Nirmatrelvir and Ritonavir (Monograph)
Brand name: Paxlovid
Drug class: Coronavirus (COVID-19)
Warning
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are cautioned that a combined regimen of ritonavir-boosted nirmatrelvir is not an approved treatment for coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in pediatric patients 12 years of age or older, but rather, is being investigated for and is currently available under an FDA emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in this population. The American Society of Health-System Pharmacists, Inc. makes no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to the information contained in the accompanying monograph, and specifically disclaims all such warranties. Readers of this information are advised that ASHP is not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising from the use of the information contained in the monograph in any and all practice settings. Readers are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Warning
-
Ritonavir is a strong CYP3A inhibitor and can increase exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events.
-
Prior to prescribing ritonavir-boostednirmatrelvir, review all medications taken by the patient to assess potential drug-drug interactions and determine if dose adjustment, interruption, and/or additional monitoring is needed for any concomitant therapies.
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Consider the benefit of ritonavir-boosted nirmatrelvir treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed.
Introduction
Antiviral agent; nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor and ritonavir is a potent inhibitor of CYP3A isoenzyme. Ritonavir decreases metabolism and increases plasma concentrations of nirmatrelvir.
Uses for Nirmatrelvir and Ritonavir
Coronavirus Disease 2019 (COVID-19)
Nirmatrelvir with low-dose ritonavir (ritonavir-boosted nirmatrelvir) is FDA-labeled for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.
Ritonavir-boosted nirmatrelvir is also authorized under an emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in pediatric patients (≥12 years of age weighing ≥40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death.
Not approved for use as pre-exposure or post-exposure prophylaxis for the prevention of COVID-19.
May be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs; the combination therapy also may be prescribed for an individual patient by a state-licensed pharmacist under certain conditions.
There are several therapeutic options available for treatment of adults with mild to moderate COVID-19 who are at high risk of disease progression. When selecting an appropriate treatment, consider factors such as clinical efficacy and availability of the various options, feasibility of administering parenteral medications (i.e., remdesivir), potential for significant drug-drug interactions (e.g., those associated with the use of ritonavir-boosted nirmatrelvir), time from symptom onset, and regional prevalence of variants of concern.
The National Institutes of Health (NIH) COVID-19 treatment guidelines panel recommends use of ritonavir-boosted nirmatrelvir or remdesivir, in order of preference, for treatment of nonhospitalized adult patients with COVID-19 who do not require hospitalization or supplemental oxygen but are at high risk for progression to severe disease. If ritonavir-boosted nirmatrelvir and remdesivir are unavailable, not feasible, or clinically inappropriate, the panel recommends molnupiravir.
The Infectious Diseases Society of America (IDSA) suggests a 5-day treatment course of ritonavir-boosted nirmatrelvir, dosed based on renal function, starting within 5 days of symptom onset over no ritonavir-boosted nirmatrelvir treatment in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progression to severe disease. Patients with mild to moderate COVID-19 who are hospitalized for reasons other than COVID-19 and who are at high risk of progression to severe disease may also receive ritonavir-boosted nirmatrelvir.
Ritonavir-boosted nirmatrelvir has the potential for significant drug-drug interactions with other medications and may not be an optimal choice for all patients. However, because the combination is the only highly effective oral antiviral available for treatment of COVID-19, the NIH guideline panel states that drug-drug interactions that can be safely managed should not preclude the use of this regimen.
Consult the most recent guidelines available from NIH ([Web]) and IDSA ([Web]) for additional information.
Use of ritonavir-boosted nirmatrelvir early in the disease process when viral loads are high confers maximum benefit; therefore, it is critical to make a rapid diagnosis and treat nonhospitalized patients with COVID-19 early in the disease course.
Case reports suggest that some patients who have completed a 5-day course of ritonavir-boosted nirmatrelvir and have recovered can experience viral rebound (i.e., a recurrence of symptoms or a new positive viral test after having tested negative). There is currently no evidence that additional treatment for COVID-19 is needed for COVID-19 rebound. Based on currently available data, CDC states that patient monitoring continues to be the most appropriate management for such patients.
