Pharmacy interns may benefit in hearing from patients about their experience with gout, especially the debilitating pain. This may help future pharmacists empathize and develop better relationships with patients, which can improve patient outcomes.¹¹⁵

The entire pharmacy team could engage in alleviating misconceptions about gout. Some patients with gout have reported stigma regarding their condition from friends, family members, and healthcare workers.¹¹⁶ Some patients with gout have even reported an internalized stigma. Stigmatization may be due to the misbelief that gout is benign, preventable, or self-inflicted.

Did you know that May 22 is National Gout Awareness Day?

Jim states that he feels embarrassed about wearing slippers that expose his swollen toe. The pain is so intense that he is unable to tolerate a close-toe shoe.

Table 5 summarizes some medications that may increase serum uric acid level.

Table 5 – Managing Medications that Increase Serum Uric Acid Level and Risk of Gout Attack^{20,110,117-119}
Medication	Mechanism	Recommendation
Loop and thiazide diuretics Use: hypertension, edema	Decrease urate excretion	The guideline recommends switching to a different antihypertensive and suggests losartan when feasible.
Aspirin (low-dose, 81 mg) Use: prevention of CVD	Increases uric acid renal reabsorption and decreases secretion	The guideline conditionally recommends against discontinuing low-dose aspirin with appropriate indication.
Niacin Use: dietary supplement	Inhibits the enzyme uricase, thus inhibiting the oxidation of uric acid, or decreases uric acid excretion	The guideline does not provide a specific recommendation for niacin-induced hyperuricemia. Experts recommend adequate hydration.

After looking into Jim’s medication profile and inquiring about his OTC products, the pharmacist does not identify any medication that may be increasing his serum uric acid level.

CONCLUSION

Gout is the most common type of inflammatory arthritis. Untreated gout can lead to complications such as degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement. ULT is indicated for chronic gout management. Allopurinol is the first-line urate-lowering agent. Colchicine, NSAIDs, and corticosteroids are indicated for acute flares, and, in lower doses, for gout flare prophylaxis upon initiating ULT. Diet and lifestyle modifications complement the pharmacologic therapy. The pharmacy team plays a crucial role in identifying drug-induced hyperuricemia and educating patients about the importance of adherence to ULT. Gout flares are painful and debilitating. Pharmacists can recommend initiation of anti-inflammatory therapy for acute gout flares. Pharmacy technicians can ensure patients have refills for their anti-inflammatory medication to facilitate the medication-in-pocket approach.

Jim’s uncontrolled gout may be due to various reasons that pharmacy team can investigate. Inquiring about Jim’s drinking habits and educating him about the negative impact of alcohol on gout management is a necessary first step in his therapy. If an adequate trial of dietary changes does not control his symptoms, then switching to a different XOI or adding probenecid, depending on what he has tried so far, would be appropriate.

Treating Gout without Doubt

Pharmacist POST-TEST
1. Which of the following patient factors accounts for about 90% of gout cases?
a) Overproduction of uric acid
b) Underexcretion of uric acid
c) Liver dysfunction

2. Why does the American College of Rheumatology (ACR) define hyperuricemia as serum uric acid level greater than or equal to 6.8 mg/dL?

a) All patients with serum uric acid level ≥ 6.8 mg/dL experience gout
b) Serum uric acid level ≥ 6.8 mg/dL is insoluble in the blood
c) Patients with serum uric acid level ≥ 6.8 mg/dL experience urate kidney stones

3. Which of the following is involved in the pathogenesis of gout?

a) Chronic deposition and crystallization of urate in the joints and tissues
b) Chronic deposition and crystallization of calcium in the joints and tissues
c) Increased glomerular filtration rate of uric acid due to caffeine intake

4. Which of the following is a complication of untreated gout?

a) Renal stones
b) Congestive heart failure
c) Visual changes

5. Which of the following findings confirms a diagnosis of gout?
a) Elevated uric acid
b) Tophi in tissues and/or bones
c) Burning upon urination

6. According to the American College of Rheumatology (ACR) guideline, which one of the following is a goal of chronic gout therapy?
a) Limiting gout attacks to a maximum of 2 attacks per year
b) Preventing future gout attacks
c) Decreasing the renal excretion of uric acid

7. A 55 year-old-man presents with his first acute gout attack. In the absence of contraindications, which of the following medications is an appropriate first-line therapy for this patient?

a) Colchicine
b) Intramuscular methylprednisolone
c) Anakinra

8. Which one of the following statements is accurate about colchicine drug interactions?
a) Co-administration of colchicine with P-glycoprotein inhibitors increases the risk of colchicine toxicity
b) Co-administration of colchicine with P-glycoprotein inhibitors decreases colchicine efficacy
c) Co-administration of colchicine with CYP 450 3A4 inhibitors decreases colchicine efficacy

9. In the absence of contraindications, which one of the following medications is the first-line urate-lowering therapy?
a) Allopurinol
b) Febuxostat
c) Probenecid

10. A patient presents to fill his first prescription for allopurinol. Which one of the following is an appropriate counseling point for this patient?
a) Start taking allopurinol today and continue indefinitely
b) Discontinue allopurinol once you achieve uric acid level of < 6 mg/dL c) Keep allopurinol on hand and start taking at the first sign of a gout attack 11. A patient experiences an acute attack of gout. You review his medication profile. Which of the following medications may be aggravating his gout? a. atorvastatin b. niacin c. losartan 12. Which of the following is an appropriate nonpharmacologic intervention for gout? a. Increasing intake of purine-containing foods b. Switching from beer or wine to hard alcohol c. Applying ice to sore joints if tolerable

Treating Gout without Doubt
Technician POST TEST question

1. According to the American College of Rheumatology (ACR), what is the definition of hyperuricemia?

a) uric acid level > 6 mg/dL
b) uric acid level ≥ 6.5 mg/dL
c) uric acid level ≥ 6.8 mg/dL

2. Which of the following statements is accurate about gout attacks?

a) Gout attacks happen only in the big toe joint
b) Gout attacks happen only in the morning
c) Gout attacks happen in any joint

3. When should patients with a first gout attack seek medical care?
a) Only if the pain is unbearable
b) Only if the pain lasts more than 10 days
c) Anytime patients experience their first gout attack

4. A patient calls the pharmacy saying that he is starting to experience a gout attack. The patient asks the pharmacy technician to refill his medication-in-pocket prescription. Which one of the following medications can the patient use for medication-in pocket approach?
a) Allopurinol
b) Naproxen
c) Probenecid

5. A pharmacy technician is refilling a patient’s medication-in pocket prescription for colchicine. The technician notices that after this fill, the prescription has no more refills. The patient’s next appointment is in eight months. What is the best next step?

a) Send a refill request to the clinician’s office
b) Inactivate the prescription
c) Tell the patient to request a prescription during their next visit

6. What is the goal of therapy for a patient taking allopurinol as part of a gout regimen?
a) Achieving a serum uric acid level < 6 mg/dL b) Terminating an acute gout attack c) Decreasing the intensity of pain during an acute gout attack 7. Which one of the following nonpharmacologic therapy is beneficial for patients with gout? a) Decreasing the intake of foods high in purines b) Increasing alcoholic beverages consumption c) Decreasing the intake of caffeine 8. A patient visits the pharmacy counter frequently to check-out some OTC products. In the past three months, the patient has purchased the same product four times. Which one of the following OTC products may imply uncontrolled gout? a) Vitamin C b) Ibuprofen c) Dextromethorphan 9. A medication guide should accompany which of the following medications? a) NSAIDs b) Allopurinol c) Probenecid 10. Which one of the following medications Is a urate oxidase enzyme? a) Pegloticase b) Colchicine c) Probenecid 11. A patient experiences an acute attack of gout. You review his medication profile. Which of the following medications may be aggravating his gout? a. atorvastatin b. niacin c. losartan 12. Which of the following is an appropriate nonpharmacologic intervention for gout? a. Increasing intake of purine-containing foods b. Switching from beer or wine to hard alcohol c. Applying ice to sore joints if tolerable

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111. Hansten PD, Tan MS, Horn JR, et al. Colchicine Drug Interaction Errors and Misunderstandings: Recommendations for Improved Evidence-Based Management. Drug Saf. 2023;46(3):223-242. doi:10.1007/s40264-022-01265-1
112. Ford ES, Choi HK. Associations between concentrations of uric acid with concentrations of vitamin A and beta-carotene among adults in the United States. Nutr Res. 2013;33(12):995-1002. doi:10.1016/j.nutres.2013.08.008
113. Onder, M.E., Zengin, O. YouTube as a source of information on gout: a quality analysis. Rheumatol Int 41, 1321–1328 (2021). https://doi.org/10.1007/s00296-021-04813-7
114. Alliance for Gout Awareness. goutalliance.org. Published November 14, 2022. Accessed August 10, 2023. https://goutalliance.org/
115. 5 Ways Pharmacists Can Show Empathy. Pharmacy Times. https://www.pharmacytimes.com/view/5-ways-pharmacists-can-show-empathy
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117. UpToDate. www.uptodate.com. https://www.uptodate.com/contents/diuretic-induced-hyperuricemia-and-gout. Updated March 2023. Accessed April 16, 2023.
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Motivation to be the Best Drug Information Station

After completing this application-based continuing education activity, pharmacists will be able to

Recognize key elements of a drug information request
Describe a typical process for researching drug information requests
Prioritize information in the final written response
Identify the best language to use based on the inquiring party’s needs

After completing this application-based continuing education activity, pharmacy technicians will be able to

Identify questions that are within the pharmacy technician’s scope of practice
Recognize tools and resources to use when attempting to answer a drug information question
Complete the steps to completing a drug information request that is within the pharmacy technician’s scope of practice

Pharmacists and pharmacy technicians often field questions from patients or other healthcare providers. Pharmacists may be more accustomed to answering questions than pharmacy technicians are, but that doesn't mean that pharmacy technicians can't answer appropriate questions. Pharmacy staff members should know their scope of practice and be willing and able to answer questions that fall within the scope of practice. Using an organized approach can help pharmacy staff members answer questions efficiently and effectively. Documentation is also an important aspect of drug information questions, as is saving the information in case it is needed later.

INTRODUCTION

A drug information (DI) request is a medication-related question posed by any interested party, but usually a healthcare professional or a patient. As the healthcare team’s drug expert, one of a pharmacist’s main duties is answering these queries effectively and providing an answer that is appropriate for the inquirer’s level of expertise. Pharmacy technicians and pharmacy interns also answer some drug information questions (see TECH TALK SIDEBAR). This continuing education activity outlines various drug information questions that pharmacy staff field most often and describes a methodical approach to ensure pharmacy staff answer requests effectively and accurately.¹

TECH TALK SIDEBAR: Questions within the Pharmacy Technician’s Scope of Practice?^2,3

Pharmacy technicians and interns can answer general questions that are within the bounds of their education and training. That vague statement requires some interpretation. If the answer is common knowledge (not specialized pharmaceutical knowledge), technicians can answer. In addition to working with supervising pharmacists to interpret the statement, pharmacy technicians and interns need to know state law governing their scope of practice.

Pharmacy technicians and interns are often the first point of contact for customers who want over-the-counter (OTC) medications. Technicians can answer general questions about ingredients if the information is on the label. Some examples include

Does this product contain acetaminophen? What brands of acetaminophen do you stock?
Where are the medicines for pain?
Is there a less expensive generic or store brand for this product?
Do you have any [insert name of prescription medication] in stock?
Do I need to refrigerate this liquid antibiotic?
What does “analgesic” mean?
What does “sustained release” mean?
Is this prescription for a controlled substance?
Why can’t I refill this prescription today?

Pharmacy technicians and interns can also convey information from the pharmacist but should be careful. A PRO TIP is that if technicians or interns don’t understand what the pharmacist says, they should ask the pharmacist to make the information clearer. And if the answer is long or complicated, they should write it down and recite it back to the pharmacist before transmitting it to the person with the question.

Helping customers find specific medications or classes of medications is within the technician’s scope of practice. When patients have questions about their medications, doses, and how best to administer them, technicians may hesitate to answer. If the information is clearly printed on the prescription label, on the auxiliary labels, or contained in an FDA-approved Medication Guide, the technician or intern can answer.

Technicians and interns need to work with the supervising pharmacist to determine if they can answer other questions. When in doubt, technicians should consult with or refer the question to the pharmacist. Technicians and interns must refer questions about potential adverse effects, administration problems, possible alternative medications, and clinical issues to the pharmacist. Before referring the patient, they can collect some baseline information. They cannot counsel or give advice, even if the medication is OTC.

Depending on the practice setting, the nature and complexity of DI requests can vary. Being able to answer DI requests is every pharmacy employee’s responsibility (although the type of information varies and at a certain level, the response is the pharmacist’s primary responsibility). Having an organized approach to answering DI questions is highly relevant when working within the community and hospital settings.⁴

Pharmacy employees who work primarily within a community setting can expect to receive DI requests from patients and from practitioners. These requests can range from asking about drug storage requirements (which a technician can usually answer) to consequences of taking an OTC medication in combination with prescription drugs, to requests regarding the safety of a medication for an uncommon or off-label indication. Pharmacists who work in hospital settings can expect to receive most DI requests from colleagues within the care team. For instance, a DI request could come from a prescriber asking about medication absorption and distribution in a patient with comorbid conditions, or from a nurse asking if a medication can be crushed. Pharmacists who work in industry settings, however, may receive medication information requests that vary greatly from those received in clinical settings.⁴

All DI requests require referencing reliable materials and sometimes, various internal policy or research documents. While DI requests are diverse, they all require similar analysis of sources and communication to provide a quality answer. Because pharmacy employees at different levels of responsibility can answer DI questions, this continuing education activity will call the person asking the question the requestor and the person finding the answer the respondent.

SCREENING THE REQUEST

One of the most confounding situations in the pharmacy occurs when someone asks a question, the respondent spends times finding an answer, and then the requestor says, “Oh, that’s not what I needed to know!” Sometimes, requestors don’t really know how to ask questions effectively. This is a problem that all customer service fields encounter, and answering DI requests is both a clinical function and a customer service. It’s why when you call many customer service lines, the customer service representative will say, “OK, what I hear you asking is….” and then rephrase the question.⁵

To answer DI requests effectively, the respondent must thoroughly understand the question.⁵ Very specific questions tend to be easily answerable, while others are more general or vague. In both instances, respondents need to ensure they understand the question. They can rephrase the question in their own words and say, “Let me make sure I understand. Do you mean….”, or they can use open ended questions (questions that cannot be answered with a yes or a no) to ask the requestor to provide more information. This avoids answering a question that wasn’t asked or intended or was poorly formulated.

Often, requestors don’t know how to ask a question that will provide the information they need. The hallmark of this type of question is that the requestor may use jargon inappropriately or words that don’t seem to make sense. Respondents can say, “Excuse me, I’m not sure I understood entirely. Can you rephrase the question?” or “Pardon me, but I didn’t quite understand the question. Can you tell me a little more about what you want to know and why?” That final word—WHY—provides the impetus for the requestor to provide necessary information.

Once the question has coalesced and both parties agree on its intent, the respondent can solicit important details from the requester and, if applicable, the patient, before delving into a search. At this point, the respondent needs to spend time actively listening to the requestor’s explanations.

This can be difficult if the requestor is long-winded, difficult to understand, or cognitively impaired, so it requires patience. Here’s a PRO TIP for listening: it’s called the traffic-light-rule.⁶ During the first 30 seconds (which seems like a short period of time, but is actually relatively long), the requestor’s “talking light” is green. Pharmacy staff should let them talk. In the next 30 seconds, the requestor’s light is yellow: pharmacy staff probably have enough information and should make note of comments or questions. After one minute, the requestor’s talking light is red: pharmacy staff should be comfortable stopping the requestor politely or asking questions.⁶

Before continuing, review the following DI requests. How would you proceed? Later in this activity, we’ll provide a description of the ideal process.

Pharmacist DI request #1: TN, 35-year-old obese female (BMI = 32.4 kg/m²) with uncontrolled type 2 diabetes will start on an atypical antipsychotic today to manage schizophrenia. TN’s psychiatric nurse practitioner (NP) calls with questions about drug selection. The NP mentions that TN’s drug formulary lists aripiprazole, haloperidol, olanzapine, and quetiapine as tier 1 preferred options. The NP wants your opinion as to which atypical antipsychotic may be most appropriate to prescribe for TN. What do you suggest?

Pharmacist DI Request #2: You work at a tertiary care internal medicine center. MS, an 80-year-old female, was recently admitted to the medicine floor. She had fallen when she was trying to use the restroom at her nursing home and presented to the emergency department with a wrist fracture. She suffers from insomnia and other comorbidities. Her medication list includes lisinopril 20 mg daily, metformin 500 mg twice daily, rosuvastatin 20 mg daily, and lorazepam 0.5 mg PRN anxiety and sleep. The nursing home staff states that MS received more doses of lorazepam in recent weeks. The medical resident believes that the increased lorazepam use could have contributed to the fall and wants to know if trazodone would be a safer replacement for MS’s insomnia. How do you respond?

Technician DI Request #1: I left this medication in my bathroom for four days, and then I noticed it says, “Keep in the refrigerator.” My house is cold, and the bottle didn’t feel warm. Is this still good, and if it isn’t, what should I do?

Technician DI Request #2: My child is having trouble swallowing her medication and refuses to take it. Are there any easier ways I could give it to her?

