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Numerous Wrong Dose Errors with PAXLOVID

Problem: In the last few months, ISMP and the US Food and Drug Administration (FDA) have received numerous reports of wrong dose errors related to PAXLOVID (nirmatrelvir and ritonavir). Paxlovid is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. The dosing errors occurred at various points throughout the medication-use process, including prescribing or dispensing the wrong strength, improper renal dosing, and self-administration errors. A recent analysis of national oral antiviral (LAGEVRIO [molnupiravir] and Paxlovid) dispensing data through May 21, 2022, for the treatment of COVID-19 showed that 87% of these drugs were dispensed by pharmacies. Therefore, the following information has major implications for pharmacists.

Paxlovid Packaging Configurations

Paxlovid is currently available in two configurations. For patients with normal renal function (estimated glomerular filtration rate [eGFR] equal to or greater than 90 mL/minute) or mild renal impairment (eGFR below 90 mL/minute but more than or equal to 60 mL/minute), Paxlovid is available in a carton holding 30 tablets contained in 5 daily-dose blister cards (Figure 1). Each blister card contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). The dose, administered twice a day, in the morning and evening, is 2 tablets of nirmatrelvir (150 mg each, 300 mg total) and 1 tablet of ritonavir (100 mg). In January 2022, ISMP published a special alert related to Paxlovid safety risks, in which we noted that patients with moderate renal impairment (eGFR below 60 mL/minute, but more than or equal to 30 mL/minute) must take only 1 tablet of nirmatrelvir (150 mg) along with 1 tablet of ritonavir (100 mg) together, twice daily. Patients with severe renal impairment with an eGFR below 30 mL/minute should not receive the drug.

When Paxlovid first became available, dispensing pharmacists needed to remove 1 of the 2 nirmatrelvir tablets for both the morning and evening doses from each of the blister cards before dispensing Paxlovid to patients with moderate renal impairment. In some reported cases, extra tablets were not removed for renal dosing, or, by mistake, pharmacies removed ritonavir instead of the nirmatrelvir component. To mitigate these dosing risks, in April 2022, cartons of Paxlovid for patients with moderate renal impairment became available with reduced-dose blister packages designed to provide just 1 tablet of nirmatrelvir (150 mg) along with 1 tablet of ritonavir (100 mg) to be administered twice daily (Figure 2). Instead of 30 tablets in the carton for patients with normal renal function or mild renal impairment, each carton contains just 20 tablets divided into 5 daily-dose blister cards for patients with moderate renal impairment.

Figure 1. For patients with normal renal function or mild renal impairment, each Paxlovid carton contains 5 daily-dose blister packages with 2 tablets of nirmatrelvir 150 mg (300 mg total) and 1 tablet of ritonavir 100 mg for each morning and evening dose (30 tablets in total).
Figure 1. For patients with normal renal function or mild renal impairment, each Paxlovid carton contains 5 daily-dose blister packages with 2 tablets of nirmatrelvir 150 mg (300 mg total) and 1 tablet of ritonavir 100 mg for each morning and evening dose (30 tablets in total).
Figure 2. For patients with moderate renal impairment, each Paxlovid carton contains 5 daily-dose blister packages with 1 tablet of nirmatrelvir 150 mg and 1 tablet of ritonavir 100 mg for each morning and evening dose. One blister for the morning and evening dose is intentionally left empty (20 tablets in total).
Figure 2. For patients with moderate renal impairment, each Paxlovid carton contains 5 daily-dose blister packages with 1 tablet of nirmatrelvir 150 mg and 1 tablet of ritonavir 100 mg for each morning and evening dose. One blister for the morning and evening dose is intentionally left empty (20 tablets in total).

Recently Reported Errors

Many of the recently reported errors have happened during patient self-administration and generally involved patients taking the wrong tablets (e.g., took 3 tablets of nirmatrelvir from the same blister card and no ritonavir, took 2 ritonavir tablets and 1 nirmatrelvir tablet for each dose, took the entire day’s dose [6 tablets] at one time, took 2 nirmatrelvir tablets from one blister and 1 nirmatrelvir tablet from another blister for each dose). Dispensing errors involved providing the carton with reduced-dose blister packages intended for patients with moderate renal impairment to patients with normal renal function or mild renal impairment, or vice versa. Several of the reported errors involved improper renal dosing, such as prescribing or dispensing Paxlovid to patients with severe renal impairment. Other prescribing errors included ordering the standard dose for patients with moderate renal impairment and vice versa, prescribing the incorrect quantity (e.g., 30 tablets for moderate renal impairment dosing), providing directions to take 2 tablets twice a day in conflict with the instructions on the package prescribed, and not checking or asking patients about renal function or concomitant drug use to avoid drug-drug interactions.