Related/similar drugs
Paxlovid, remdesivir, Lagevrio, Actemra, molnupiravir, tocilizumab
Nirmatrelvir and Ritonavir Dosage and Administration
General
Pretreatment Screening
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Consider the potential for drug interactions prior to and during treatment.
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Monitor baseline renal and liver function.
Dispensing and Administration Precautions
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Ritonavir-boosted nirmatrelvir is available in 2 packaging configurations: a dose pack that contains 300 mg nirmatrelvir and 100 mg ritonavir and a dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. Healthcare providers should be aware of differences in the ritonavir tablet appearance, including shape, color, and debossing depending on the package provided to the patient. In patients with moderate renal impairment, only dispense the dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. If this lower strength dose pack is unavailable for dispensing to patients with moderate renal impairment, pharmacists should refer to instructions in the document entitled “Important Paxlovid EUA dispensing information for patients with moderate renal impairment.”
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Prescriptions must specify the numeric dose of each active ingredient in the antiviral drug combination (e.g., 300 mg nirmatrelvir with 100 mg ritonavir). Wrong-dose medication errors have occurred with ritonavir-boosted nirmatrelvir during prescribing, dispensing, and administration of the drug. Many of these errors have occurred during patient self-administration and generally involved patients taking the wrong combination of nirmatrelvir tablets and ritonavir tablets from the blister card. The blister card indicates which tablets need to be taken in the morning and evening each day.
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Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to ritonavir-boosted nirmatrelvir is mandatory. The FDA fact sheet for healthcare providers should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.
Other General Considerations
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Patients should continue isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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Patients on ritonavir- or cobicistat-containing HIV or hepatitis C virus treatment regimens should continue their treatment as indicated. No dosage adjustment is required when ritonavir-boosted nirmatrelvir is coadministered with other products containing ritonavir or cobicistat.
Administration
Oral Administration
Administer orally without regard to food.
Swallow tablets whole; do not chew, break, or crush.
Must administer nirmatrelvir in conjunction with low-dose ritonavir at the same time twice daily. Ritonavir is a pharmacokinetic enhancer that improves the pharmacokinetic profile of nirmatrelvir.
Paxlovid is available as a 5-day dose pack of 10 blister cards; each blister card contains a single dose (one or two 150-mg nirmatrelvir tablets and one 100-mg ritonavir tablet).
If a dose of ritonavir-boosted nirmatrelvir is missed by ≤8 hours, take the prescribed dose as soon as possible. If a dose is missed by >8 hours, administer prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.
Dosage
Pediatric Patients
Treatment of Mild to Moderate COVID-19 in Patients at Risk for Progression
Oral
≥12 years of age weighing ≥40 kg: FDA EUA permits use of 300 mg of nirmatrelvir (two 150-mg tablets) orally twice daily in conjunction with 100 mg of ritonavir (one 100-mg tablet) orally twice daily for 5 days. Complete full 5-day treatment course.
Dosage adjustment required in patients with moderate renal impairment. (See Renal Impairment under Dosage and Administration.)
Initiate therapy as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset even if baseline symptoms are mild.
If hospitalization occurs due to progression to severe or critical COVID-19 after initiation of ritonavir-boosted nirmatrelvir therapy, treatment course may be continued per the clinician's discretion.
Adults
Treatment of Mild to Moderate COVID-19 in Patients at Risk for Progression
Oral
300 mg of nirmatrelvir (two 150-mg tablets) orally twice daily in conjunction with 100 mg of ritonavir (one 100-mg tablet) orally twice daily for 5 days. Complete full 5-day treatment course.
Dosage adjustment required in patients with moderate renal impairment. (See Renal Impairment under Dosage and Administration.)
Initiate therapy as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset even if baseline symptoms are mild.
If hospitalization occurs due to progression to severe or critical COVID-19 after initiation of ritonavir-boosted nirmatrelvir therapy, treatment course may be continued per the clinician's discretion.