Identify Critical Information

Although it may seem counterintuitive, beginning with the end in mind is critical and the person gathering information must determine the requestor’s preferred response format. This means asking how the requester wants to receive the response. The respondent will need to adjust the answer according to the requestor’s preferences. Some requestors will want to wait for an answer. If the information is to be communicated through email or an electronic medical record, respondents may use their organization’s required format (a SOAP note or similar formats; see Table 1), but formats used in medical records may not be the most efficient approach in person or over phone. In person or on the phone, respondents need to use a more conversational tone. Furthermore, the respondent will need to determine the requestor’s level of medical competency and tailor the response accordingly. If the requestor is a patient, it is more appropriate to use simple language than if a provider asked the same or similar question. Respondents will have to evaluate these factors critically to provide a sound and comprehensive answer.⁷

Table 1. Formats for Communicating Critical Information^8,9

Communication Format	Parts of the format	Uses
SOAP	S: Subjective information This section includes descriptive information about a patient’s symptoms, feelings and experiences. O: Objective information This section includes pertinent lab values, imaging, or diagnostic tests. A: Assessment In this section the subjective and objective information are taken into consideration to make an assessment regarding the patient's disease states. P: Plan/ Follow Up This section outlines a detailed plan regarding the patient's treatment and the follow-up and monitoring required.	This format is a widely-used written format in healthcare. It helps organize pertinent patient information and efficiently present an answer. This format is especially useful when the respondent must consider multiple pieces of information.
ISBAR	I: Introduction Introduction of the pharmacist and the respondent, and the pharmacist’s role and location. S: Situation What are the current events regarding the patient? B: Background What has happened in the past with the patient? A: Assessment Identify the problem at hand and make assessments regarding the patient's disease state. R: Recommendation Outline the next steps and your plan.	This format is beneficial for verbal communication. It helps the presenter explain the problem at hand and the solution in a time efficient way.
TITRS	T: Title Introduction of who you are and your purpose in helping the patient. I: Introduction Present the patient and the problems that the patient needs help with. T: Text State subjective and objective information that is necessary to support any recommendations. R: Recommendation Outline the treatment plan in a clear, complete, and concise manner. S: Signature Include name, title, and phone number.	This format is beneficial when a brief and concise formal consult is needed to communicate a progress note towards a medical team.

Assess the Urgency of the Response

While it is critical to provide an appropriate response for the question, doing so in a timely manner is just as critical. Asking the requestor is the simplest way to determine the expected response time. However, many times the requestor isn’t present or cannot be reached, and it is up to the respondent to determine which questions require immediate responses and which may not. Clinically critical topics include

Medication safety: does the DI request ask if a certain therapy could cause or have caused harm to the patient?
Time sensitivity of the treatment: how important is timeliness to the treatment and disease progression?
How much of a concern is the problem to the requestor: does it seem that the requestor needs an immediate response?

Sometimes, respondents don’t know the answer to the question immediately.^10,11 Pharmacy staff will never be able to answer every question, but they can handle every question gracefully and provide a complete, accurate answer within a reasonable time. When they don’t know the whole answer, they should answer what they can immediately and tell the respondent that they need to do a little more research to answer the remainder. A PRO TIP is to tell the requestor when to expect an answer (and to be sure to follow through).^10-12

Obtain Sufficient Background Information

In simple words, this step is about getting to know the patient or problem or establishing a strong understanding of the patient’s relevant characteristics by obtaining background information. Since some patients have low health literacy, obtaining this information can be a challenge. However, narrowing the search to only include relevant information and filtering unnecessary information can make the process more efficient. This could be achieved by⁷

Asking targeted questions to patients. For example, instead of asking patients if they take their medication regularly (a closed-ended question that can be answered with yes or no), asking when they last took their medications provides a more precise answer.
Identifying avenues that can provide accurate information. For example, instead of asking patients what other medications they take, checking the local profile and/or contacting their community or specialty pharmacist to receive a medication list can be more accurate.
Reviewing any available records like medical charts or dispensing records.

Identify Extraneous Information

Obtaining complete information is important but ensuring that the information is pertinent to the question being asked is just as important.

Many times, DI requests are in-depth and require researching two or more sources before arriving at an answer. While conducting this search, ensure that the sources are relevant to the problem at hand. For example, if a study suggests that a medication is contraindicated in a patient, determine if the patient’s characteristics are similar to the study’s population. Furthermore, extraneous information could come from data gathering as well. For example, a patient may have multiple diseases, but they may not all impact the problem at hand. Making this distinction is important to provide a thorough and accurate answer.⁷

Answers to Pause and Ponder

Pharmacist DI request #1: Haloperidol is not an atypical antipsychotic; therefore, it would be eliminated immediately and the remaining atypical antipsychotics would be reviewed as outlined below:

Screen Request	Pertinent patient information: past medical conditions (uncontrolled diabetes, schizophrenia). Medications on tier 1 of patient's formulary: quetiapine, olanzapine, haloperidol, aripiprazole.
Reformulate Request	This is a therapeutics drug information request because the provider is looking for the best medication to treat the patient's schizophrenia without adding any contraindications to the patient's current medication list or concomitant medical conditions.
Formulate Response	The provider made the request in writing, so a written response is most appropriate. The SBAR format would succinctly and effectively convey the message. First, we conducted a Google search and a tertiary source search (PubMed) including the pertinent patient information and request. Our search read "effects of antipsychotics on obesity and diabetes." Through this, we determined that some antipsychotics lead to changes in metabolic activity. Because the patient has diabetes that is exacerbated by weight gain, the best choice is an antipsychotic that does not have a significant effect on the metabolism. After conducting a more thorough primary source search on the metabolic effects of antipsychotics, we found that the best drug would be aripiprazole. Additionally, monitoring the BMI and efficacy would be appropriate.
Assess Understanding	Provide the response in a professional and timely manner. Document the request to display accountability and in case there is a similar question in the future. Follow up with the requestor to access the outcomes and ensure that there are no lingering questions or concerns.

Pharmacist DI request #2: Off-label use of low-dose (25 to 100 mg) trazodone, a decades-old antidepressant with drowsiness as a side effect, is common.¹³ In fact, off-label usage for insomnia has surpassed its use for depression.¹⁴The American Academy of Sleep Medicine does not recommend trazodone because of limited supporting data. A 2018 Cochrane review found equivocal evidence supporting its short-term use for insomnia, but little data on long‐term safety and efficacy exists.¹⁵ The Beers Criteria doesn’t highlight trazodone as a potentially inappropriate medication in older adults, not because of evidence demonstrating safety, but because of lack of studies demonstrating harm. However, a retrospective cohort study found low-dose trazodone was no safer with respect to fall-related injury risk than benzodiazepines among 15,582 nursing home residents aged 66 years and older. Future studies need to confirm trazodone’s safety with respect to other risks such as dependence, withdrawal, and cognitive impairment.¹⁶

Technician DI request #1:

It would depend on the medication. Some medications, like amoxicillin, are refrigerated to preserve the taste while most others, such as insulin, are refrigerated to preserve the compound. The technician should ask what medication the patient is referring to and then look up the specific storage requirements for that medication. Some places where this information is available include Drugs.com (https://www.drugs.com/medical-answers/drugs-that-require-cold-storage-166784/) and (https://www.iehp.org/en/members/helpful-information-and-resources?target=emergency-safety). If the medication is not listed in these resources or the medication’s stability has possibly been compromised (such as exposure to extreme heat), the technician should consult the pharmacist.

Technician DI request #2:

It would vary depending on the medication. Some medications have specific coating that needs to stay intact to ensure proper drug delivery, and such medications should not be crushed. Other medications do not have such restrictions and can be crushed, split in half, sprinkled in foods like applesauce, or have a liquid formulation that can be considered as an alternative with a doctor’s approval. The technicians should ask, “What medication is your child taking so that I can look it up?” Information regarding which medications can be crushed can be found in the following website https://pharmacist.therapeuticresearch.com/Content/Segments/PRL/2014/Aug/Meds-That-Should-Not-Be-Crushed-7309. If the medication or the specific dosage form is not available on the list, the technician should ask the pharmacist to review the medication.

Recognize when to ask for additional support or information. While drug information requests can be challenging, involving other healthcare professionals to hear about their experiences with similar clinical situations can offer a new perspective. Some benefits of consulting with experts include formulating a patient-specific answer to the question whereas a study may be irrelevant. When the request requires analysis beyond the scope of a drug information search, it is appropriate to reach out to a professional. While this may take additional time, arriving at the correct answer is more important than to harm the patient unknowingly. And a PRO TIP is that if reaching out will mean you cannot answer the question in the time frame promised, contact the requestor and say you need more time and why.

REFORMULATING THE REQUEST

To ensure the core request is clear, the respondent will need to ask many questions, especially if requesters don’t know what question they need to ask. Before starting to research the answer, respondents need to gather information needed from the requestor. In addition, it’s prudent to identify resources the requestor has already consulted (and their reliability in case information needs to be corrected).

Categorize the Request

Requests can be based on complex patient specific cases, for educational purposes, or geared towards a decision-making process in medication therapy for a specific patient demographic. To fully optimize patient care and provide evidence-based recommendations, it is helpful to ask specific questions and consider all factors pertinent to the specific DI request. Categorizing the request can help stay on track, address all concerns, and point the respondent to the appropriate resources. Table 2 lists common categories and the questions that can clarify the request.

Table 2. Common DI Categories and Related Questions¹

DI Category	Related Questions
Allergy/Cross-reactivity	Does the patient have any documented allergies? What caused or is suspected to have caused the allergic reaction? When did the patient take the medication, and when did the reaction occur? What type of allergic reaction occurred? Is this a class or drug specific effect?
Alternative, or Complementary Medicine	Where did the patient obtain the medication? Why is the requestor taking or interested in taking the medication? What other medications or treatments are available?
ADR/Safety	What are the possible side effects? What monitoring parameters need to be considered?
Compatibility (Y-site, syringe, IV)	What solution will medication be used in? If applicable, how will the medications be administered?
Dosage/Route/Administration	What is the route of administration? What is the recommended therapeutic dose for pediatrics, adults, and geriatrics? How should the medication be taken (with/without food, with water, etc)
Drug Identification	What was the source of the medication (e.g., domestic or foreign)? What is the generic and brand name? Where did the medication come from?
Ingredients/Stability	What physical conditions exist? (Temperature, light protectant, storage duration, diluents) Are there IV admixture compatibility/non-admixture stability data available?
Interactions	What are the possible interactions between: ● Drug-drug ● Drug-food ● Drug-lab ● Drug allergy
Kinetics	What is the onset/half-life/duration? What are the serum levels? Is dialysis a consideration? What is the medication’s bioavailability?
Pharmacoeconomics	Are there other competitors on the market? Are there cheaper alternatives with the same therapeutic effects? What is the AWP pricing?
Pharmaceutics	What is the drug route of administration and drug dosage? What patient factors will affect the drug? Age, weight, gender, organ function, current medications
Pharmacology	What factors will affect drug metabolism and bioavailability?
Pregnancy/Lactation	What health conditions does the mother have? What medications is the mother currently taking? What is the current trimester? How long has the mother been taking the medication or expected to take this medication? Will the drug be present in breast milk? How will the drug affect the infant? What is the infant's age? What health conditions do the mother and infant have? Was the infant a full term or premature delivery?
Vaccinations	Is the vaccination appropriate for the patient? What are some side effects to monitor? When should the patient get the vaccination?
Therapeutics	What is the desired effect? Is the goal cure or prophylaxis? What previous medications and doses has the patient used? Is this medication being used for an FDA approved or off-label use?
Toxicity	What are possible sequelae? What management strategies are available?

Abbreviations: ADR = adverse drug reaction; AWP = Average Wholesale Price; FDA = Food Drug Administration; IV = Intravenous

Finding Reliable Sources

Being able to locate sources efficiently and correctly for a DI request is very important. Three main types of sources are available: primary, secondary, and tertiary.

A primary source is any original research found in journals. Examples of primary sources are trial results found in the New England Journal of Medicine (NEJM) or similar journals in which researchers use a trial design to answer a specific question. (Note that NEJM and similar journals also publish secondary source materials, too.) This is the strongest Limitations of using this evidence include lack of access to journals that require paid subscriptions and lack of good search skills to find relevant papers.
Secondary sources analyze, interpret, present, or restate information from primary sources. Textbooks, books and review articles, commentaries, guidelines, and Medline are examples of secondary sources.
Tertiary sources compile information from other sources and organize it. Lexicomp , Micromedex, and DynaMed are common tertiary sources for DI requests as they use information from Food and Drug Administration-approved complete prescribing information (package inserts) and clinical studies. One limitation to be aware of is these sources are not updated rapidly therefore the information could be old and outdated.

Determine the Best Source

When evaluating DI requests, in most cases the best course of action is to start with tertiary sources, such as textbooks or DI databases, when possible.¹ These platforms provide a starting point and often suggest a basic idea for the answer. For many DI requests such as dosage, half-life, or adverse effects, the tertiary resource may provide a sound answer. Requests asking to compare two medications’ efficacy or assess the appropriateness of an uncommon or off-label medication use may require further research. Databases that identify off-label use include Micromedex. In such cases, a primary source is the best resource. References sections of databases like DynaMed and Micromedex can be a great start for finding appropriate primary sources. Using search engines such as MEDLINE, PubMed or Google Scholar (scholargoogle.com) can provide access to relevant primary literature as well.¹Reviewing two to three sources is good practice for most drug information requests. Respondents must determine the relevance of the studies by evaluating if the trial size was large enough to be statistically reliable, if its findings were clinically significant, and if the patient population is similar to the patient.

Use General Search Engines Appropriately

Using general search engines like Google, and Microsoft Edge can be an acceptable starting point for a search. A metasearch engine is usually better. A metasearch engine is a platform that aggregates the results from multiple search engines and organizes them based on their relevance. Examples of metasearch engines include Dogpile, ixquick, and Metacrawler which aggregate information from sources like Google and Yahoo as well as videos posted on various platforms.

Researchers must consider the following factors when determining a source’s credibility¹⁷:

Is the information’s original source listed and reliable?
Does the funding for the site come from a sound source such as a university (.edu), an established patient advocacy organization or a professional society (.org), or a government-funded organization (.gov)?
How is the information presented and how is it supported?
Who wrote the article on the webpage? Is the author a credible healthcare provider or a journalist writing about a medical topic?
Is the information updated and verifiable with other sources?

Table 3 matches types of information and reliable sources to find information.

Table 3. Finding Reliable Sources for Drug Information Requests

Type of Request		Source
Alternative or Complementary medicine		Natural Medicine Comprehensive Database
ADR/Safety		Lexicomp, UpToDate, Micromedex*, Package Inserts
Compatibility		FDA-approved prescribing information, Trissel’s Stability of Compounded Formulations*
Dosage/Route/Administration		Complete prescribing information, Lexicomp, Micromedex, etc.
Drug Identification		Lexicomp* (Drug I.D) Drugs.com, WebMD Pill identifier, RxResouce.org (pill identification tool)
Ingredients/Stability		Complete prescribing information, Lexicomp*
Interactions	CYP	Complete prescribing information, Lexicomp*
	HIV	HIV Drug Interactions Clinicalinfo Drug Database
Kinetics		Complete prescribing information, Lexicomp*
Pharmacoeconomics		Studies published in pharmacoeconomics journals
Pharmaceutics		PubMed* and primary sources
Pharmacology		Lexicomp, Micromedex and could require further research with primary sources
Pregnancy/Lactation		LactMed
Regulatory		The Pharmacy Practice Act, Pharmacist's Manual
Therapeutics		Dynamed, UpToDate, DiPiro’s textbook
Toxicity		MSDS, PubChem, Micromedex*
Vaccinations		CDC vaccine and immunization schedule, Lexicomp
Veterinary Information		Plumb’s Veterinary Drug Handbook

*=sources requiring a subscription or payment

Abbreviations: ADR = Adverse Drug Reactions; CDC = Center for Disease Control and Prevention; CYP = Cytochrome P450; FDA = Food and Drug Administration; MSDS = Material Safety Data Sheet; HIV = Human immunodeficiency virus

Another relevant option that many healthcare professionals are considering for answering drug information requests is artificial intelligence (AI) platforms such as ChatGPT. While these seem to be able to provide responses that are based on data and research, the issue that users run into is the AI is not able to approach/appraise situations critically. While AI can provide information that may be or seem accurate, it is cannot assess the data that it uses to ensure that it is relevant to the situation or specific patient. Additionally, AI doesn’t cite its sources, meaning that it can be difficult to assess the appropriateness of the source. Last, it is important to realize that AI has sometimes provided wrong answers that could lead to patient harm and therefore need to be checked against reliable sources.

Figure 2 summarizes a typical drug information process.

Figure 2. The Drug Information Process

FORMULATE THE RESPONSE

Verbal responses tend to be easier for most people than written responses, but respondents should document every request. One simple rule should guide the response: Use principles of clear communication. Clear communication reduces risks of misinterpretation and increases the requestor’s understanding. It optimizes patient care. Clear, concise sentences that are short (fewer than 25 to 32 words) and straightforward create an ideal response.¹⁸ It is best to be comprehensive with adequate information and complete sentences that leave no confusion. Each statement should have a clear purpose with no extraneous information or unnecessary words. Respondents must paraphrase important information from accumulated data taken from reliable sources, while avoiding copying and pasting from other outside sources. The response must focus on the audience (the requestor) and the requestor’s background, remembering that different types of professionals have different education and focus.¹⁸

Organize and Evaluate Information

Organizing information makes research and presentation straightforward and simple for the audience to understand quickly. Templates are available to help keep information organized and formulated, but they have advantages and disadvantages.

Pros: Templates provide consistency that makes it easier for requesters to follow. (Saving your responses to DI requests is a PRO TIP, discussed in the SIDEBAR) Templates also provide an idea about how the completed presentation will look and reduce the time associated with creating the response. Some organizations provide templates for their employees. Lacking an approved template, respondents can find customizable templates from their workplace or university. Example templates found in the appendices show how useful templates can be. Templates can act as checklists to remember what should be included in a drug information response.
Cons: Many templates limit the amount of allowable customization or text, and respondents must be knowledgeable about editing templates. Templates may also limit the approach to the topic and limit the information to standard or predictable fields; this is a problem when the question is unique or unusual. It is important to understand that templates are guides in answering requests and are not restrictions.

Templates that can be used while answering drug information questions have different strengths and limitations. The choice of template can be dependent on the pharmacist’s preference as well as the type of drug information request. We reviewed the templates in the addendum and assessed their utility. Take a minute to look at them. How do your assessments compare to ours?