Contributing Factors

Before the reduced-dose blister package for patients with moderate renal impairment became available, we mostly received error reports involving pharmacy staff failing to remove 1 of the nirmatrelvir tablets for each dose on all 5 blister cards and/or omitting auxiliary stickers (provided by the manufacturer) to alert patients to the altered packaging and removal of the unneeded tablets. However, even with the availability of the reduced-dose blister package for patients with moderate renal impairment, we continue to receive reports of Paxlovid dosing errors with the following contributing factors:

  • The prescriber was unaware of the required dose adjustment needed for patients with moderate renal impairment

  • The prescriber was unaware of the patient’s renal function (or the patient’s concomitant drugs to screen for drug-drug interactions; see a reported Paxlovid drug-drug interaction in our June 2, 2022, newsletter)

  • Prescribers’ confusion about the two available packages and the number of tablets per regimen

  • The new moderate renal impairment dose packaging may not be stocked in certain pharmacies

  • Mix-ups between look-alike cartons of the standard and moderate renal impairment doses

    • The reduced-dose blister package and carton fail to note it is for patients with moderate renal impairment

  • Confusion when referring to the tablets by their color or the blister package colors

    • Tablet colors are not visible in the blister packages

  • Error-prone and inconsistent format of displaying Paxlovid in electronic health records (EHRs)

    • For example, the nirmatrelvir dose was listed as “150 mg, two tablets” rather than “300 mg,” which may lead to administration of only 1 tablet of nirmatrelvir

  • Confusing blister pack instructions for patients 

Safe Practice Recommendations: To prevent dosing errors with Paxlovid, consider the following recommendations:

Increase awareness. Educate practitioners about the availability of the reduced-dose blister package for patients with moderate renal impairment. Remind practitioners to avoid prescribing and dispensing Paxlovid for patients with severe renal impairment.

Check EHR and prescribing system configuration. Check your EHR or prescribing system to see how the dose and tablet strength fields are displayed, and make the required alterations to ensure it is intuitive for the prescriber to select 2 of the 150 mg nirmatrelvir tablets to make up a 300 mg dose. On drop-down menus, it is safest to list the strength of Paxlovid as a 300 mg and 100 mg dose pack, or, for moderate renal impairment, a 150 mg and 100 mg dose pack (as stated on the cartons).

Clinical decision support. If possible, provide dose guidance for Paxlovid in prescribing systems, such as providing an order sentence with the required reduced dosing for patients with moderate renal impairment.

Check and confirm renal function. Confirm the patient’s renal function before prescribing or dispensing Paxlovid. (See the FDA Paxlovid Patient Eligibility Screening Checklist Tool for Prescribers to support clinical decision making and to screen for significant drug interactions.) If possible, prescribers should document on prescriptions the patient’s most recent eGFR and date. Pharmacists without access to the patient’s medical record will need to contact the prescriber if this information is not included.

Avoid communicating the dose by tablet or blister color. Do not refer to the tablets as pink (nirmatrelvir) and white (ritonavir), or by any other colors, or by the color of the blister package, as this can cause the patient to misunderstand which medications to take.

Educate patients. Mark Paxlovid prescriptions for mandatory patient education, and explore ways to use technology to prompt mandatory patient education when the prescription is picked up. Show patients how the medication is labeled on the blister pack, and teach them about the two different medications that they will be taking twice a day. Encourage them to remove each tablet just prior to taking the dose and not ahead of time (e.g., transferring them to a medication box). Use the teach-back method, making sure that patients can demonstrate how they will take the morning and evening doses. Also provide patients with the Fact Sheet for Patients, Parents, and Caregivers.

Recommendations for the manufacturer. To differentiate the two packages, Pfizer should consider adding a banner on the renal dosing cartons to specify that this package configuration is for patients with moderate renal impairment. Also, Pfizer should provide patient education tools, such as laminated cards, for each package type.

Suggested citation:

Institute for Safe Medication Practices (ISMP). Numerous wrong dose errors with Paxlovid. ISMP Medication Safety Alert! Acute Care. 2022;27(13):1-3.