Special Populations
Hepatic Impairment
Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment of ritonavir-boosted nirmatrelvir necessary.
Severe hepatic impairment (Child-Pugh class C): Pharmacokinetic profile and safety of nirmatrelvir and ritonavir not established; ritonavir-boosted nirmatrelvir not recommended in such patients.
Renal Impairment
Moderate renal impairment (eGFR 30 to <60 mL/minute): Reduce nirmatrelvir dosage to 150 mg twice daily in conjunction with ritonavir 100 mg twice daily for 5 days. Prescribing clinicians must specify the numeric dose of nirmatrelvir and ritonavir (e.g., 150 mg nirmatrelvir with 100 mg ritonavir for patients with moderate renal impairment) on prescriptions and should counsel patients about renal dosing instructions. When dispensing ritonavir-boosted nirmatrelvir for patients with moderate renal impairment, only dispense the dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. If this lower strength dose pack is unavailable for dispensing to patients with moderate renal impairment, the pharmacist should refer to the document entitled “Important Paxlovid EUA dispensing information for patients with moderate renal impairment”.
Mild renal impairment (eGFR 60 to <90 mL/minute): No dosage adjustment necessary.
Severe renal impairment (eGFR <30 mL/minute): Appropriate dosage not established; use not recommended in such patients.
Geriatric Patients
No specific dosage recommendations.
Cautions for Nirmatrelvir and Ritonavir
Contraindications
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History of clinically significant hypersensitivity reactions (e.g., toxic epidermal necrolysis [TEN] or Stevens-Johnson syndrome) to nirmatrelvir, ritonavir, or any other ingredient in the preparation.
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Concomitant use of drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; these drugs include, but are not limited to, alfuzosin, ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, colchicine (in patients with renal and/or hepatic impairment), lurasidone, pimozide, silodosin, eplerenone, ivabradine, dihydroergotamine, ergotamine, methylergonovine, lovastatin, simvastatin, voclosporin, lomitapide, eletriptan, ubrogepant, finerenone, naloxegol, sildenafil (Revatio) for treatment of pulmonary arterial hypertension, triazolam, oral midazolam, flibanserin, and tolvaptan.
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Concomitant use of potent CYP3A inducers that can significantly reduce nirmatrelvir or ritonavir plasma concentrations and result in potential loss of virologic response and possible resistance; these drugs include, but are not limited to, apalutamide, carbamazepine, phenobarbital, primidone, phenytoin, lumacaftor/ivacaftor, rifampin, rifapentine, and St. John's wort (Hypericum perforatum). Do not start ritonavir-boosted nirmatrelvir immediately after discontinuation of any of these drugs due to the delayed offset of the recently discontinued CYP3A inducer.
Warnings/Precautions
Serious Adverse Reactions Due to Drug Interactions
Nirmatrelvir must be used in conjunction with ritonavir. Failure to administer nirmatrelvir with the recommended dosage of ritonavir will result in subtherapeutic nirmatrelvir concentrations and inadequate virologic response. Consider the cautions, precautions, contraindications, and drug interactions associated with nirmatrelvir and ritonavir.
Concomitant use of ritonavir-boosted nirmatrelvir with certain drugs is contraindicated or requires particular caution. Concomitant use with some drugs may result in clinically important adverse effects, including severe, life-threatening, or fatal events, due to higher exposures of the concomitant drug or higher exposures of nirmatrelvir and/or ritonavir. Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted nirmatrelvir and possible development of viral resistance.
Ritonavir is a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events. (See Boxed Warning.)
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, reported. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome reported in patients receiving ritonavir.
Immediately discontinue treatment if signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis develop and initiate appropriate treatment and/or supportive care.
Hepatotoxicity
Hepatotoxicity (i.e., elevations in serum aminotransferase concentrations, clinical hepatitis, jaundice) reported in patients receiving ritonavir.
Use ritonavir with caution in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis.