Template 1 located in Appendix 1:

Pros: Extensive prompts for what should be included in a drug information response. This format is very detailed which could be useful for less experienced users.

Cons: Could be too detailed to be used for a wide range of requests. It lacks space, so users will have to use it against a document that they have already created.

Template 2 located in Appendix 2:

Pros: This format displays the drug information request topic quickly, organizes patient information and the response, and includes references to use for evidence-based literature support. It is broad enough to be used for multiple types of requests. It could be especially helpful for pharmacists who receive a wide variety of requests as it allows them to focus and tailor responses appropriately.

Cons: Insufficient prompts or guidance responders, making it more suitable for experienced pharmacy staff. This would too broad for beginners or pharmacy students because it does not outline various aspects of drug information responses.

SIDEBAR: Saving FAQs for Future Use: The FAQ File^19,20

Pharmacy staff often notice that they receive the same or similar questions repeatedly. Each time a requestor asks the question, the respondent must answer again. When employees in the pharmacy discuss questions they receive, they may find that although each of them has only answered a specific question once or twice, collectively they are answering the same question often. A frequently asked question (FAQ) file has numerous advantages. It can

Save time for everyone including the requestor
Standardize the answer so that it is consistent each time staff answer the specific question
Provide the answer in clear language
Create an answer that technicians and students can give to requestors without asking the pharmacist to intervene
Refer requestors to web sites or documents for additional information

To develop a reliable FAQ file, pharmacy staff should take several steps:

Identify the questions that are asked frequently.
Develop a simple format for all FAQs. Usually, the actual question appears at the top of the documents, with the answer below.
Start small and ask one employee to draft the FAQ.
Have two or three people review the FAQ, including a pharmacist and at least one or two support personnel. Encourage reviewers to provide constructive criticism. If the FAQ usually comes from a colleague or patient, involve colleagues and patients in the review.
A good process for reviewing FAQs is to ask a reviewer to read to a certain point and then stop. The project coordinator should ask, “Can you tell me in your own words what you just read?” If the reviewer explains and the information is incorrect, the project coordinator should not correct the reviewer; rather, the project coordinator should make a note that the section needs work and why.
The project reviewer should ask additional, open-ended questions including
- What’s your general reaction to this draft FAQ?
- What did you like about this draft FAQ?
- What did you dislike about this draft FAQ?
- Is anything in this draft FAQ confusing?
- What would you do if you got this document?
- What do you think the writer was trying to do with this document?
- And here’s a PRO TIP: Often, people will not answer directly because they do not want to appear uneducated or picky. A way to circumvent this issue is to ask, “Thinking of other people you know who might get this document…”
  - What about the document might work well for them?
  - What about the document might cause them problems?
- Once the FAQ completes the process and is ready for “prime time,” save it in a format that cannot be edited (i.e. a PDF that is locked for editing) and upload it to a shared file or drive where all employees can access the document and print or clip it to an email when needed.

Finally, drugs and drug information change over time. Organizations that use FAQ files must schedule routine review (at least annually and more often if necessary) to ensure that the content in FAQ files remains current and correct.

Proofing and Editing Drafts

Proofing and editing written drafts entails first fact-checking the narrative and the sources used, and then reviewing the text to ensure it is clear and professional. The respondent must re-assess and re-evaluate each source and the information gathered. Asking other healthcare professionals who have expertise to contribute to or proofread the draft is smart. Collaborating with colleagues can be beneficial, especially in healthcare. The recent emphasis on interdisciplinary approaches reminds us that healthcare professionals from multiple backgrounds need to collaborate and exchange information more often than not. Colleagues can also help confirm or modify any information, while also giving feedback to learn how to better future drug information requests.

Once the data is confirmed as accurate, the last step is to double check for spelling and grammar errors and ensure the response is clear and concise. A skilled pharmacy technician is often an exceptional collaborator in this step.

Document, Document, Document

Documentation is helpful when pharmacy employees have to refer back to that specific topic on a similar drug information question or when colleagues have a similar request in the future. Documenting the response will aid as a reference point and could help clinicians in the future make decisions regarding patient care.²¹ Documentation will also display accountability and the respondent’s value to the organization and the interdisciplinary team. Many healthcare organizations have policies and procedures for documenting DI requests, and all staff should follow them if they exist.

ASSESS REQUESTOR’S UNDERSTANDING AND SATISFACTION

Following up after responding to a DI request is a professional action. The respondent should follow up with the requestor in a timely manner and assess the outcomes. If the requestor is not completely satisfied, the respondent can adjust the answer and recommendations appropriately.⁷ Follow-up will also reveal if the requestor has implemented the recommendation (and if it worked), provide feedback for potential modifications in future DI requests, and show professionalism and dedication to patient care. A PRO TIP is to document the follow-up and outcomes.

CONCLUSION

Pharmacy teams have serious responsibilities related to DI requests, which can cover a broad spectrum of topics and specialties. Pharmacists, pharmacy technicians, and pharmacy students should use a methodical approach, followed by documentation. As the ever-changing landscape of healthcare, medicine, and technology continues to advance, the providing drug information will remain an integral part of the pharmacist’s responsibilities.

Table 4 provides additional resources.

Table 4. Additional Resources

Systematic Approach to Answering Drug Information Requests This resource helps characterize the various types of drug information requests	https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/preceptor-toolkit/sicp-busy-day-systematic-approach-answering-drug-info-requests.ashx?la=en&hash=7C8B36648FAB999DE761D3AE37BFE48A847B8551
7 Tips on Improving Communication in Your Pharmacy This resource provides guidance on how best to speak with patients	https://www.pbahealth.com/elements/7-tips-on-improving-communication-in-your-pharmacy/
Formulating an Effective Response: A Structured Approach This resource provides strategies to answer formulated drug information requests.	https://accesspharmacy.mhmedical.com/content.aspx?bookid=2275&sectionid=177197497 :
ASHP Guidelines on the Pharmacist’s Role in Providing Drug Information This resource provides suggestions on how to answer a formulated drug information request.	https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacists-role-providing-drug-information.pdf
How To Evaluate Health Information on the Internet: Questions and Answers This resource provides approaches on how to find credible sources to answer drug information requests.	https://ods.od.nih.gov/HealthInformation/How_To_Evaluate_Health_Information_on_the_Internet_Questions_and_Answers.aspx

Templates:

Requirements checklist for drug information Response1 - UBC Blogs. Accessed July 3, 2023. https://blogs.ubc.ca/oeetoolbox/files/2019/01/Requirements-Checklist-for-Drug-Information-Response.pdf.

Drug Information Request and Response Form.; 2017. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/DIR-Example.pdf

PHRM Handbook. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/Drug-Information-Request-and-Response-Fillable-Form-.pdf

Pharmacy: Motivation to be the Best Drug Information Station

Pharmacists Post-test

After completing this education activity, pharmacists will be able to
1) Recognize key elements of a drug information request
2) Describe a typical process for researching drug information requests
3) Prioritize information in the final written response
4) Identify the best language to use based on the inquiring party’s needs

1. Which of the following describes a good practice in answering complicated drug information requests?
A. Reviewing at least two sources when looking for answers
B. Using a couple of metasearch engines (e.g., Dogplie)
C. Using tertiary sources (e.g., Micromedex, Lexicomp)

2. A patient approaches the community pharmacy counter asking about experiencing GI upset when taking his daily medications. His medications include metformin, prednisone and lisinopril. Which of the following is an appropriate targeted question to obtain key information?
A. Are you taking your medications at the correct times?
B. How are you taking your medications?
C. Are you taking your medications with food?

3. Which of the following are elements of screening a response to correctly identify the key elements in a drug information request?
A. Setting aside extraneous information to focus on pertinent information
B. Relying solely on the patient’s recollection of medical information
C. Asking closed-ended questions to extract targeted information

4. Which of the following correctly identifies the process of answering a drug information request?
A. Screen request for pertinent information, reformulate request, formulate response, assess understanding
B. Assess understanding, reformulate request, screen request for pertinent information, formulate response
C. Formulate response, reformulate request, access understanding, screen request for pertinent information

5. A doctor asks how many hours prior to dialysis medication X should be administered to ensure an optimal response. Which category would the question fall under?
A. ADR inquiry
B. Therapeutics
C. Kinetics

6. If asked a question about the dosing for atorvastatin for a 40-year-old patient recently diagnosed with dyslipidemia, which of the following sources would be the most appropriate place to look for the answer?
A. Natural medicine comprehensive database
B. LactMed
C. Lexicomp

7. Which of the following correctly pairs the appropriate language and the type of requestor who is asking for information?
A. Patient: “Possible adverse events include gastrointestinal upset and an increase frequency of bowel movements.”
B. Provider: “The patient may have a tummy ache and have to go to the bathroom to poop a lot.”
C. Nurse: “Patients who take this medication may develop some side effects including nausea and diarrhea”

8. Which of the following statements identifies the purpose of the “assess understanding” step
A. To gauge requestors’ satisfaction and determine if they implemented the recommendation or need further assistance
B. To test the requesters health literacy and attempt to match the language you use to the language they understand
C. To provide new information to requestors so that they have multiple options in case the first answer didn’t resolve their problem

9. You have been tasked with creating a general drug information template. Which of the following are important aspects to include in your template
A. Prior medical history; lab values; current medications
B. Patient’s education; reference authors; siblings’ ages
C. Patient’s age, financial status, current medications

10. A patient approaches the pharmacy stating that she left a refrigerated medication on her front porch for more than 24 hours. She asks if it is still safe to use the medication. Which of the following is the most efficient way to answer?
A. Google the name of the drug and look for a patient or nurse blog site
B. Look at the package insert for the medication in the pharmacy database
C. Find two the primary sources for the stability in various temperatures

Pharmacy: Motivation to be the Best Drug Information Station

Pharmacy Technician Post-test

After completing this education activity, pharmacy technician’s will be able to
1) Identify questions that are within the pharmacy technician’s scope of practice
2) Recognize tools and resources to use when attempting to answer a drug information question
3) Complete the steps to completing a drug information request that is within the pharmacy technician’s scope of practice

1. Which of the following questions would require counseling from a licensed pharmacist?
A. Do I store this liquid antibiotic at room temperature or refrigerate it?
B. Is there a less expensive generic or store brand for this product?
C. What other medications should I avoid taking with this prescription?

2. A patient approaches the community pharmacy counter asking about experiencing GI upset when taking his daily medications. His medications include metformin, prednisone, and lisinopril. Which of the following is an appropriate targeted question to obtain key information?
A. Are you taking your medications at the correct times?
B. How are you taking your medications?
C. Are you taking your medications with food?

3. When can pharmacy technicians answer questions and help customers find specific medications or classes of medications while staying within their scope of practice?
A. If information is clearly printed on the prescription label, on auxiliary labels, or in an FDA-approved Medication Guide.
B. If the supervising pharmacist is busy and will not have time to help a customer for at least 15 minutes to an hour.
C. When the technician does not like the specific customer and would like to see the customer leave as soon as possible

4. Which of the following correctly identifies the process of answering a drug information request?
A. Screen request for pertinent information, reformulate request, formulate response, assess understanding
B. Assess understanding, reformulate request, screen request for pertinent information response, formulate response
C. Formulate response, reformulate request, access understanding, screen request for pertinent information

5. A 58-year-old woman comes to the pharmacy counter and tells you she received her Shingrix vaccine two weeks ago and does not remember when she needs to come back for her next Shingrix dose. Where would a pharmacy technician be able to find information about vaccine scheduling to answer the patient’s question?
A. Trissel’s Stability Compendium
B. LactMed and lexicomp
C. CDC Vaccine and Immunization Schedule

6. According to the traffic-light-rule, what should the pharmacy staff member do after one minute of listening?
A. Pharmacy staff should let patients continue to talk because it’s unlikely they have disclosed enough information.
B. Pharmacy staff probably has enough information and should make note of comments or questions.
C. Pharmacy staff should be comfortable stopping the requestor politely or asking additional questions.

7. A mother is picking up her son’s antibiotic prescription and asks if there is a specific way that her son should take the medication. Where would you find this information about the route of administration for antibiotics?
a) PubMed
b) Pharmacists Manual
c) Lexicomp

10. A patient approaches the pharmacy stating that she left a refrigerated medication on her front porch for more than 24 hours. She asks if it is still safe to use the medication. Which of the following is most efficient way to answer?
A. Google the name of the drug and look for a patient or nurse blog site
B. Look at the package insert for the medication in the pharmacy database
C. Find two the primary sources for the stability in various temperatures

References

1. Systematic Approach to Answering Drug Information Requests Systematic Approach to Answering Drug Information Requests Step 1: Obtain Background Information. Accessed August 8, 2023. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/preceptor-toolkit/sicp-busy-day-systematic-approach-answering-drug-info-requests.ashx?la=en&hash=7C8B36648FAB999DE761D3AE37BFE48A847B8551
2. Understanding Your Scope of Practice as a Pharmacy Technician. Career Advice. Accessed March 25, 2023. https://www.careerstep.com/blog/news/understanding-your-scope-of-practice-as-a-pharmacy-technician/
3. Foster P. What You Can and Can’t Say to Customers as a Pharmacy Technician. October 28, 2016. Accessed March 25, 2023. https://www.pennfoster.edu/blog/2016/october/what-you-can-and-can-not-you-say-to-customers-as-a-pharmacy-technician
4. ASHP Guidelines on the Pharmacist’s Role in Providing Drug Information Background and Rationale. Accessed August 8, 2023. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacists-role-providing-drug-information.pdf
5. Martin SW. Strategies for Answering Your Customers’ Toughest Questions. Harvard Business Review. June 28, 2012. Accessed March 25, 2023. https://hbr.org/2012/06/handling-customers-toughest-qu
6. Nemko M. How to handle difficult clients. Psychology Today. February 25, 2021. Accessed March 25, 2023. https://www.psychologytoday.com/us/blog/how-do-life/202102/how-handle-difficult-clients
7. Malone PM, Witt BA, Malone MJ, Peterson DM. Formulating an Effective Response: A Structured Approach | Drug Information: A Guide for Pharmacists, 6e | AccessPharmacy | McGraw Hill Medical. Accessed August 8, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2275§ionid=177197497
8. Podder V, Lew V, Ghassemzadeh S. SOAP Notes. Published 2022. Accessed August 8, 2023. https://www.ncbi.nlm.nih.gov/books/NBK482263
9. Burgess A, van Diggele C, Roberts C, Mellis C. Teaching clinical handover with ISBAR. BMC Medical Education. 2020;20(2):1-8. doi:https://doi.org/10.1186/s12909-020-02285-0
https://bmcmededuc.biomedcentral.com/articles/10.1186/s12909-020-02285-0
10. Compassionate Geek. IT Customer Service Skills: What To Do When You Don’t Know The Answer To A Customer Question. Accessed March 25, 2023. https://compassionategeek.com/customer-service-skills-when-you-dont-know-the-answer/
11. Expert Panel Forbes Councils Member. Leaders: Nine Good Ways To Handle A Business Question You Don't Know The Answer To. June 7, 2021. Accessed March 25, 2023. https://www.forbes.com/sites/theyec/2021/06/07/leaders-nine-good-ways-to-handle-a-business-question-you-dont-know-the-answer-to/?sh=39d2b40823ba
12. Csizmadia A. Oops, I don’t know: How to respond to a customer’s question when you don’t know the answer. September 25, 2018. Accessed March 25, 2023. https://www.liveagent.com/blog/oops-i-don’t-know-how-to-respond-to-a-customers-question-when-you-don’t-know-the-answer/
13. Gill LL. Consumer Reports. Should You Take Trazodone for Insomnia? Accessed January 26, 2022. https://www.consumerreports.org/insomnia/trazodone-for-insomnia-should-you-take-a9455377183/
14. Jaffer KY, Chang T, Vanle B et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci 2017;14:24-34.
15. Everitt H, Baldwin DS, Stuart B et al. Antidepressants for insomnia in adults. Cochrane Database of Systematic Reviews 2018;5:CD010753.
16. Bronskill SE, Campitelli MA, Iaboni A et al. Low-dose trazodone, benzodiazepines, and fall-related injuries in nursing homes: a matched-cohort study. J Am Geriatr Soc 2018;66:1963-71.
17. How To Evaluate Health Information on the Internet: Questions and Answers. ods.od.nih.gov. National Institutes of Health. Published June 24, 2011. Accessed August 8, 2023. https://ods.od.nih.gov/HealthInformation/How_To_Evaluate_Health_Information_on_the_Internet_Questions_and_Answers.aspx
19. U.S. Department of Health & Human Services. National Institutes of Health Naional Cancer Institute. Making Health Communications Programs Work. Accessed March 25, 2023. https://www.cancer.gov/publications/health-communication/pink-book.pdf
18. Clear Writing Assessment. Centers for Disease Control and Prevention. Accessed match 25, 2023. https://www.cdc.gov/nceh/clearwriting/docs/Clear_Writing_Assessment-508.pdf
20. JIMDO. How to Write an FAQ Page–with Example. October 21, 2021. Accessed March 25, 2023. https://www.jimdo.com/blog/how-to-write-an-faq-page-with-examples/
21. 7 Steps to Respond to Drug Information Requests. Pharmacy Times. Accessed August 8, 2023. https://www.pharmacytimes.com/view/7-steps-to-respond-to-drug-information-requests

Set Your Ascites on Improving Patient Care: The Pharmacy Team’s Role in Hepatorenal Syndrome Management

Hepatorenal syndrome (HRS) is a specific type of kidney injury unique to patients with end stage liver disease, also known as cirrhosis. Patients with cirrhosis have scarred, stiff livers in which blood cannot flow through easily. Portal hypertension changes blood flow resulting in several consequences: ascites, esophageal varices, and HRS. The American Association for the Study of Liver Diseases guidelines describe two distinct forms of HRS. Therapies such as volume resuscitation (e.g., with crystalloids or albumin) and vasoconstrictors (e.g., norepinephrine or terlipressin) focus on restoring blood flow to the kidneys before they are irreparably injured. Sometimes, clinicians must select therapies based on availability of intensive care unit beds and monitoring equipment. Clinicians also need to consider factors when patients leave the hospital and are discharged to home. Pharmacists and pharmacy technicians who are familiar with the basics of HRS can help clinicians make appropriate choices, counsel patients thoroughly, and contribute to better patient outcomes.

INTRODUCTION

Hepatorenal syndrome (HRS), a type of kidney injury unique to patients with advanced liver disease, carries a grim prognosis. Therapies such as volume resuscitation (e.g., crystalloids or albumin) and vasoconstrictors (e.g., norepinephrine or terlipressin) focus on restoring blood flow to the kidneys before they are irreparably injured. Pharmacists and pharmacy technicians can play a crucial role in helping select and monitor therapies for treatment of this syndrome, and perhaps more importantly, by helping patients avoid developing HRS in the first place. By educating patients to avoid certain over the counter (OTC) medications that can worsen the condition (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), and teaching patients to monitor their diuretic use by weighing themselves daily and monitoring their blood pressure, engaged pharmacists and pharmacy technicians can make a large difference in their patients’ clinical outcomes.

HRS: A Complication of Cirrhosis

Cirrhosis, an advanced state of liver disease, is increasingly common and an important cause of mortality.¹ Globally, in 2017 the estimated incidence of people living with compensated cirrhosis was 112 million. In 2019, cirrhosis was associated with 2.4% of deaths worldwide.² Classically, cirrhosis in developed countries is most commonly due to hepatitis C infection and alcohol misuse.¹ However, over the past decade, the incidence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically with improvement in diagnostic criteria and screening. At the same time, treatment improvements for hepatitis B and C infections have decreased viral hepatitis-related deaths in some areas of the world. The COVID-19 pandemic has also had significant impact, with data collected from multiple countries showing a substantial increase in alcohol consumption, and an increase in alcohol-associated cirrhosis deaths.^2,3 Testing and treatment rates for hepatitis B and C declined internationally between January 2019 and December 2020,⁴ and treatment delays are predicted to lead to excess liver-related deaths.^2,5

PAUSE AND PONDER: How will the new hepatitis C direct-acting antivirals (e.g., elbasvir, glecaprevir, ledipasvir, pibrentasvir, sofosbuvir, velpatasvir, and voxilaprevir) change the landscape of HRS?

Although the causes of cirrhosis may be shifting, the transition from chronic liver disease to cirrhosis is generally the same. Chronic inflammation of the liver leads to fibrosis and scarring, causing structural and hemodynamic changes within the liver (Figure 1). One of the main consequences is development of portal hypertension. Portal hypertension results because the scarring of the liver makes it more difficult for blood to flow through it, leading to increased blood pressure in the portal vein as blood is delivered from the splanchnic organs (stomach, small intestine, colon, pancreas, and spleen) (Figure 2). The obstruction of blood flow through the portal vein additionally results in dilation of the splanchnic circulation as a compensatory mechanism aimed at restoring blood flow. In turn, increased blood flow to the splanchnic circulation worsens portal hypertension.¹

Figure 1. Stages of Liver Disease.

Figure 2. The splanchnic circulation. The splanchnic circulation describes blood flow to the abdominal organs. Blood from these “splanchnic” organs is delivered to the portal vein, and accounts for the majority of the blood flow to be processed by the liver.

Pathophysiology of HRS

Portal hypertension and the changes in blood flow that result are the main drivers of several consequences of cirrhosis. These complications include the development of ascites, espophageal varices, and HRS.

Ascites is fluid accumulation in the peritoneal cavity that commonly appears as abdominal swelling or bloat. A patient with significant ascites will often test positive for a “fluid wave.” That is, when a patient is lying flat and someone applies pressure to the abdominal midline, a clinician can tap one flank sharply, and an impulse or “shock wave” will travel through the fluid in the abdomen. The clinician will be able to be feel the tap on the other side.

Esophageal varices are enlarged veins in the esophagus that can lead to bleeding that commonly presents as “coffee ground” looking emesis (or vomitus) that is a result of the blood being digested in the stomach then regurgitated through the esophagus. In the case of HRS, the portal hypertension and splanchnic vessel dilation mean that blood tends to pool in the splanchnic circulation, decreasing effective arterial volume (i.e., a decreased amount of blood effectively perfusing organ tissue, including the kidneys). Additionally, the body activates various compensatory mechanisms aimed at increasing blood volume (e.g., the renin-angiotensin system and the sympathetic nervous system). This action is an attempt to restore effective blood volume, which leads to vasoconstriction of the kidney arterioles and further hypoperfusion of the kidney (Figure 3).⁶

Figure 3. Changes in blood flow with cirrhosis. The image on the left represents normal splanchnic and portal blood flow. The image on the right shows blood flow to a cirrhotic liver. Blood from the splanchnic organs meets increased resistance in the portal vein, leading to portal hypertension. The splanchnic arteries vasodilate which worsens portal hypertension and leads to decreased blood flow to the kidneys.

ABBREVIATIONS: ADH: antidiuretic hormone, IMA: inferior mesenteric artery, RAAS: renal angiotensin aldosterone system, RBF: renal blood flow, GFR: glomerular filtration rate, SMA: superior mesenteric artery

Prevalence and Prognosis

HRS is a type of acute kidney injury (AKI) that is unique to patients with decompensated cirrhosis. HRS occurs in the absence of hypovolemia or any structural changes to the kidney—in fact, the kidneys often function normally following liver transplantation.⁷HRS is common in patients with cirrhosis, and risk of development increases as the severity of cirrhosis and the duration with which the patient has had it increase. In one study of patients with cirrhosis and ascites, the incidence of HRS increased from 18% at one year to 39% after five years.⁸ The development of HRS is unfortunately associated with a very poor prognosis, and often the only way to reverse the kidney failure is to receive a liver transplant.⁷

Classification and Diagnosis

Two distinct forms of HRS have been described. According to the American Association for the Study of Liver Diseases (AASLD) guidelines⁹

Type 1 HRS is a rapid increase in creatinine (0.3 mg/dL or greater) within 48 hours or an increase in serum creatinine to levels that are at least 50% higher than the most recent baseline value measured within three months. It often has a precipitating factor, such as a bacterial infection, gastrointestinal bleeding, or over-diuresis. This type of HRS is more common and more severe, making up 75% of cases and having a median survival of one month.
Type 2 HRS takes a longer time to develop and is defined as an estimated glomerular filtration rate of less than 60 mL/minute/1.73m²for three months or more in the absence of other (structural) causes. This is the same definition used for all patients with chronic kidney disease (CKD). Type 2 HRS often co-occurs with other complications of cirrhosis (i.e., refractory ascites) and has a median survival of about seven months.⁸

In recent years the nomenclature has been updated so that type 1 HRS is referred to as HRS-AKI and type 2 is called HRS-CKD.^6,9

Sometimes it is hard to know that a patient with end-stage liver disease is in kidney failure. These patients may have decreased muscle mass, are prone to malnutrition, and may take diuretics to control volume status. All three of those factors make serum creatinine an unreliable surrogate measure of kidney function.¹⁰

In patients with cirrhosis and ascites who meet the criteria for AKI, the diagnosis of HRS-AKI becomes one of exclusion. Clinicians must attempt to rule out hypovolemia, shock, medication-induced AKI, and structural kidney injury. In the absence of these alternative causes for AKI, a diagnosis of HRS-AKI can be made, and treatment commenced as soon as possible, as early intervention is key to decreasing mortality.⁹

Sidebar: Why is serum creatinine unreliable in advanced liver disease?

In clinical practice, clinicians often estimate kidney function by measuring a patient’s serum creatinine and inputting the value into a kidney function estimating equation. Creatinine is a byproduct of creatine, an amino acid produced by the liver and released into the circulation to reach target tissues, such as muscle. Creatinine is released during normal muscle metabolism. It is used in kidney function estimates because the glomerulus filters it freely, and so theoretically the rate at which the kidneys clear creatinine should be similar to the glomerular filtration rate itself.

However, a patient’s serum creatinine value is not affected by glomerular filtration rate alone. A malfunctioning liver may produce lower amounts of creatinine’s precursor, creatine. Additionally, patients with cirrhosis may have decreased oral intake due to nausea, ascites, and/or ongoing alcohol use. This means they consume less creatine is consumed from the diet as well. Finally, since creatinine is a product of muscle tissue breakdown and patients with cirrhosis tend to have significantly reduced muscle mass, they may generate less creatinine from the creatine. The end result is a serum creatinine that is normal or even lower than that seen in healthy individuals.

Hence, kidney function estimates that rely on creatinine tend to overestimate kidney function in these patients and even small absolute increases in creatinine could represent an acute kidney injury.

PAUSE AND PONDER: Is there a better way to measure true kidney function in patients with end-stage liver disease?

Current and Emerging Therapies for HRS

Therapies used to treat HRS aim at removing the precipitating factor and increasing blood flow to the kidneys. First, clinicians must identify and treat the potential etiology leading to the decline in kidney function (e.g., antibiotic therapy in the treatment of an infection of ascites fluid called spontaneous bacterial peritonitis [SBP], proton pump inhibitors, and endoscopic intervention to stop a gastrointestinal bleed). Removing the cause is one of the most important factors in ensuring that the change in kidney function is not permanent.

Fundamentally the kidney receives insufficient blood flow secondary to a decrease in effective arterial blood flow, so initial therapy’s main goal is to improve the patient’s mean arterial pressure as soon as possible. The most common goal cited is to increase the patient’s mean arterial pressure (MAP) to greater than 65 mmHg to improve perfusion to target end organs, specifically the kidney.^11,12 The goal is to improve kidney function and give the patient additional time to secure a liver transplant or stabilize the end stage disease and decrease mortality. This continuing education activity will review the agents used to improve kidney function in the setting of HRS. Table 1 summarizes guideline recommendations for initial management of patients with HRS-AKI.

Table 1. Summary of Society Guidelines for Initial Management of HRS-AKI in the ICU^{9,22,23,32,33}
Society	HRS-AKI Definition	Volume expander	Vasopressor of choice	Target
American Association for the Surgery of Trauma 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause	Lactate ringers or Plasmalyte over Normal Saline; albumin 20-25% 1 gm/kg/day x 48 hours	Norepinephrine, Terlipressin	MAP > 65 mmHg, increased urine output
American Association for the Study of Liver Disease 2021	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause; use SCr values for the last 3 months prior to event to evaluate baseline	Albumin 1 gm/kg on day 1, then 40 to 50 gm daily while receiving vasopressor therapy	Terlipressin,* Norepinephrine 0.5 mg/h ; max 3 mg/h	Increase MAP by at least 10 mmHg above pre-treatment baseline or urine output >200 mL over 4 hours; albumin to maintain CVP between 4-10 mmHg; Continue treatment until SCr back to baseline up to 14 days; if SCr remains at or above pre-treatment values after 96 hours stop vasopressor therapy
European Association for the Study of the Liver 2010	Kidney failure in the setting of liver disease unexplained by another cause	Albumin 1 gm/kg/day (max 100 gm/day)	Terlipressin 1 mg every 4 to 6 hours in combination with albumin, if SCr does not improve by at least 30% in 72 hours increase dose to 2 mg every 4 hours	Increase in MAP by at least 5 mmHg by day 3
American Gastroenterological Association 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% from baseline or urine output is <0.5 mL/kg/hr for > 6 hours	Albumin 1 gm/kg/day x 48 hours, if no improvement continue 1 gm/kg x 1 day then 20 to 40 gm daily while receiving vasopressor therapy	Terlipressin 1 mg every 4 to 6 hours; increase to 2 mg every 4 to 6 hours if reduction in SCr < 25% by day 3 if available up to 14 days, alternative norepinephrine or midodrine/octreotide	Increase MAP by at least 10 mmHg or urine output by at least 50 mL/h for at least 2 hours, maintain priority for liver transplant if survive
*not approved in US at the time of guideline construction
ABBREVIATIONS: CVP = central venous pressure; MAP = mean arterial pressure; SCr = serum creatinine

PAUSE AND PONDER: When might these interventions be considered “too late?” What would you do then?

Crystalloids

Initial evaluation of patients includes an assessment of their effective arterial blood volume status. Early cessation of home medications that impact blood pressure or volume status, such as diuretics (e.g., spironolactone, furosemide) will allow a more accurate determination. If the patient’s effective arterial blood volume is not optimized, inadequate blood flow to the kidney can precipitate acute kidney injury in the setting of cirrhosis.

Crystalloids, such as normal saline and Lactated Ringer’s, stay within the intravascular space and provide appropriate initial fluid replacement. However, clinicians must provide fluid replacement (also referred to in this case as fluid resuscitation) carefully and with appropriate monitoring as patients can become volume overloaded. Patients with end stage liver disease have low albumin levels and tend to lack the oncotic pressure (a type of osmotic pressure induced by plasma proteins, especially albumin) required to keep crystalloids within the intravascular space. Even minimal resuscitation can produce significant peripheral edema and pulmonary edema, and worsen ascites.¹³

Pharmacists should provide support in appropriate monitoring of volume status and ensuring serum electrolytes are frequently obtained. Fluids may need to be stopped abruptly in response to volume overload to prevent hypervolemic hyponatremia (low sodium levels).¹⁴ Appropriate understanding of the patient’s intravascular volume status will determine if using albumin during resuscitation is appropriate.

Albumin

Patients with end-stage liver disease typically have reduced or low albumin levels because the liver is no longer able to manufacture these proteins. Reduced albumin decreases the circulating oncotic pressure which yields fluid leakage from blood vessels into other areas of the body (e.g., peritoneal space), reducing the arterial blood volume going to the kidney. This becomes especially apparent when a precipitating event such as a hemorrhage or infection occurs, which further decreases circulating blood volume. Clinicians often administer concentrated albumin (e.g., 25% or 25 grams/100 mL) every six to eight hours to increase the intravascular circulating blood volume. Albumin allows fluid to move from the interstitial spaces back into the blood stream and keeps exogenously administered crystalloids in the vessels, thereby increasing blood flow to the kidneys.¹² Clinicians should reserve concentrated albumin for patients with baseline low serum albumin (e.g., less than 3 mg/dL) who are also volume overloaded and limit them to just the amount that restores hemodynamic stability.¹⁵

Patients who have inadequate total body volume or those who have capillary leak (e.g., septic shock) may benefit from less concentrated (e.g., 5%) albumin infusions. A recent single center open-label, randomized study evaluated hypotensive patients with end-stage liver disease and compared volume replacement with albumin to normal saline.¹⁶ The primary outcome was to determine which approach could reverse a mean arterial pressure less than 65 mmHg more effectively within the first hours of resuscitation. Of note this trial excluded patients who needed immediate interventions, such as variceal bleed or vasopressor agents.¹⁷ The researchers randomized patients to receive 250 mL of 5% albumin over 30 minutes followed by 50 mL/hr for three hours or normal saline 30 mL/kg over 15 to 30 minutes followed by 100 mL/h over three hours. Albumin was more effective than normal saline in improving mean arterial pressure above 65 mmHg in the first hour (25.3% albumin vs 14.9% normal saline, p = 0.03) of resuscitation. The benefit continued over the next three hours (p < 0.001) and survival was also better in patients resuscitated with albumin than those treated with saline (43.5% vs 38.3%).^16,18 The researchers note that results are predicated on appropriate management of the underlying causes of hypotension (i.e., sepsis).

Albumin is expensive, can be and has been subject to shortages. It should be used with stewardship in end stage liver disease and HRS; however, the evidence for benefit is robust especially when combined with other modalities.¹⁶ It is important to understand the patient’s volume status and hemodynamic goals to select the appropriate concentration and frequency.^19,20 The AASLD Guidelines for the Diagnosis, Evaluation and Management of Ascites, Spontaneous Bacterial Peritonitis and HRS suggest that patients who present with HRS should receive 1 gram/kg albumin on day 1 and then 40 to 50 grams per day until kidney function improves and other therapies are no longer needed.^9,15 The daily dose may be reduced (e.g., 20 to 40 grams/day) if given in combination with vasopressor agents with a goal to maintain adequate volume. Clinicians sometimes use a surrogate measure of volume using a central venous catheter to measure central venous pressure (CVP), which reflects the amount of blood in the patient’s anterior vena cava and venous tone. In this case, a CVP goal between 10 and 15 mmHg is targeted.^10,21 Unfortunately CVP can be unreliable when ascites is present and clinicians may need to employ other invasive methods along with close monitoring for the development of pulmonary edema.^9,22,23

Ensuring albumin is available for patients with HRS is necessary. Some ways to aid centers in managing their supplies when shortages occur include limiting scheduled orders to 24 hours (e.g., 1 gram of 25% every 8 hours for 24 hours). Limiting “evergreen” orders to 24 hours will ensure clinicians assess patients appropriately before administering additional albumin and may prevent unappreciated volume overload. Also, standardized order sets will prevent use of partial vials, larger than needed vials (e.g., 250 mL or 500 mL) and inappropriate ordering of the incorrect concentration (e.g., 5% versus 25%). Teaching hospitals may also benefit from limiting albumin orders to certain clinical situations or diagnoses to avoid ubiquitous use for volume resuscitation in patients (e.g., trauma) who can be resuscitated with crystalloid.

Vasopressors

Vasopressors are given in combination with resuscitation, specifically albumin. The exogenous albumin facilitates adequate oncotic pressure to keep fluid in the vasculature, allowing vasopressors to constrict the vessels, increase mean arterial pressure, and supply fluid to the kidney. Vasopressors will be ineffective and can make kidney function worse if fluid in the vasculature is insufficient. Therefore, prescribers should only institute vasopressors along with or after volume resuscitation. The main adverse effects associated with any vasopressor therapy are related to ischemia (poor blood flow) in the peripheral limbs/tissues (e.g., fingertips, skin), gastrointestinal tract, or heart.⁹ Limited head-to-head trials exist to identify which agent or combination is the most effective in reversing HRS beyond early implementation of therapy in combination with albumin volume expansion. Table 2 summarizes the pros, cons, and considerations related to vasopressor agents used in the treatment of HRS.