HIV-1 Resistance Development
Because nirmatrelvir is coadministered with ritonavir, cross-resistance to HIV protease inhibitors (HIV PIs) may occur in individuals with uncontrolled or undiagnosed HIV-1 infection.
EUA Requirements for Patient Monitoring and Mandatory FDA MedWatch Reporting
Safety and efficacy of ritonavir-boosted nirmatrelvir not established in pediatric patients; use in this population is authorized under an EUA.
Completion of FDA forms to report all medication errors and all serious adverse events potentially related to ritonavir-boosted nirmatrelvir in the EUA authorized population is mandatory. Consult the FDA fact sheet for instructions on reporting.
Specific Populations
Pregnancy
Nirmatrelvir: Data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Reduced fetal body weight observed in animal studies
Ritonavir: Published observational studies have not identified an increase in the risk of major birth defects when ritonavir was used in pregnant women. Published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage.
Estimated background risk of major birth defects and miscarriage in the indicated population unknown. COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.
Lactation
Nirmatrelvir: Not known whether nirmatrelvir is distributed into human or animal milk or has effects on the breast-fed infant or milk production.
Ritonavir: Limited published data indicate that ritonavir is present in human milk. Not known whether ritonavir has effects on the breast-fed infant or milk production.
Consider developmental and health benefits of breast-feeding along with the mother’s clinical need for ritonavir-boosted nirmatrelvir and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.
Females with COVID-19 who are breast-feeding should follow clinical guidelines to avoid exposing the infant to the virus.
Females and Males of Reproductive Potential
Use of ritonavir may reduce efficacy of combined hormonal contraceptives; advise patients to use an effective alternative contraceptive method or an additional barrier method of contraception until completion of one additional menstrual cycle.
Pediatric Use
The FDA EUA permits use of ritonavir-boosted nirmatrelvir for the treatment of COVID-19 in certain pediatric patients ≥12 years of age weighing ≥40 kg. Use of ritonavir-boosted nirmatrelvir is not authorized for pediatric patients <12 years of age or those weighing <40 kg.
Safety and efficacy of ritonavir-boosted nirmatrelvir not established in pediatric patients.
Pharmacokinetics of ritonavir-boosted nirmatrelvir not evaluated in pediatric patients <18 years of age. EUA-recommended dosage of ritonavir-boosted nirmatrelvir is expected to result in plasma concentrations of the drugs in patients ≥12 years of age weighing ≥40 kg that are comparable to those observed in adults.
Geriatric Use
In an integrated data set of 1,578 patients who received nirmatrelvir and ritonavir, 10% were ≥65 years of age and 2% were ≥75 years of age. No overall differences in safety were seen between elderly and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
Moderate hepatic impairment: Pharmacokinetics of nirmatrelvir not substantially altered following administration of ritonavir-boosted nirmatrelvir.
Severe hepatic impairment: Pharmacokinetic profile and safety of nirmatrelvir and ritonavir not studied.
Renal Impairment
Mild renal impairment (eGFR 60 to <90 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 30 or 24%, respectively, following administration of ritonavir-boosted nirmatrelvir.
Moderate renal impairment (eGFR 30 to <60 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 38 or 87%, respectively, following administration of ritonavir-boosted nirmatrelvir.
Severe renal impairment (eGFR <30 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 48 or 204%, respectively, following administration of ritonavir-boosted nirmatrelvir.
Common Adverse Effects
Most common adverse reactions (≥1%) include dysgeusia and diarrhea.
Drug Interactions
Consider drug interactions associated with both nirmatrelvir and ritonavir.
Ritonavir-boosted nirmatrelvir is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp, and OATP1B1. Co-administration of ritonavir-boosted nirmatrelvir with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of these drugs and increase the risk of adverse events. Co-administration of ritonavir-boosted nirmatrelvir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.
Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce therapeutic effect ofritonavir-boosted nirmatrelvir.