Table 2. Vasopressor Agents Pros, Cons and Considerations
Medication	Pros	Cons	Considerations
Norepinephrine	Frequently used in the ICU setting, team comfort with monitoring for adverse effects and ease/experience with titration	May be less effective in hypothermia, pH dysregulation, continuous infusion	May require ICU setting, especially for acute titration; may require a central line
Terlipressin	Does not require a central line, or continuous infusion	Requires additional monitoring for ischemia which may require ICU level care to ensure safety	Requires monitoring for ischemic events
Octreotide	Can be given outside the ICU	Slow response, IV or subcutaneous administration	May be continued as an outpatient
Midodrine	Available as an oral agent, can be given outside the ICU	Slow response, only available as an oral agent; frequency of dosing	May be provided on discharge to help maintain blood pressure in the setting of hypotension

ABBREVIATIONS: ICU = intensive care unit; IV = intravenous

Norepinephrine

Norepinephrine is an exogenous catecholamine that targets alpha-1-adrenergic receptors which helps improve peripheral vascular resistance.²⁴ Norepinephrine has been used consistently in the United States (U.S.) for many years and has been the agent of choice until the recent approval of terlipressin. Norepinephrine’s limitation is that it can be less effective, as are other catecholamines, if patients have temperature or pH dysregulation. Appropriate resuscitation and correction of these variables can improve norepinephrine’s efficacy. A meta-analysis comparing the effectiveness of norepinephrine and terlipressin suggests that norepinephrine is as effective in increasing mean arterial pressure and reversal of kidney dysfunction.²⁴ The most frequent doses of norepinephrine cited in terlipressin head-to-head trials were between 0.5 to 3 mg/hour and/or 0.05 to 0.7 mcg/kg/minute titrated to increase mean arterial pressure 10 mmHg above baseline or increasing urine output to more than 200 mL/hour.²⁴ Clinicians must monitor norepinephrine administration carefully to prevent complications of vasoconstriction, such as cardiac or digital ischemia and therefore it is often restricted to the intensive care unit (ICU).²⁴

Terlipressin

Terlipressin is a prohormone of lysine-vasopressin, causing extended release of lysine-vasopressin and activation of V1 and V2 receptors allowing intermittent administration.²⁴ V1 receptors are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region. Activating V1 receptors constricts the splanchnic vessels (reducing delivery of blood flow to the portal vein, lowering portal pressure) which subsequently may improve blood flow to kidneys. Additionally, activation of the V2 receptors causes reabsorption of water in the kidney.^24,25 Terlipressin has been evaluated in several prospective, placebo-controlled clinical trials evaluating its efficacy in improving kidney function in HRS.¹⁸ Specifically, a recent prospective, randomized, double-blind controlled trial evaluated the effectiveness of terlipressin against placebo in combination with albumin in reversing HRS-AKI.²⁵ Terlipressin was more effective than placebo in reversing HRS (32% vs 17%, p < 0.006), but did yield more respiratory failure.²⁵ This trial was an impetus for U.S. Food and Drug Administration (FDA) approval of terlipressin in 2023.

The FDA approved terlipressin for rapid reduction in kidney function in the setting of cirrhosis with no other etiology, or reversal of HRS at a dose of 1 mg administered by intravenous bolus every six hours.¹⁰ If the patient’s serum creatinine fails to improve or increases within the first 96 hours then prescribers should discontinue terlipressin. If improvement is marginal (e.g., less than 30% from baseline) the dose can be increased to 2 mg every six hours.¹⁰ Therapy should be continued until the patient’s serum creatinine is 1.5 mg/dL or less for two days or a maximum of 14 days. Prescribers should use terlipressin with caution in patients with a history of ischemic conditions (e.g., cardiac, mesenteric).¹⁰ Terlipressin should not be used in patients who have a serum creatinine exceeding 5 mg/dL, in patients who are hypoxic (SpO₂less than 90%), or in patients who develop ischemia.^10,23

Terlipressin is often given outside the ICU and does not need continuous cardiac monitoring, which may make it desirable for longer term administration.¹⁰ Initial clinical trials compared norepinephrine continuous infusion (1 mcg/kg/minute increased every four hours to increase MAP by 10 mmHg) to terlipressin (1 mg every four hours; increased to 2 mg every four hours after three days) combined with albumin to maintain a CVP between 10 and 15 mmHg. These trials defined a complete response as an improvement in serum creatinine by at least 30% from baseline within 14 days of therapy. There was no difference in responders between norepinephrine and terlipressin (70% and 83%).^21,26,27 Therefore terlipressin’s benefit may lie in its intermittent dosing and ability to be administered outside the ICU.

Terlipressin’s most common adverse reactions (≥10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea. Terlipressin does have some additional considerations. It also has a boxed warning for possible serious or fatal respiratory failure, and clinicians need to monitor patients’ oxygen saturation carefully.²⁸

Terlipressin is supplied as a single dose 0.85 mg vial that must be stored under refrigeration and protected from light. Vials are reconstituted with 5 mL of sodium chloride and if not used, must be refrigerated and expire after 48 hours. The initial dose based on the approved labeling is one vial (0.85 mg) every six hours; which can be increased to two vials (1.7 mg) every six hours.²⁸

Midodrine and Octreotide

Midodrine and octreotide in combination have been a staple in the treatment of acute HRS for the last two decades in the U.S. Midodrine, an oral tablet, is like norepinephrine and produces vasoconstriction through alpha-1-adrenergic receptors.²⁴ Octreotide injection is a somatostatin analogue that decreases the release of vasodilatory substances and glucagon leading to vasoconstriction of the splanchnic circulation.²⁴ Because norepinephrine must be administered in the ICU, some healthcare facilities favor the combination of midodrine and octreotide. They also use midodrine/octreotide if they have not added terlipressin to their formularies.²³ Unfortunately, patients tend to respond slowly to the combination and the combination requires an extended duration for full benefit.²³ Octreotide cannot be given without midodrine but midodrine may be continued long-term (e.g., post-discharge) to maintain blood pressure in patients who are persistently hypotensive.^23,29

Researchers recently published a single center experience with standardizing administration of midodrine and octreotide for treatment of HRS at their center.²⁹ They wanted to standardize the use and dosing of albumin in combination with midodrine dosed at 2.5 to 10 mg three times daily and octreotide 50 to 100 mcg subcutaneously three times daily for 14 days and compare it to previous unstandardized prescribing. The goal was to obtain a full response: a serum creatinine within 0.3 mg/dL of baseline within seven to 14 days. Use of the standardized protocol was more effective in producing a full response than the historical unstandardized practice (25% vs 10%, p = 0.07).²⁹ Additionally, the researchers also found that fewer patients in the protocol group required kidney replacement therapy. Guidelines suggest initiating midodrine at a dose of 7.5 mg three times daily and titrating it to 12.5 mg three times daily in combination with octreotide.²³ The combination may still be in favor because it is a cost-effective alternative to terlipressin outside the ICU.

Midodrine is supplied in three tablet strengths which include 2.5 mg, 5 mg and 10 mg.³⁰ This allows outpatient tapering or adjustment if the patient experiences tachycardia. Unfortunately, it is short acting and requires three times daily dosing initially. In practice, dropping the middle of the day dose without reducing the strength allows improved adherence once the patient’s blood pressure is stable. Midodrine’s labeling includes a boxed warning for possible marked elevation of supine blood pressure, and clinicians should monitor supine and standing blood pressure regularly.³⁰

Octreotide is supplied in single dose ampules or multidose vials that must be stored in the refrigerator and protected from light; multidose vials must be discarded within 14 days. Octreotide is stable for 14 days at room temperature.³¹ Doses of 50 mcg to 100 mcg are administered every eight hours around the clock during the inpatient stay. If patients continue on octreotide as outpatients, the hospital pharmacy often needs to supply the doses. Patients and caregivers need appropriate education on subcutaneous injections and disposal of injection materials. In practice, the dose used in the hospital with success is often continued and not reduced to allow for the shortest duration possible. Octreotide subcutaneous injections on the outpatient side typically require additional insurance approval and preparation so discharge planning early is important.³¹

The Role of Pharmacists and Pharmacy Technicians in the Treatment of HRS

Pharmacists and pharmacy technicians can play an integral role in improving outcomes for patients presenting with or who have a history of HRS. Prevention is the key! Patients with end-stage liver disease should avoid medications that can precipitate HRS such as non-steroidal anti-inflammatory drugs and will require appropriate adjustment or discontinuation (if possible) of potential nephrotoxic agents (e.g., certain antimicrobials).

Ensuring patients with a history of spontaneous bacterial peritonitis (SBP) are on appropriate antibiotic prophylaxis can prevent subsequent SBP events that decrease blood flow to the kidneys. In the ambulatory setting, careful blood pressure monitoring and adjustment of blood pressure medications commonly used to treat portal hypertension (e.g., carvedilol), can ward off hypotensive events that can precipitate HRS.

Table 3 summarizes some lifestyle counseling tips that can help empower patients to play an active role in optimizing their care and preventing HRS episodes. Additionally, general management of concurrent disease states, such as heart failure and diabetes, can aid in maintaining optimal hemodynamics.

Table 3. Lifestyle Counseling Points for Patients with Cirrhosis at risk for HRS^35-37
Avoid alcohol	Even if the cause of liver damage isn’t drinking, alcohol use can increase the amount of damage. Patients who cease alcohol can experience dramatic improvements in some of the complications of cirrhosis.
Low sodium diet (especially in patients with ascites)	Limit sodium intake. This can be quite difficult, but if it can be done will help quite a bit with volume management. Patients with ascites are often asked to target ≤2 g/day. (For reference, 1 teaspoon of salt contains 2.3 g!)
Weight loss in patients who are overweight	Even a small amount of weight loss (e.g., a few pounds) can have a beneficial effect in patients with NAFLD or chronic HCV.
Protect yourself from infections	Patients need to stay up to date on vaccinations, wash their hands frequently, and avoid people who are sick.
Organize medication schedule	Patients with liver impairment can take seven to 10 medications a day—some administered multiple times a day. Investing in a strong adherence-enhancing system with alarm reminders or reminders from caregivers can be key.
Use OTC medications carefully	NSAIDs, such as ibuprofen and naproxen, can precipitate acute kidney injury.
Monitor weight daily (if on diuretic treatment)	Patients need to weigh themselves first thing in the morning after urinating. They should report significant weight changes to their providers (e.g., losing 1 pound or more a day or gaining more than 5 pounds in a week).

SIDEBAR: Did you know…acetaminophen can be a great choice for patient with HRS?³⁴

Imagine a situation where a medical intern is cross-covering in the medical intensive care unit and receives a call from a nurse about a patient with HRS. The patient is experiencing some mild pain and the nurse would like an as-needed medication to help.

Or…

You are working in the pharmacy and receive an order for oxycodone 5 mg every six hours as needed for mild pain. You are very concerned that this patient has both kidney and liver insufficiency and oxycodone is not a good choice but what else can you recommend?

What about acetaminophen?!?

Acetaminophen tends to have a bad rap mainly because it is in so many prescription and OTC products. It’s often in the news for causing liver toxicity. Oftentimes patients and providers do not think about the total acetaminophen exposure (the total daily dose of acetaminophen) and that is where the danger can come in. When the amount of acetaminophen’s toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) exceeds the liver’s glutathione stores, NAPQI starts to stick to hepatocytes (the liver’s main structural component). NAPQI acts like an antigen and stimulates the immune system to attack the liver.

Fortunately, it takes a significant amount administered at one time or consistently over several days to expend the glutathione stores. Doses up to 2,000 mg per day are safe and effective in most patients with severe liver insufficiency. (The maximum daily dose in healthy adults is 3900 mg.) Pharmacists and pharmacy technicians can ensure providers and patients with liver disease know they have alternative options. They can also help patients avoid reaching for a NSAID, especially if the patient has had a recent bout of HRS or if the patient is taking other medications that would suggest the presence of liver insufficiency (e.g., lactulose, rifaximin, norfloxacin). Remember prevention of HRS is the key!

When a hospital admits a patient, healthcare providers need to understand what the patient was taking at home and stop or continue the appropriate medications at the right doses. For example, prescribers should discontinue medications that could be reducing blood pressure (e.g., beta blockers and alpha beta blockers) on admission.^11,16 They need to consider adjusting home medications for kidney dysfunction and restarting medications needed to manage other complications of end-stage liver disease (e.g., lactulose for encephalopathy).

When prompt administration of resuscitation with albumin is needed, the team may need help selecting the appropriate concentration. Patients who are significantly volume overloaded but have fluid in the extravascular space (e.g., in the abdominal cavity) would likely benefit from concentrated (25%) albumin. With the multidisciplinary team, the pharmacy team needs to understand the patient’s volume status and goals of therapy. Helping teams develop protocols to treat HRS can aid in goal-directed therapy and allow quick implementation of pharmacologic interventions to improve blood flow to the kidneys.

At discharge pharmacists and pharmacy technicians must ensure that medications are appropriately adjusted for the patient’s current kidney and liver function after the acute event has resolved or stabilized. The pharmacy team should be involved in educating patients on how to organize their new medication regimens, how to monitor their responses to therapy and recognize common adverse effects, and how appropriate lifestyle changes can increase the effectiveness of therapy and help avoid the advanced complications of liver disease.

CONCLUSION

HRS is a common complication for patients with advanced liver disease and ascites. Patients are in a state of decreased effective arterial blood flow to the kidneys and other end organs, and kidney injury is easily precipitated by nephrotoxic agents, over-diuresis, or bacterial infection. Acute treatment is aimed at restoring blood flow to the kidneys with the use of volume resuscitation and splanchnic vasoconstrictors. Pharmacists and pharmacy technicians can identify medications that may worsen kidney function, and assist in the appropriate prescribing, monitoring, and stewardship of these agents. Additionally, appropriate patient education—empowering patients to monitor their fluid/blood pressure status and avoiding OTC medications that can worsen their condition or precipitate HRS—is key in optimizing patient outcomes.

Set Your Ascites on Improving Patient Care: The Pharmacy Team’s Role in HRS Management
Pharmacist post-test
JC is a 56-year-old patient with end-stage liver disease secondary to non-alcoholic steatohepatitis (NASH) who presents to the emergency department with her caregiver after she was found disoriented in the backyard overnight. An arterial line is placed and the initial mean arterial pressure is 40 mmHg with a central venous pressure of 3 mmHg.

Past Medical History:
• Type 2 diabetes
• NAFLD, biopsy proven six years ago
• variceal bleed last year
• ascites and recent worsening encephalopathy.
Vital signs:
• blood pressure 72/30 mmHg
• temperature 102.3 F (39 C)
• weight 56 kg, last weight 58 kg one week ago
• no urine output
Labs:
• Scr 3.8 mg/dL (Scr 0.7 mg/dL last week).
No signs of edema or ascites.
Current medications: pantoprazole 40 mg daily, furosemide 40 mg every other day, carvedilol 6.25 mg twice daily, lactulose 30 mL TID, glipizide 10 mg daily, citalopram 10 mg daily.

Please use the case above to answer the next 5 questions.

1. JC’s blood pressure is 80/50 mmHg in triage, an arterial line is placed and CVP is initially 3 mmHg. What is the most appropriate immediate intervention given this information?
A. Normal saline 500 mL bolus
B. Vasopressin 0.04 units/min continuous infusion
C. Midodrine 10 mg three times daily

2. During JC’s admission the team requests your evaluation of the patient’s home medications. Which home medication would you discontinue on admission?
A. Carvedilol
B. Lactulose
C. Citalopram

3. What should the patient’s goal mean arterial pressure (MAP) be?
A. Increase MAP by 30%
B. Decrease MAP to 30 mmHg
C. MAP of at least 65 mmHg

4. The team is trying to determine what dose and concentration of albumin to administer. Based on only the information in the case, which initial dose and concentration is the most appropriate?
A. 100 grams of 5% albumin
B. 60 grams of 25% albumin
C. 60 grams of 5% albumin

5. The hospital is currently on ICU diversion and no critical care beds are available, so she must be cared for on the internal medicine unit. That unit cannot manage central lines. What is the most appropriate regimen to improve the patient’s MAP in addition to the currently infusing albumin?
A. Terlipressin
B. Norepineprhine
C. Octreotide

6. A patient has received terlipressin 1 mg every 6 hours for the past four days and the patient’s serum creatinine has increased from 3.5 mg/dL to 5 mg/dL. How should terlipressin be adjusted?
A. Stop terlipressin
B. Increase terlipressin dose to 1 mg every four hours
C. Increase terlipression dose to 2 mg every six hours

7. Which of the following medications should be avoided in patient with hepatorenal syndrome and/or liver cirrhosis?
A. Acetaminophen
B. Naproxen
C. Guaifenesin

8. HR is a 53-year-old Hispanic male who presents from hepatology clinic with an acute rise in serum creatinine. Admission medication reconciliation notes that his primary care doctor recently started him on losartan, and his blood pressure was 74/52 mmHg on admission. Following hydration with normal saline and stopping all other offending medications, the doctor prescribes midodrine and octreotide. What hemodynamic change can you expect following initiation of midodrine?

A. Decrease in blood pressure
B. Increase in portal pressure
C. Increased blood pressure

9. Which of the following is the most accurate rationale for combining albumin with other agents that cause vasoconstriction to manage hepatorenal syndrome?

A. Exogenous albumin administration decreases intravascular oncotic pressure and allows for a decrease in mean arterial pressure when combined with vasoconstricting agents
B. When specifically used in the setting of infection, exogenous albumin administration allows for enhanced delivery of protein bound antimicrobials to their required site of action
C. Use of intravenous concentrated albumin allows fluid from the extravascular space to be pulled into the blood stream and increases blood volume and delivery to the kidney

10. Which of the following best describes the pathophysiology of HRS?
A. Increased blood flow to the kidney in the setting of splenic vasodilation
B. Decreased blood flow to the kidney in the setting of portal hypertension
C. Decreased blood flow to the kidney in the setting of splenic vasoconstriction

11. Which of the following is a definitive treatment required to resolve HRS?
A. Liver transplant
B. Kidney transplant
C. Portal vein transplant

12. Which of the following best describes the main difference between Type I HRS and Type II HRS?
A. Type 1 HRS is associated with a higher rise in serum creatinine (at least 0.3 mg/dL from baseline).
B. Type 1 HRS happens more quickly (increase in serum creatinine over the most recent baseline taken within the past three months).
C. Type 1 HRS shows the presence of structural kidney disease (e.g., polycystic kidney disease or glomerular, interstitial, or vascular diseases).