The following drug interactions are based on studies using ritonavir-boosted nirmatrelvir. Guidelines from the National Institutes of Health (NIH) state that because ritonavir-boosted nirmatrelvir is the only highly effective oral option for treatment of COVID-19, drug-drug interactions that can be safely managed should not preclude the use of this regimen; consult the most recent version of the NIH COVID-19 guidelines ([Web]) for specific recommendations regarding safety of coadministration of specific drugs with ritonavir-boosted nirmatrelvir.
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
CYP3A Inducers: Potential pharmacokinetic interaction with drugs that induce CYP3A (decreased plasma concentrations of nirmatrelvir and ritonavir, which may lead to reduced virologic response).
Substrates of CYP3A
Substrates of CYP3A: Potential pharmacokinetic interaction with drugs principally metabolized by CYP3A (increased plasma concentrations of drug metabolized by CYP3A). Concomitant use of nirmatrelvir and ritonavir with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Concomitant use of nirmatrelvir and ritonavir with other CYP3A substrates may require dosage adjustment or additional monitoring.
Specific Drugs
|
Drug |
Interaction |
Comments |
|---|---|---|
|
Alfuzosin |
Possible increased alfuzosin concentrations and increased risk of serious and/or life-threatening reactions (e.g., hypotension) |
Concomitant use contraindicated |
|
Aliskiren |
Possible increased concentrations of aliskiren |
Avoid concomitant use |
|
Antiarrhythmic agents (amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine) |
Possible increased concentrations of the antiarrhythmic agent |
Amiodarone, dronedarone, flecainide, propafenone, quinidine: Concomitant use contraindicated Lidocaine (systemic), disopyramide: Caution advised; therapeutic concentration monitoring recommended for the antiarrhythmic agent, if available |
|
Anticoagulants, oral (apixaban, rivaroxaban, warfarin, dabigatran) |
Dabigatran: Possible increased dabigatran concentrations and increased risk of bleeding Rivaroxaban: Possible increased rivaroxaban concentrations and increased risk of bleeding Warfarin: Possible altered warfarin concentrations Apixaban: Possible increased apixaban concentrations and increased risk of bleeding |
Dabigatran: Depending on indication and renal function, reduce dosage of dabigatran or avoid concomitant use; refer to product labeling for dabigatran Rivaroxaban: Avoid concomitant use Warfarin: Closely monitor INR if concomitant use is necessary Apixaban: Dosing recommendations depend on apixaban dosage; refer to product labeling for apixaban |
|
Anticonvulsants (carbamazepine, phenobarbital, primidone, phenytoin) |
Decreased concentrations of nirmatrelvir/ritonavir and potential loss of virologic response and possible resistance |
Concomitant use contraindicated |
|
Antifungals, azoles (isavuconazonium, itraconazole, ketoconazole, voriconazole) |
Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and increased nirmatrelvir and ritonavir concentrations Itraconazole: Possible increased itraconazole concentrations and increased nirmatrelvir and ritonavir concentrations Ketoconazole: Possible increased ketoconazole concentrations and increased nirmatrelvir and ritonavir concentrations Voriconazole: Possible decreased voriconazole concentrations and increased nirmatrelvir and ritonavir concentrations |
Voriconazole: Avoid concomitant use Ketoconazole, isavuconazonium, itraconazole: Refer to the respective product labels for additional information Dosage reduction of nirmatrelvir and ritonavir not necessary |
|
Antimycobacterials (bedaquiline, rifabutin, rifapentine, rifampin) |
Bedaquiline: Possible increased bedaquiline concentrations Rifabutin: Possible increased rifabutin concentrations Rifapentine: Possible decreased nirmatrelvir/ritonavir concentrations Rifampin: Substantially decreased nirmatrelvir/ritonavir concentrations and possible loss of virologic response and development of resistance |
Rifampin, rifapentine: Concomitant use contraindicated; consider alternative antimycobacterial (e.g., rifabutin); do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of rifampin or rifapentine Bedaquiline, rifabutin: Refer to respective product label for additional information |
|
Antineoplastic agents (apalutamide, abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine) |