Set Your Ascites on Improving Patient Care: The Pharmacy Team’s Role in HRS Management
Pharmacy technician post-test
1. Which of the following is a reason that liver disease affects the kidneys?
A. Toxins that are cleared by the liver are toxic to the kidneys
B. The treatments for liver disease release nephrotoxins
C. Liver disease affects blood flow to the kidneys

2. Which of the following best describes main difference between Type I HRS and Type II HRS?
A. Type 1 HRS is associated with a higher rise in serum creatinine (at least 0.3 mg/dL from baseline) over any time period.
B. Type 1 HRS happens more quickly (increase in serum creatinine over most recent baseline taken within the past three months).
C. Type 1 HRS shows the presence of structural kidney disease (e.g., polycystic kidney disease or glomerular, interstitial, or vascular diseases).

3. A patient with a past medical history of cirrhosis and ascites comes into the pharmacy complaining of mild to moderate knee pain and asks for help picking an over-the-counter analgesic. Which of the following will the pharmacist most likely recommend because of safety concerns?
a. Naproxen
b. Low dose acetaminophen
c. Ibuprofen

4. A patient is picking up prescriptions for furosemide and spironolactone. Which of the following should the patient remember to do to prevent an over-diuresis that can precipitate HRS?
a. Weigh himself daily in the morning after he urinates; record his weights
b. Eat a high sodium diet; read labels carefully and aim for more than 2 grams/day
c. Practice good sleep hygiene; aim for an average 7 hours/night

5. JC is a 55-year-old patient admitted to the intensive care unit with worsening ascites and hepatorenal syndrome. His mean arterial pressure is 50 mmHg, and the ICU doctor orders IV crystalloids. Which home medication might the team want to discontinue?
A. Carvedilol
B. Lactulose
C. Citalopram

6. Which of the following is a definitive treatment required to resolve HRS?
A. Liver transplant
B. Kidney transplant
C. Portal vein transplant

7. Which of the following is a vasopressor of the splanchnic circulation?
A. Lactated ringers
B. Terlipressin
C. Albumin

8. Which of the following is the most accurate rationale for combining albumin with other agents that cause vasoconstriction in the management of hepatorenal syndrome?
A. Exogenous albumin administration decreases intravascular oncotic pressure and allows for a decrease in mean arterial pressure when combined with vasoconstricting medications
B. When specifically used in the setting of infection, albumin allows for enhanced delivery of protein bound antimicrobials to their required site of action
C. Use of intravenous concentrated albumin pulls fluid from the extravascular space into the blood stream and increases blood volume and delivery to the kidney

9. What is a drawback to the use of midodrine and octreotide in the treatment of HRS?
A. It constricts the splanchnic circulation.
B. It was not available in the United States until 2023.
C. It takes an extended number of days for full benefit.

10. Which of the following medications needs to be administered in the intensive care unit?
A. Albumin
B. Norepinephrine
C. Octreotide

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7. Arroyo V. The liver and the kidney: mutual clearance or mixed intoxication. Contrib Nephrol. 2007;156:17-23.
8. Ginès A, Escorsell A, Ginès P, Saló J, Jiménez W, Inglada L, Navasa M, Clària J, Rimola A, Arroyo V, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology. 1993 Jul;105(1):229-36.
9. Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, Wong F, Kim WR. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug;74(2):1014-1048.
10. Wong F, Kwo P. Practical Management of HRS-AKI in the Era of Terlipressin: What the Gastroenterologist Needs to Know. Am J Gastroenterol 2023 Jun 1;118(6):915-920.
11. Chandna S, Zarate ER, Gallegos-Orozco JF. Management of Decompensated Cirrhosis and Associated Syndromes. Surg Clin North Am. 2022 Feb;102(1):117-137.
12. Patidar KR, Peng JL, Pike F, et al. Associations Between Mean Arterial Pressure and Poor ICU Outcomes in Critically Ill Patients With Cirrhosis: Is 65 The Sweet Spot? Crit Care Med. 2020 Sep;48(9):e753-e760.
13. Francoz C, Durand F, Kahn JA, Genyk YS, Nadim MK. Hepatorenal Syndrome. Clin J Am Soc Nephrol. 2019 May 7;14(5):774-781.
14. Maynard E. Decompensated Cirrhosis and Fluid Resuscitation. Surg Clin North Am. 2017 Dec;97(6):1419-1424.
15. Nanchal R, Subramanian R, Karvellas CJ, et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary, and Renal Considerations. Crit Care Med. 2020 Mar;48(3):e173-e191.
16. Philips CA, Maiwall R, Sharma MK, et al. Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): a randomized controlled trial. Hepatol Int. 2021 Aug;15(4):983-994.
17. Cullaro G, Kanduri SR, Velez JCQ. Acute Kidney Injury in Patients with Liver Disease. Clin J Am Soc Nephrol. 2022 Nov;17(11):1674-1684.
18. Mujtaba MA, Gamilla-Crudo AK, Merwat SN, Hussain SA, Kueht M, Karim A, Khattak MW, Rooney PJ, Jamil K. Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older. Ann Hepatol. 2023, Vol. 28, p. 101126.
19. Kugelmas M, Loftus M, Owen EJ, Wadei H, Saab S. Expert perspectives for the pharmacist on facilitating and improving the use of albumin in cirrhosis. Am J Health Syst Pharm. 2023, Vol. epub.
20. Zheng X, Bai Z, Wang T, et al. Human Albumin Infusion for the Management of Liver Cirrhosis and Its Complications: An Overview of Major Findings from Meta-analyses. Adv Ther. 2023, Vol. 40, pp. 1494-1529.
21. Nassar Junior AP, Farias AQ, D' Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One. 2014, Vol. 9, p. e107466.
22. Seshadri A, Appelbaum R, Carmichael SP 2nd, et al. Management of Decompensated Cirrhosis in the Surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document. Trauma Surg Acute Care Open. 2022, Vol. 7, p. e000936.
23. Flamm SL, Wong F, Ahn J, Kamath PS. AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review. Clin Gastroenterol Hepatol. 2022, Vol. 20, pp. 2702-2716.
24. Flamm SL, Brown K, Wadei HM, Brown RS, Kugelmas M, et al. The Current Management of Hepatorenal Syndrome–Acute Kidney Injury in the United States and the Potential of Terlipressin. Liver Transplantation . 2021, Vol. 27, pp. 1191-1202.
25. Wong F, Curry MP, Reddy KR, Rubin RA, Porayko MK, Gonzalez SA, et al. Terlipressin plus albumin for the treatment of hepatorenal syndrome type 1. N Engl J Med 2021;384:818-828. N Engl J Med. 2021, Vol. 384, pp. 818-828.
26. Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia MT, Martini S, Balzola F, Morgando A, Rizzetto M, Marzano A. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007, Vol. 47, pp. 499-505.
27. Martín-Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, Soriano G, Terra C, Fábrega E, Arroyo V, Rodés J, Ginès P and Investigators, TAHRS. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008, Vol. 134, pp. 1352-1359.
28. Terlivaz [package insert]. Mallinckrodt Pharmaceuticals;2023.
29. Hiruy A, Nelson J, Zori A, et al. Standardized approach of albumin, midodrine and octreotide on hepatorenal syndrome treatment response rate. Eur J Gastroenterol Hepatol. 2021, Vol. 33, pp. 102-106.
30. Midodrine [package insert]. Upsher-Smith Laboratories; 2020.
31. Octreotide Acetate Inejction [package insert]. Fresenius Kabi; 2022.
32. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417.
33. Pitre T, Kiflen M, Helmeczi W, et al. The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis. Crit Care Med. 2022 Oct 1;50(10):1419-1429.
34. Rogal SS, Hansen L, Patel A, Ufere NN, Verma M, Woodrell CD, Kanwal F. AASLD Practice Guidance: Palliative care and symptom-based management in decompensated cirrhosis. Hepatology. 2022 Sep;76(3):819-853.
35. Nobili V, Carter-Kent C, Feldstein AE. The role of lifestyle changes in the management of chronic liver disease. BMC Med. 2011 Jun 6;9:70.
36. Saleh ZM, Bloom PP, Grzyb K, Tapper EB. How Do Patients With Cirrhosis and Their Caregivers Learn About and Manage Their Health? A Review and Qualitative Study. Hepatol Commun. 2020 Nov 17;5(2):168-176.
37. US Department of Veterans Affairs. Ascites due to Cirrhosis. 2018. https://www.hepatitis.va.gov/pdf/ascites-fact-sheet.pdf Accessed 6/30/2023.

The Nitty Gritty: Dry Eye Guidance for the Pharmacy Team

Dry eye disease (DED) is a multifactorial condition affecting the ocular surface and tear function. Symptoms include burning, itching, and watery eyes. DED affects millions of people in the United States. Many underlying factors contribute to DED making therapeutic management difficult. Left untreated, DED can result in visual changes affecting everyday activities such as reading and driving. Simple environmental changes often help alleviate symptoms. Before seeking healthcare professional assistance, many people self-treat with over-the-counter artificial tear products, leading to high costs and frustration. Treatment involves patient education, environmental and lifestyle modifications, topically applied products, and, in severe cases, surgical procedures. Several recently approved products offer alternative treatment approaches. A knowledgeable, informed pharmacy team is prepared to counsel patients on product choice and to make appropriate referrals contributing to better patient outcomes.

INTRODUCTION

The feeling of grit under the eyelids is uncomfortable, annoying, and frustrating and can pose a serious health issue. This feeling, often accompanied by burning, itching, redness, and visual disturbances, is a symptom of keratoconjunctivitis sicca, otherwise known as dry eye disease (DED). At its simplest, DED is inflammation of the cornea and conjunctiva from tear hyperosmolarity (higher concentration of solutes like salts, sugars, or other dissolved particles) and tissue dryness. Left untreated, DED may result in severe eye inflammation, corneal ulcers, and vision loss.¹

DED affects approximately 16.4 million people, or 6.8% of the United States (U.S.) adult population.^2,3 DED is likely underreported and underdiagnosed, with estimates as high as 22.9 million adults experiencing symptoms.² Researchers estimate DED’s global prevalence is as high as 50%.⁴

Despite this prevalence, experts began to recognize DED as a disease state only about 30 years ago.^5,6 Initially described as a component of Sjogren’s syndrome (an autoimmune disease involving tear and saliva glands), DED emerged as a separate condition as ocular surface study progressed. The National Eye Institute first defined DED in 1995.¹

The Tear Film and Ocular Surface Society (TFOS) is a non-profit organization focused on eye health research and education.⁵ In 2015, the Dry Eye Workshop II (DEWS II), organized by TFOS, examined multiple aspects of DED. The workshop updated the definition, diagnosis, and classification of DED, the disease’s impact, therapeutic management options, and clinical trial design.⁵

TFOS DEWS II defines DED as "… a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles."⁵ In simpler terms, DED occurs when the tear film, which keeps the eyes moist, becomes imbalanced, leading to problems like tear film instability, high concentration of substances in the tears, inflammation and damage on eye surface, and abnormal nerve sensations.

Many risk factors contribute to DED development (Table 1). Women are two to three times more likely to develop DED than men.^3,4 Risk of developing DED increases with age. Adults aged 50 or older are three times more likely to develop symptoms than those 18 to 49 years old.^2,3 However, DED’s incidence is rising steadily in the younger population, possibly due to increased disease awareness.³ Digital device use may also contribute. Studies show that using digital devices decreases blink rate and increases incomplete blinks, leading to ocular surface dryness and, ultimately, DED.^4.7

Table 1. Dry Eye Disease Risk Factors^1,4,5

Modifiable

Non-modifiable

Androgen deficiency

Computer use

Contact lens wear

Environment

Medications

Age ≥ 50 years

Asian race

Connective tissue diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus)

Diabetes

Female sex

Meibomian gland dysfunction

DED impacts the American economy significantly. Several factors contribute to DED burden: direct costs of medical care, the impact of lost productivity, and the associated quality of life burden. In the U.S., estimates of direct medical costs exceed $3.84 billion, fueled by healthcare professional visits, pharmacologic therapies, and surgical procedures.^4,8 The cost of lost productivity (i.e., time spent seeking and receiving treatment, avoidance of aggravating work environments, and inability to perform work due to visual changes) is even more substantial. One study estimates that these indirect costs total $11,302 per patient annually.⁸ If more than 16 million people have DED, that totals more than $150 billion annually.^4,8

Beyond monetary costs associated with DED, the disease also affects vision-related quality of life (VR-QoL). As DED progresses, visual quality decreases. Individuals with DED are three times more likely to report visual difficulties than those without.⁴ This impacts many daily activities such as reading, driving, watching television, and smartphone use.⁴ DED-associated pain and discomfort, along with difficulty in activities of daily living, impact mental health negatively.⁸ A 2021 study examined self-reported health status and psychological burden in patients with DED. The study associated DED with having a negative self-perception of health status and experiencing increased psychological stress.⁹

A Deeper Look at DED

A better understanding of DED requires review of the surface anatomy of a healthy eye (see Figure 1). The eye's surface consists of the ocular surface and ocular adnexa (accessory anatomical parts).¹⁰ The ocular surface includes the cornea, conjunctiva (including goblet cells), and tear film. The ocular adnexa includes the eyelids, lacrimal and meibomian glands, tear ducts, and the connecting muscles and nerves.¹⁰

Figure 1. Eye Surface Anatomy and Tear Film Formation

Tears lubricate the eye, and the tear film—which provides nutrients and moisture, removes microbes, and smooths the ocular surface—has three layers^10,11:

Outermost lipid layer, produced by meibomian glands
Aqueous layer, produced by the lacrimal gland
Innermost mucin layer, produced by goblet cells

Tear film instability, primarily increased tear osmolarity, leads to ocular surface damage in DED.⁷ DED's categorization is based on the mechanism leading to tear hyperosmolarity. In aqueous deficient dry eye disease (ADDE), decreased tear secretion increases tear film osmolarity. Increased evaporation of tears leads to hyperosmolarity in (you guessed it) evaporative dry eye disease (EDE).⁵

ADDE is further categorized based on the underlying cause: Sjogren’s Syndrome or non-Sjogren’s syndrome. As mentioned, Sjogren’s syndrome is an autoimmune disease attacking the salivary and lacrimal glands resulting in dry mouth and eyes. Non-Sjogren’s syndrome ADDE has various causes, including lacrimal deficiency, lacrimal gland duct obstruction, and systemic drugs. These mechanisms decrease tear secretion, resulting in tear hyperosmolarity.^5,10

Meibomian gland dysfunction (MGD) is the primary cause of EDE.^12,13 Meibomian glands line the inside of the upper and lower eyelid. Lipid secretion by meibomian glands forms a coating on the aqueous layer, impeding tear evaporation and providing protection against environmental irritants. Risk factors for MGD include aging, hormonal changes, contact lens wear, diet, and systemic and topical medications.¹³

Separation of DED into ADDE and EDE implies mutual exclusivity, but many patients presenting with DED exhibit characteristics of both. Recent evidence indicates the two classifications co-exist, with more patients presenting with EDE due to MGD.^6,14,15 Regardless of the subtype or mechanism, the result is a vicious, self-perpetuating cycle of inflammation.^6,16 Tear film hyperosmolarity triggers an innate inflammatory immune response, activating CD4+ T-cells. This leads to conjunctival and corneal cell death and impaired lacrimal gland function, further decreasing tear production.^16,17 This further increases tear hyperosmolarity, which continues the cycle.

Diagnosing DED is problematic due to its multi-factorial nature and inconsistent symptom presentation. Exploring differential diagnoses using triaging questions is crucial to exclude diseases that mimic DED, including allergic, bacterial, or viral conjunctivitis; blepharitis; and rheumatic disorders.^5,18 A thorough patient history screens for risk factors such as smoking, contact lens wear, and certain systemic and topical medications. Several questionnaires also exist to help clinicians screen for DED. The Dry Eye Disease Questionnaire (DEQ-5) contains five items asking patients to rate the frequency of eye discomfort, eye dryness, and watery eyes during a typical day.¹⁸ The Ocular Surface Disease Index (OSDI) is another popular questionnaire. The OSDI questionnaire asks a series of 12 questions assessing eye symptoms, vision issues (e.g., reading, driving), and environmental conditions.¹⁸

Patients with positive questionnaire results should progress to a more detailed tear film and ocular surface examination. A positive result in any of the following tests is diagnostic of DED¹⁸:

Tear breakup time (TBUT): There are two methods for measuring TBUT, using fluorescein dye or illumination of the cornea. Both measure how long it takes for tears to break up after a blink. Lower TBUT scores indicate tear instability.
Osmolarity: Clinicians use a device with a test strip to gain a sample of the tear film from both eyes to check tear osmolarity. An osmolarity of 308 mOsm/L or greater in either eye or a difference of more than 8 mOsm/L between the eyes is diagnostic of DED.
Ocular surface staining: After applying dye to the lower eyelid’s inner lining, clinicians examine the ocular surface for missing or damaged epithelial cells. Positive scores range from five to nine spots depending on the dye used.

Clinicians also commonly deploy the Schirmer test to evaluate the eye’s ability to produce tears. A notched paper strip placed over the lower eyelid stimulates tear production during the test. After five minutes, a length of wetting greater than 10 mm indicates normal tear function. Values less than 5 mm signify tear insufficiency.¹⁸

Pause and ponder: How would vision loss affect your everyday life?