Apalutamide: Possible decreased systemic exposure to nirmatrelvir and ritonavir, loss of virologic response, and development of nirmatrelvir resistance Ibrutinib, neratinib, venetoclax: Possible increased antineoplastic concentrations Encorafenib, ivosidenib: Possible increased antineoplastic concentrations and potential for serious and/or life-threatening adverse effects (e.g., QT-interval prolongation) Vincristine, vinblastine: Possible increased antineoplastic concentrations and potential for clinically important hematologic or GI adverse effects Abemaciclib, ceritinib, dasatinib, nilotinib: Possible increased antineoplastic concentrations |
Apalutamide: Concomitant use contraindicated; do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of apalutamide due to delayed offset of apalutamide Encorafenib, ibrutinib, ivosidenib, neratinib, venetoclax: Avoid concomitant use |
|
Antipsychotics (clozapine, lurasidone, pimozide, quetiapine, aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin) |
Possible increased concentrations of the antipsychotic agent and potential for adverse effects |
Lurasidone, pimozide: Concomitant use contraindicated because of serious and/or life-threatening reactions such as arrhythmias Quetiapine: If concomitant use is necessary, reduce quetiapine dosage and monitor for quetiapine adverse effects Clozapine: If concomitant use is necessary, consider reducing clozapine dosage and monitor for adverse reactions Aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin: Dosage adjustment of the antipsychotic agent recommended |
|
Antiretroviral agents, HIV protease inhibitors (PIs) (atazanavir, darunavir, tipranavir) |
Possible increased systemic exposure to the HIV PI |
In patients currently receiving a ritonavir- or cobicistat-boosted HIV regimen, continue treatment as indicated and monitor for increased adverse events from ritonavir, nirmatrelvir, or the HIV PI |
|
Antiretroviral agents, other (efavirenz, maraviroc, nevirapine, zidovudine, bictegravir/emtricitabine/tenofovir) |
Possible increased concentrations of efavirenz, maraviroc, nevirapine, bictegravir, and tenofovir Possible decreased concentrations of zidovudine No change in emtricitabine concentrations |
Refer to the respective product labels for additional information |
|
Avanafil |
Possible increased concentrations of avanafil |
Do not use nirmatrelvir/ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established |
|
Benzodiazepines (midazolam, triazolam, clorazepate, clonazepam, diazepam, estazolam, flurazepam) |
Possible increased concentrations of the benzodiazepine |
Oral midazolam or triazolam: Concomitant use contraindicated due to potential for extreme sedation and respiratory depression Parenteral midazolam: Use concomitantly with caution and in monitored setting where respiratory depression and/or prolonged sedation can be managed; consider reduced midazolam dosage, especially if multiple midazolam doses are given Clorazepate, clonazepam, diazepam, estazolam, flurazepam: Dosage decrease for these drugs may be needed; monitor for adverse effects |
|
Bosentan |
Possible increased bosentan concentrations and decreased nirmatrelvir/ritonavir concentrations |
Discontinue bosentan for ≥36 hours prior to initiating ritonavir-boosted nirmatrelvir; refer to product labeling for bosentan |
|
Bupropion |
Possible decreased concentrations of bupropion and its active metabolite (hydroxybupropion) |
Monitor for adequate clinical response to bupropion |
|
Buspirone |
Possible increased concentrations of buspirone |
Dosage reduction may be necessary for buspirone; monitor for adverse effects |
|
Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil) |
Possible increased concentrations of the calcium-channel blocking agent |
Use concomitantly with caution; clinical monitoring recommended If concomitant use cannot be avoided, dosage reduction of calcium-channel blocking agent may be necessary |
|
Cilostazol |
Possible increased cilostazol concentrations |
Dosage adjustment of cilostazol recommended; refer to product labeling for cilostazol for additional information |
|
Clopidogrel |
Potential for decreased concentrations of clopidogrel's active metabolite |
Avoid concomitant use |
|
Colchicine |
Possible increased colchicine concentrations and potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment |
Concomitant use contraindicated |