Treatment Goals

Treatment goals for DED are to decrease ocular inflammation and restore ocular surface homeostasis (balance). DED's complexity and heterogeneous presentation necessitate an individualized approach. TFOS DEWS II recommendations emphasize identifying the disease’s root cause to determine an appropriate management approach.¹⁴ From there, the report outlines a stepwise, flexible approach to guide treatment based on patient-specific disease etiology and severity.¹⁴ Table 2 briefly summarizes recommended management steps.

Table 2. Treatment Steps in DED Management¹⁴

Step 1:

· Education

· Environmental modifications

· Lifestyle modifications

· Dietary supplementation

· Eyelid hygiene

· Medication review

· Artificial Tears

Step 2:

· Preservative-free artificial tears

· Prescription therapy

· Tear Conservation

· Overnight treatments

· In-office treatments

Step 3:

· Tear stimulation

· Biological tear substitutes

· Therapeutic contact lenses

Step 4:

· Prescription therapy

· Surgical intervention

NON-PHARMACOLOGIC TREATMENT

One of the first steps, patient education, is essential for successful disease management.¹⁴ Patient education starts with thoroughly explaining DED’s chronic nature, including the ongoing, often long-term nature of therapeutic management. Discussing the patient’s home and work environment during the session may identify contributing factors.¹⁴ The environment affects overall health and well-being. Air pollution, low humidity, high altitude, and wind contribute to DED development.¹⁴ Adding an air humidifier inside or using protective eyeglasses outside can help mitigate DED symptoms. Other strategies include minimizing exposure to digital screens, cigarette smoke, and air conditioning.¹⁹

Proper lid hygiene is important in managing many eye conditions, including DED.¹⁴ Patients can use a cotton swab to scrub the eyelid with a dilute solution of baby shampoo to keep the area free of crusty build-up and environmental contaminants. Warm eye compresses also promote good lid hygiene and help alleviate DED symptoms. Unfortunately, lid hygiene adherence is poor, with estimates of just over 50% adherence at six weeks.¹⁴ Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

Identifying medications that may contribute to DED is an important task for pharmacy staff. Many medication classes produce drying effects on the body, intentionally or as an adverse effect.^14,19 Table 3 lists examples of medications that may worsen DED. Pharmacists and pharmacy technicians should review patient profiles to identify drying medications, including ophthalmic formulations, as medications for glaucoma (an eye condition causing progressive vision loss) may contribute to DED.¹⁴ Mitigating options to consider include changing the route of administration from oral to topical, substituting with a therapeutic alternative, and adjusting doses.¹⁴

Table 3. Examples of Medications that Worsen Dry Eye Disease^14,19

Drug Class	Examples
Antihistamines and decongestants	Chlorpheniramine Diphenhydramine Fexofenadine Loratadine Pseudoephedrine
Antidepressants · TCA · SSRI · SNRI	Amitriptyline Citalopram Duloxetine Fluoxetine Sertraline Venlafaxine
Anti-Parkinson’s	Levodopa
Antipsychotics	Aripiprazole Perphenazine Quetiapine
Beta-blockers	Atenolol Carvedilol Metoprolol Propranolol
Diuretics	Furosemide Hydrochlorothiazide
Proton pump inhibitors	Omeprazole Pantoprazole
Hormone therapy	Estrogen

DED = dry eye disease; TCA = tricyclic antidepressants; SSRI = serotonin-selective reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor

Diet and Nutrition

An emerging body of evidence suggests that certain diet changes and nutritional supplementation may play a role in DED treatment. Dehydration increases tear osmolarity, so maintaining adequate hydration is important to disease control.¹⁴ Lactoferrin is an anti-inflammatory glycoprotein found in natural tears. Studies have found decreased lactoferrin levels in patients with DED leading researchers to the explore lactoferrin topical application and oral supplementation as treatment for the condition. One study found improved dry eye symptoms and tear film stability in patients taking an oral lactoferrin supplement.²⁰ Oral lactoferrin is available as a supplement in many retail locations.

Supplementation with omega-3 fatty acids also shows potential in DED. Omega-3 fatty acids block proinflammatory substances and are essential for ocular surface homeostasis.¹⁴ Some studies have found that omega-3 fatty acid supplementation improves TBUT and Schirmer scores.^21,22 Conversely, The Dry Eye Assessment and Management (DREAM) trial reported no difference between groups receiving omega-3 fatty acids and placebo.²³ While oral omega-3 fatty acids show benefit for some patients, further study is necessary. These conflicting results prompted studies for alternative administration routes. Topical application of omega-3 fatty acids shows promise. A systematic review of 10 studies (five in animals and five in humans) showed overall improvement in ocular surface staining and TBUT.²⁴ Further study is necessary to evaluate long-term efficacy and optimize dosage and delivery formulations.

Artificial Tears

Patients often attempt self-treatment before seeking healthcare professional assistance. Tear replacement with artificial tear (AT) formulations is essential for patient comfort and a mainstay of initial and ongoing therapy. Global sales of AT reached $2.64 billion in 2019, and experts predict this to reach $4.30 billion by 2027.²⁵ Many AT products line the pharmacy shelves, all touting their ability to lubricate the eye. Faced with the confusing array of products, patients often employ a trial-and-error approach for AT selection, leading to high costs and frustration. Knowing the differences between ATs enhances the pharmacy team’s ability to counsel patients effectively.

AT supplementation is generally safe and well tolerated and associated adverse effects are mild, including blurred vision and ocular discomfort.¹⁴ Most ATs are water-based with viscosity-enhancing agents added for lubrication. Osmolarity, viscosity, and pH vary between products. Table 4 describes the components of AT products and their functions.

Table 4. Components of Artificial Tear Products^11,14,26

Component	Purpose	Examples
Viscosity-enhancing agents (lubricants)	Aid lubrication Increase tear film thickness Protect ocular surface Promote tear retention Improve goblet cell density	Carbomer 940 (polyacrylic acid) Carboxymethyl cellulose (CMC) Dextran Glycerin Hyaluronic acid (HA) Hydroxypropyl-guar (HP-guar) Hydroxypropyl methylcellulose (HPMC) Polyvinyl alcohol Polyvinylpyrrolidone Polyethylene glycol (PEG)
Lipids	Restore the lipid layer Increase lipid layer thickness Prevent evaporation	Mineral oil Castor oil Flaxseed oil
Osmoprotectants	Balance osmotic pressure	Trehalose Levocarnitine Erythritol Betaine
Preservatives	Prevent microbial growth in multi-dose formulations	Benzalkonium chloride (BAK) Sodium chlorite Sodium perborate
Buffers	Control pH	Sodium borate Sodium citrate Sodium phosphate
Electrolytes	Promote ocular surface homeostasis	Potassium Calcium Magnesium Phosphate

Viscosity-enhancing agents, or demulcents, are the most common ingredient in AT and typically listed as the active ingredient on product packaging. The higher the viscosity (i.e., the thicker the product), the longer the ocular surface retention time, but differences in viscosity can influence product choice. High viscosity can create visual disturbances and buildup on the eyelid leading to decreased adherence.²⁶ These products are best for nighttime use, and patients should use lower-viscosity products during the day.²⁶ Many products contain multiple viscosity-enhancing agents. Commonly paired agents include carboxymethyl cellulose (CMC) with hyaluronic acid (HA) and hydroxypropyl-guar (HP-guar) with HA.^14,26 Studies suggest that combining viscosity-enhancing components improves symptom control.¹⁴

There is significant interest in developing novel formulations to increase the spreading and retention time of applied drops.¹⁴ Lipid-containing eye drops are gaining in popularity as understanding of DED’s pathophysiology progresses.¹⁴ Lipids restore and thicken the lipid layer of the tear film and prevent tear evaporation. Formulated as oil-in-water emulsions, lipid-containing products contain macro-, micro-, or nano-particles. Particle size is important. Macro particles are associated with cloudy, blurred vision. As particle size decreases, blurring decreases.¹⁴

Osmoprotectants balance osmotic pressure, as the name implies, to protect and prevent corneal and conjunctival cell death.²⁶ Levocarnitine and erythritol protect cells from hyperosmolar stress and improve DED’s symptoms.²⁶ Clinical trials have shown that trehalose is more effective at improving ocular surface staining than saline.^14,26

Multi-dose products contain preservatives to prevent microbial growth, but these can also worsen symptoms in DED. Benzalkonium chloride (BAK), the most common preservative, may cause corneal damage and interfere with tear film stability.¹⁴ Newer “disappearing preservatives” (e.g., sodium chlorite, sodium perborate) have a lower impact on the ocular surface. Exposure to light or the ocular surface breaks down these compounds, minimizing toxicity.^14,27 Even newer preservatives carry risk, making preservative-free drops the best choice, especially in patients with severe DED. Preservative-free AT products are available in disposable single-use units but are generally more expensive.¹⁴

The pH of ATs affects product activity, stability, patient comfort, and safety.¹⁴ Adding electrolytes to reproduce the electrolyte profile of the tear film aids osmotic balance. Studies show that hypotonic solutions (i.e., having a lower osmotic pressure) decrease DED signs.²⁶

No large-scale, randomized clinical trials have evaluated all currently available AT formulations. Some clinical trials evaluate individual AT products, and a few head-to-head studies exist.^16,28 Several published systematic reviews have concluded that ATs treat DED safely and effectively. One systematic review of more than 60 studies published in 2022 drew the following conclusions²⁷:

Combination formulations, including the following, may be more effective than single-ingredient products: CMC and HA, HA and trehalose, CMC and glycerin, and HA and coenzyme Q10.
Formulations containing polyethylene glycol (PEG) may be more effective than those with CMC.
Preservative-free formulations are preferable.
Patients with EDE and/or MGD should use drops containing phospholipids.
Patients should administer AT four times daily for one month to assess efficacy.
Patience is key; sometimes, it may take up to four months of consistent use to see improvement.

Another literature review of 18 studies compared commercially available AT products and concluded that products containing CMC, hydroxypropyl methylcellulose (HPMC), or HA were the most beneficial in improving patient comfort level.²⁹ This study also determined that clinicians should recommend administration three to four times daily for two months to assess patient response before escalating therapy. The use of a preservative-free formulation is preferable.²⁹ If patients choose or clinicians recommend preservative-containing eye drops, administration should be limited to four to six times daily.²⁹Researchers created a stepwise approach to selecting AT products²⁹:

Step 1: Start with CMC, HPMC, or HA-based formulations
Step 2: Move to formulations with PEG or PEG and glycerin
Step 3: Consider gel or lipid formulations
Step 4: Progress to ointments, liposomal sprays, or prescription inserts

Both studies reached similar conclusions. Adherence and persistence are key to successfully evaluating an individual product, a fact that pharmacy staff should reiterate to patients. While some trial and error may be necessary, following the above recommendations allows patients and providers an organized approach to AT selection. While AT are a mainstay of early symptomatic treatment of dry eye disease, they do not address DED’s underlying causes. Prescription therapies target the underlying inflammatory processes.

Hydroxypropyl cellulose ophthalmic insert (HCOI) is a prescription-only lubricant insert containing 5 mg of hydroxypropyl cellulose. The insert is preservative-free and designed to provide continuous lubrication throughout the day. Patients insert HCOI once daily using an applicator.³⁰ They rinse the applicator in hot water then use the grooved end to pick up the insert. Patients then place the insert in a pocket created by pulling out the outer corner of the eyelid. The HCOI softens and slowly dissolves, stabilizing and thickening the tear film, prolonging TBUT. One study comparing HCOI to using AT four or more times a day found increased TBUT and decreased foreign body sensation with HCOI compared to AT.^30,31 Reported adverse effects include blurred vision, eye irritation, eyelid matting, and light sensitivity.³⁰

Pause and Ponder: A patient approaches the pharmacy counter with a plastic bag full of bottles of different brands of artificial tears. Dumping them on the counter, she states, “None of these work! I don’t know what to do next.” What advice would you give her?

PRESCRIPTION THERAPIES

Available prescription therapies (outlined in Table 5) target the inflammatory cycle of DED through different mechanisms with varying degrees of success.

Table 5. Prescription Therapies to Treat Dry Eye Disease^28,32-36

Drug	Brand Name (Manufacturer)	Formulation(s)	Dosing	Supplied
Cyclosporine A	Restasis (Allergan)	0.05% emulsion	1 drop in each eye BID	Single-use vials
	Cequa (Sun Pharma)	0.09% solution	1 drop in each eye BID	Single-use vials
	Generic (Mylan)	0.05% solution	1 drop in each eye BID	Single-use vials
Lifitegrast	Xiidra (Novartis)	5% solution	1 drop in each eye BID	Single-use containers
Loteprednol	Eysuvis (Kala Pharma)	0.25% suspension	1-2 drops in each eye QID for up to 2 weeks	Multi-dose 10 mL bottle
Perfluorohexyloctane	Meibo (Bausch & Lomb)	100% solution	1 drop in each eye QID	Multi-dose 5 mL bottle
Varenicline	Tyrvaya (Oyster Point Pharma)	0.03 mg/0.05ml solution	1 spray in each nostril BID	Multi-dose nasal spray

ABBREVIATIONS: BID, twice daily; QID, four times daily

Cyclosporine A

Cyclosporine A (CsA) is an anti-inflammatory immune modulator approved for use in DED more than two decades ago.¹⁶ Calcineurin activates T-cells, increasing inflammatory cytokine production. CsA inhibits calcineurin to prevent T-cell activation, disrupting the inflammatory cycle in DED.¹⁶

Many clinical trials have evaluated CsA’s safety and efficacy in DED treatment.^1,5,14,37 Results consistently show that CsA improves Schirmer test scores, corneal staining results, and goblet cell density. Improvement often takes several months, making patient education key to adherence.^1,5,14,37 Topical CsA alleviates symptoms in approximately 50% of patients.¹ Patients using CsA experience decreases in blurred vision, ocular dryness, foreign body sensation, and watery eyes.^1,14 Treatment often causes stinging and irritation. Other adverse effects include blurred vision, ocular itching, eye redness, and foreign body sensation.³⁷ Pretreatment with an ophthalmic steroid such as loteprednol may decrease CsA’s adverse effects.^1,38

As a hydrophobic (water-fearing) substance, CsA is challenging to formulate into an ophthalmic topical formulation. Initially, products used castor oil and corn oil as vehicles, but poor bioavailability and adverse effects preclude their use.¹⁶ The first commercially available CsA product, a 0.05% emulsion, uses a castor oil-in-water emulsion, which reduces but does not eliminate adverse reactions.³⁷

Approval of CsA 0.09% nanomicellar solution introduced a novel formulation.^16,37 Clinical efficacy trials found a response as early as day 28.¹⁶At the end of 12 weeks, 17% of study participants receiving CsA 0.09% experienced increased tear production with a Schirmer score greater than 10 mm. Reported adverse effects included mild instillation site pain, eye irritation, blepharitis, and headache.³² Preliminary studies suggest CsA 0.09% is more effective and better tolerated than CsA 0.05%.¹⁶

Lifitegrast

Approved in 2016, the novel drug lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist.³³ LFA-1 binds to intracellular adhesion molecule-1 during inflammation, activating T-cell migration and resulting in ocular inflammation. Lifitegrast binds to LFA-1, preventing this interaction and decreasing T-cell-mediated inflammation.³³ The U.S. Food and Drug Administration (FDA) approved this drug based on four randomized, double-masked, 12-week efficacy and safety trials.^33,39-41 All studies showed a reduction in patient-rated eye dryness scores at the end of 12 weeks. Patients in three of the four studies experienced reduced corneal staining scores.³³

The one-year multicenter, randomized, placebo-controlled SONATA study evaluated lifitegrast safety.⁴² Reported adverse effects included burning, reduced visual acuity, dry eye, and taste changes. Researchers observed no serious adverse events and discontinuation rates were 12.3% and 9% for lifitegrast and placebo, respectively.⁴² A 2021 retrospective review of 600 patient charts examined real-world experience with lifitegrast in DED.⁴³ Most patients continued treatment for six months and showed improvement in DED symptoms. Patients also experienced improved quality of life at three and 12 months of treatment.⁴³

Perfluorohexyloctane

Perfluorohexyloctane, formerly known as NOV3, reduces tear evaporation from the ocular surface.⁴⁴ The drug’s exact mechanism in DED is unclear. In May 2023, the FDA approved an ophthalmic formulation containing perfluorohexyloctane for treating DED in adults 18 and older based on data from two phase 3 clinical trials: GOBI and MOJAVE.^44,45

These trials evaluated efficacy and safety in more than 1,200 patients with DED meeting similar inclusion and exclusion criteria based on tear film break-up time, ocular surface disease scores, and MGD evaluations. Both trials were multi-center, randomized, double-masked, and saline-controlled.^44,45 GOBE and MOJAVE results also consistently showed statistically significant reductions in reported symptoms of DED. Reported adverse events occurred in less than 4% of study participants and included blurred vision, blepharitis, instillation site pain, and conjunctival redness.^44,46 Patients must remove contact lenses before and for at least 30 minutes after administration of perfluorohexyloctane drops.³⁴

Perfluorohexyloctane should be available in the second half of 2023.⁴⁴

Short-Term Corticosteroids

Corticosteroids are potent inhibitors of inflammatory mediators.¹⁴ Many clinical trials have demonstrated their efficacy in breaking the inflammatory cycle of DED. Unfortunately, long-term therapy is associated with increased intraocular pressure, cataracts, and risk of infection.¹⁴

Loteprednol is a synthetic corticosteroid derived from prednisolone. Its rapid breakdown into inactive metabolites reduces risk of adverse reactions.⁴⁷ A retrospective safety study concluded that loteprednol therapy carries a low risk of treatment-related elevated intraocular pressure compared to other steroids.⁴⁸ Several loteprednol ophthalmic formulations are available, but only the 0.25% suspension is FDA approved for the short-term treatment of DED. This formulation uses mucus-penetrating particle (MPP) technology to allow nanoparticle penetration through the mucin layer.^47,49

The FDA approved loteprednol 0.25% suspension based on the STRIDE series of trials.³⁶ These trials randomized patients with DED to the drug or a vehicle control four times daily in both eyes for two weeks. All trials reported significant improvements in eye redness and discomfort at the end of two weeks.³⁶

One role for topical steroids in DED is pre-treatment prior to topical CsA therapy. A 2014 study compared loteprednol versus AT during a two-week lead-in period to CsA.³⁸ Patients self-administered either loteprednol or AT four times daily for two weeks, followed by CsA twice daily plus either loteprednol or AT twice daily for an additional six weeks. Both groups showed improved ocular staining and OSDI and Schirmer scores. Loteprednol provided more rapid relief of DED symptoms and resulted in a lower CsA discontinuation rate than AT.³⁸

Patients with moderate-to-severe DED with adequate long-term control may still experience periodic symptom exacerbation. Short-term pulse steroid therapy (using steroids of a week or two, then tapering and resuming if necessary) can be useful for patients with symptom exacerbations.¹⁴

Varenicline Nasal Spray

Pharmacy staff may recognize varenicline as a treatment for smoking cessation, but a newer nasal spray formulation shows utility for treating DED. Tear film production results from stimulating afferent nerves in the cornea and conjunctiva and parasympathetic nerves in the lacrimal gland, meibomian glands, and goblet cells.^50,51 This neural pathway is accessible through central nervous system or peripherally through the nasal cavity. While the drug’s mechanism in DED is not fully understood, experts theorize that varenicline, a cholinergic agonist, activates this pathway to stimulate tear production.^50,51

The randomized, double-masked, vehicle-controlled, 28-day ONSET-1 and ONSET-2 trials evaluated varenicline nasal spray’s safety and efficacy.^50,51 Participants self-administered one spray of varenicline solution or vehicle in each nostril twice daily. Both studies found a significant improvement in tear production measured by Schirmer scores. The most common patient-reported adverse effects included sneezing, cough, throat irritation, and nasal irritation.^50,51 The 2021 MYSTIC study examined varenicline nasal spray's long-term safety and efficacy compared to placebo over a 12-week period.⁵² Patients reported no severe or serious adverse events during the study; sneezing was the most common adverse reaction, occurring in 82% of patients.⁵²

Varenicline packaging includes two glass bottles, each containing a 15-day drug supply. Patients must initially prime the bottle by pumping seven sprays into the air away from the face. Re-priming by pumping one spray into the air is necessary after five days of nonuse.³⁵

Steps for administration of varenicline nasal spray³⁵:

Blow nose if needed to clear nostrils
Remove the cap and clip from the bottle
Hold the bottle upright, placing one finger on each side of the applicator and thumb on the bottom of the bottle
Tilt head back slightly
Insert the applicator tip into one nostril, pointing it toward the ear on the same side of the nostril, leaving space between the tip and the wall of the nostril
Place tongue on roof of mouth and breath gently while pumping one spray into the nostril
Repeat in other nostril
Wipe the applicator with a clean tissue and replace the cap and clip

Antibiotics

Clinicians sometimes use oral or topical antibiotics with anti-inflammatory effects off-label to treat DED due to MGD.¹⁴ Many patients experience MGD due to overgrowth of eyelid flora, so reduction of eyelid flora and inflammation improves patient-reported symptoms.⁵³Oral administration of doxycycline and minocycline in small doses (40 to 400 mg of doxycycline and 50 to 100 mg of minocycline) to treat MGD improves patient-reported symptoms.^1,53 Unfortunately, gastrointestinal adverse effects limit the use of these medications. One study found that azithromycin 1% eyedrops improved eyelid inflammation and tear film lipid layer stability.⁵⁴

EMERGING THERAPIES

New and novel therapies are also in the pipeline for DED treatment. Pharmacy staff should be aware of their potential place in therapy and prepared to incorporate them upon approval.

Reproxalap

Exploring another causative mechanism in DED, reproxalap is a reactive aldehyde species (RASP) inhibitor. RASP molecules are found at the top of the inflammatory cascade and are elevated in many inflammatory diseases. They bind to and disrupt the function of enzymes and ion channels, which activates pro-inflammatory mediators. RASP inhibition, therefore, decreases pro-inflammatory substances associated with DED.^55,56

A randomized, double-masked, phase 2a trial evaluated the efficacy of three formulations of reproxalap: 0.1% and 0.5% solutions and a 0.5% lipid solution.⁵⁵ Participants used the products four times daily for 28 days. The study found a significant improvement in four questionnaire scores, Schirmer test values, tear osmolarity, and tear staining scores. Within one week, patients reported symptom improvement. Researchers concluded that reproxalap could potentially alleviate DED symptoms.⁵⁵

A separate randomized, double-masked, phase 2b trial compared reproxalap 0.01% and 0.25% to a control vehicle solution.⁵⁶ Patients self-administered drops four times daily for a total of 12 weeks. The study found statistically significant improvements in ocular dryness and staining over 12 weeks.⁵⁶

A 2021 tolerability study compared ocular adverse effects between two formulations of reproxalap 0.25% (one solution, one lipid-based) and lifitegrast 5% solution.⁵⁷ Over seven days, study participants received one dose of each solution with a 3-day washout period between administrations. Researchers assessed adverse effects after 1 hour. Reproxalap formulations were similar to one another and superior to lifitegrast in ocular discomfort, blurry vision, and dysgeusia.⁵⁷

Reproxalap offers a novel approach to treating the underlying inflammatory process involved in DED. Preliminary study results show improvements in DED symptoms and better patient tolerability, potentially leading to lower discontinuation rates and improved patient outcomes.

Cationic Cyclosporine

A cationic (positively charged) 0.1% CsA nanoemulsion is available in Europe to treat DED.⁵⁸ Experts theorize that a cationic emulsion increases the surface time of CsA on ocular tissues. All FDA-approved products are anionic (negatively charged). Clinical trials are evaluating CsA 0.1% nanoemulsion for FDA approval.⁵⁸

PHARMACY TEAMS: FRONT-LINE SUPPORT

Pharmacists and pharmacy technicians are among the most accessible healthcare providers. People routinely turn to neighborhood pharmacies for advice on many health topics. Most people self-treat dry eye symptoms long before seeking professional help. These facts make the pharmacy team essential in supporting people suffering from DED. The SIDEBAR provides basic counseling information about eye products.

SIDEBAR: Counseling Tips for Eyedrop and Eye Ointment Administration^59,60

Proper administration of ophthalmic formulations is key to their success. Administration is awkward, and many patients struggle with it. Advising patients on proper technique is a key role for the pharmacy team. General tips for all ophthalmic products include

Confirm you have the correct product
Check expiration date
Read the directions
Wash your hands
If using both eyedrops and eye ointment, wait five to ten minutes between drops, and administer the eyedrops at least 10 minutes before the ointment
Using a mirror may make it easier to see what you are doing

Eyedrops:

Gently shake the bottle

Be sure the eye dropper is clean, and do not let it touch any surface
Tilt your head back and look up

Pressing your finger gently on the skin just beneath the lower eyelid, pull your lower eyelid down and away from your eyeball to make a “pocket” for the drops
With the other hand, hold the eye drop bottle upside down with the tip just above the pocket
Squeeze the prescribed number of eye drops into the pocket
If you think you did not get the drop of medicine into your eye properly, use another drop
Blink a few times so that the medicine spreads across your eye
For at least 1 minute, close your eye and press your finger lightly on your tear duct (small hole in the inner corner of your eye) to keep the eye drop from draining into your nose

Wash your hands

Wait at least 10 minutes before you use other eye products, especially ointments, gels, or other thick eye drops

Eye ointment:

Be sure the top of the ointment tube is clean, and don’t let it touch any surface, including the eye, eyelid, or lashes. (If it does, call your pharmacy and arrange to get another tube of eye ointment.)
Tilt your head back and look up
With one hand, pull the lower eyelid down with one or two fingers to create a small pouch
With the other hand, position the medicine above your eye
Put a thin line of ointment in the pouch. Close the eye for 30 to 60 seconds to let the ointment absorb
Wash your hands
Eye ointments can cause some temporary blurring of vision

Knowledge of risk factors, including precipitating medications (revisit Table 3 for a refresher), aids in identifying patients at risk for developing DED. Technicians are often the first point of contact at the pharmacy counter, routinely fielding questions. Actively listening and asking open-ended questions help gather necessary information. Patients reporting dry eye symptoms or buying AT products may need counseling or a referral to a pharmacist or an eye care professional.

Educating patients about avoiding certain environmental factors is important. Remind patients that minimizing exposure to wind or smoke, taking a break from digital screens, and using a humidifier may help alleviate symptoms. Adherence to therapeutic interventions is key in DED treatment. Some interventions, such as lid hygiene, are time-consuming, and many patients stop after only a few days. Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

Advising patients on selecting an appropriate AT product decreases frustration and increases overall patient satisfaction. Proper administration of ophthalmic preparations can be difficult for some patients, particularly older individuals. Taking the time to counsel on proper technique sets patients up for successful administration and improved outcomes.

Patients with severe refractory DED may not benefit enough from lifestyle modifications and pharmacologic therapy. Many other interventions exist including¹⁴

Punctal plugs blocking the tear ducts to promote tear conservation
Pulsed light therapy delivered in office with a handheld flash gun
Tear stimulation utilizing topical and systemic secretagogues
Biological tear substitutes utilizing patient-derived serum
Use of therapeutic contact lenses made of silicone hydrogel
Surgery to correct any causative physiological abnormalities

Pharmacy staff should recognize when patients with worsening DED symptoms may require escalation of therapy and refer them to an eye care provider when appropriate.

Pause and Ponder: Consider your home and work environment. Could you take steps to minimize conditions contributing to developing dry eye?

CONCLUSION

You may have noticed a recurring theme throughout this activity: education. Helping patients understand the chronic nature of DED and navigate treatment options improves patient care and outcomes. Education must include the entire pharmacy team. Understanding the roles of each treatment allows for effective management and counseling. Educated pharmacy teams can assist patients with product selection, counsel on the timing and administration of treatments, improve safety, and provide referrals when appropriate.

The Nitty Gritty: Dry Eye Guidance for the Pharmacy Team

Posttest

Learning Objectives:
1. Describe the etiology and pathophysiology of dry eye disease (DED) and its impact on quality of life
2. Identify available and emerging over-the-counter and prescription therapies to treat DED
3. Optimize artificial tear selection based on patient-specific characteristics
4. Infer when to refer patients to the pharmacist or an eye care provider for DED

Pharmacists:
1. Which of the following is a risk factor for developing DED?
A. Caucasian race
B. Digital device use
C. Obesity

2. How does meibomian gland disease (MGD) contribute to DED?
A. Decreased lipid secretion affecting the outer layer of the tear film
B. Increased lipid secretion affecting the outer layer of the tear film
C. Decreased tear secretion leading to tear film instability

3. Prince Charming shares with you his recent DED diagnosis. Which of the following medications in his profile is most likely contributing to his symptoms?
A. Duloxetine
B. Donepezil
C. Erythromycin

4. Which of the following is a function of viscosity-enhancing agents in artificial tears?
A. Balance osmotic pressure
B. Control pH
C. Increase lubrication

5. Olaf stops by the pharmacy asking for assistance selecting an artificial tear product. He describes mild dry eye symptoms he is experiencing with the change in seasons. As a first choice, you suggest a product containing which of the following?
A. Carboxymethylcellulose (CMC)
B. CMC and hyaluronic acid (HA)
C. Polyvinyl alcohol

6. Which of the following is the most appropriate way to advise Olaf to use the recommended AT product to effectively manage symptoms and assess efficacy?
A. Apply 1-2 drops in each eye 1-2 times a day for 4-6 months
B. Apply 1-2 drops in each eye 4-6 times a day for 1-2 weeks
C. Apply 1-2 drops in each eye 3-4 times a day for 1-2 months

7. Buzz Lightyear recently received a diagnosis of DED due to MGD. Which of the following would be an appropriate first-line treatment choice?
A. Artificial tears formulated with mineral oil
B. Loteprednol 0.25% ophthalmic suspension
C. Oral omega-3 fatty acid supplements

8. Elsa started using cyclosporine A 0.05% eye drops for DED last month. While picking up her first refill, she mentions the drops are controlling her symptoms well but causing a burning sensation when she administers them. Which of the following is the most appropriate response?
A. Let her know this is a known adverse effect and to continue therapy as prescribed
B. Recommend she stop using the drops immediately, as she may be harming her eyes
C. Offer to contact her eye care provider to switch to cyclosporine A 0.09%

9. Which of the following is a novel eye drop approved for long-term use in DED?
A. Perfluorohexyloctane
B. Varenicline
C. Loteprednol

10. Snow White frequently stops by the pharmacy to ask for guidance about treating her DED. Today she shared that her AT is no longer working, and it’s the fifth one she has tried. You confirm she is properly and consistently administering ATs. Which of the following is the BEST recommendation for Snow White?
A. Assist her in selecting a more appropriate AT product to try based on trial-and-error
B. Advise her to reach out to her ophthalmologist to explore prescription therapies
C. Tell her that she must move out of the dusty cabin she shares with the seven dwarves

Pharmacy Technicians:
1. Dry eye disease (DED) affects approximately how many U.S. adults?
A. 7 million
B. 16 million
C. 23 million

2. Which of the following is a risk factor for developing DED?
A. Caucasian race
B. Digital device use
C. Obesity

3. Prince Charming shares his recent diagnosis of DED. Which of the following medications in his profile may be a contributing factor?
A. Duloxetine
B. Donepezil
C. Erythromycin

4. Why is it important to engage with patients at the counter and ask open-ended questions?
A. So you can stay updated with their vacation plans and get some destination ideas
B. To help gather important health-related patient information and optimize therapy
C. It’s not important; the patient wants to pick up their prescription as quickly as possible

5. Which of the following is a function of viscosity-enhancing agents in artificial tears?
A. Balance osmotic pressure
B. Control pH
C. Increase lubrication

6. Cinderella approaches the register with two open bottles of AT and a receipt from one week ago. She asks if she can return the products, as they did not work. Which of the following is the BEST response?
A. Refer Cinderella to the front end of the store to process the refund
B. Issue Cinderella a refund and suggest she speak to an ophthalmologist
C. Refer Cinderella to the pharmacist for counseling

7. Buzz Lightyear stops at the counter to purchase artificial tear eye drops. When he asks you how to use them, what should you do?
A. Tell him to follow the directions on the box; they clearly outline how to use them
B. Offer Buzz a patient handout explaining eye drop use, and refer him to the pharmacist
C. Explain that his doctor is the best person to educate him about eye drop administration

8. Olaf stops by the pharmacy, complaining that his eyes always feel dry, especially when he is outside sledding. Which of the following is the BEST suggestion?
A. Wear eye protection when sledding to reduce wind exposure
B. Watch YouTube videos of other people sledding instead
C. Build a snowman friend on top of the mountain and play there

9. Elsa seems quieter than usual when picking up her prescriptions. When you ask her if everything is OK, she shares that it feels like something is in her eye all the time and she is having a hard time reading her book for book club. Which of the following is the BEST response?
A. Suggest that she get the audiobook instead so she can still enjoy her book club
B. Let her know that this is common and over-the-counter therapies may help
C. Recommend that she see an eye care provider to prescribe loteprednol eye drops

10. While picking up a prescription, Snow White also purchases 4 bottles of artificial tears, stating that she goes through them like water. When you ask her if they help, she replies “Eh, not really…” How should you respond?
A. Tell her to keep it up; sometimes, artificial tears take a while to work
B. Explain that this isn’t typical and refer her to the pharmacist for counseling
C. Let her know it’s okay to stop using them if they aren’t working

References

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44. Tauber J, Berdy GJ, Wirta DL, Krösser S, Vittitow JL; GOBI Study Group. NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Randomized Phase 3 GOBI Study. Ophthalmology. 2023;130(5):516-524. doi:10.1016/j.ophtha.2022.12.021
45. Bausch + Lomb News Releases. www.bausch.com. Accessed June 9, 2023. https://www.bausch.com/news/releases/?id=156
46. Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL; MOJAVE Study Group. NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study [published online ahead of print, 2023 Mar 21]. Am J Ophthalmol. 2023;252:265-274. doi:10.1016/j.ajo.2023.03.008
47. Venkateswaran N, Bian Y, Gupta PK. Practical Guidance for the Use of Loteprednol Etabonate Ophthalmic Suspension 0.25% in the Management of Dry Eye Disease. Clin Ophthalmol. 2022;16:349-355. Published 2022 Feb 9. doi:10.2147/OPTH.S323301
48. Sheppard JD, Comstock TL, Cavet ME. Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure. Adv Ther. 2016;33(4):532-552. doi:10.1007/s12325-016-0315-8
49. Gupta PK, Venkateswaran N. The role of KPI-121 0.25% in the treatment of dry eye disease: penetrating the mucus barrier to treat periodic flares. Ther Adv Ophthalmol. 2021;13:25158414211012797. Published 2021 May 5. doi:10.1177/25158414211012797
50. Wirta D, Torkildsen GL, Boehmer B, et al. ONSET-1 Phase 2b Randomized Trial to Evaluate the Safety and Efficacy of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease. Cornea. 2022;41(10):1207-1216. doi:10.1097/ICO.0000000000002941
51. Wirta D, Vollmer P, Paauw J, et al. Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial. Ophthalmology. 2022;129(4):379-387. doi:10.1016/j.ophtha.2021.11.004
52. Quiroz-Mercado H, Hernandez-Quintela E, Chiu KH, Henry E, Nau JA. A phase II randomized trial to evaluate the long-term (12-week) efficacy and safety of OC-01 (varenicline solution) nasal spray for dry eye disease: The MYSTIC study. Ocul Surf. 2022;24:15-21. doi:10.1016/j.jtos.2021.12.007
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54: Arita R, Fukuoka S. Efficacy of Azithromycin Eyedrops for Individuals With Meibomian Gland Dysfunction-Associated Posterior Blepharitis. Eye Contact Lens. 2021;47(1):54-59. doi:10.1097/ICL.0000000000000729
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60. Eye Problems: Using Eyedrops and Eye Ointment. Kaiser Permanente. Accessed May 30, 2023. https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.eye-problems-using-eyedrops-and-eye-ointment.za1098

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