|
Corticosteroids primarily metabolized by CYP3A (betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone) |
Possible increased corticosteroid concentrations (via all routes of administration) and increased risk of adrenal insufficiency or Cushing's syndrome |
Consider alternative corticosteroid (e.g., beclomethasone, prednisone, prednisolone) |
|
Cystic fibrosis transmembrane conductance regulator potentiators (lumacaftor/ivacaftor, ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor) |
Lumacaftor/ivacaftor: Possible decreased concentrations of nirmatrelvir/ritonavir and potential loss of virologic response and resistance Ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor: Possible increased concentrations of the cystic fibrosis agent |
Lumacaftor/ivacaftor: Concomitant use contraindicated Ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor: Reduce dosage of the cystic fibrosis agent; refer to product labeling of the cystic fibrosis agent for additional information |
|
Darifenacin |
Possible increased darifenacin concentrations |
Do not exceed a darifenacin daily dose of 7.5 mg; refer to the darifenacin product labeling for additional information |
|
Dasabuvir |
Possible increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir/dasabuvir |
|
|
Digoxin |
Possible increased digoxin concentrations |
Use concomitantly with caution; monitor digoxin concentrations appropriately Refer to the digoxin product label for additional information |
|
Eletriptan |
Possible increased eletriptan concentrations and increased risk of serious and/or life-threatening adverse effects |
Coadministration of eletriptan within at least 72 hours of nirmatrelvir/ritonavir is contraindicated |
|
Elbasvir |
Possible increased elbasvir concentrations and substantially increased grazoprevir concentrations if ritonavir-boosted nirmatrelvir used with fixed combination elbasvir/grazoprevir; increased grazoprevir concentrations may increase risk of increased ALT concentrations |
|
|
Eplerenone |
Possible increased eplerenone concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for hyperkalemia |
|
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) |
Potential for serious or life-threatening adverse effects (e.g., vasospasm, ischemia of extremities or other tissues) |
Concomitant use contraindicated |
|
Estrogens |
Oral hormonal contraceptives containing ethinyl estradiol: Possible decreased ethinyl estradiol concentrations |
Use additional nonhormonal contraception methods during the 5 days of treatment and until 1 menstrual cycle after discontinuance of ritonavir-boosted nirmatrelvir |
|
Fentanyl |
Possible increased fentanyl concentrations |
Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals |
|
Flibanserin |
Possible increased flibanserin concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for hypotension, syncope, and CNS depression |
|
Finerenone |
Possible increased finerenone concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for hyperkalemia, hypotension, and hyponatremia |
|
Glecaprevir and pibrentasvir |
Increased HCV antiviral drug concentrations |
Avoid concomitant use |
|
Grazoprevir |
Increased grazoprevir concentrations which can result in increased ALT concentrations |
|
|
HMG-CoA reductase inhibitors (statins) |
Lovastatin, simvastatin: Possible increased antilipemic concentrations and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis Atorvastatin, rosuvastatin: Possible increased antilipemic concentrations and increased risk of statin-associated adverse effects |
Atorvastatin, rosuvastatin: Consider temporarily withholding atorvastatin and rosuvastatin during ritonavir-boosted nirmatrelvir therapy; atorvastatin and rosuvastatin do not need to be held prior to or after discontinuance of ritonavir-boosted nirmatrelvir Lovastatin, simvastatin: Concomitant use with ritonavir-boosted nirmatrelvir contraindicated; discontinue lovastatin and simvastatin at least 12 hours prior to initiation of ritonavir-boosted nirmatrelvir, during the 5 days of treatment, and for 5 days after completion of ritonavir-boosted nirmatrelvir therapy |
|
Hydrocodone |
Possible increased concentrations of hydrocodone |
Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals |
|
Immunosuppressive agents (cyclosporine, sirolimus, everolimus, tacrolimus) |
Possible increased immunosuppressive agent concentrations |
Cyclosporine, tacrolimus: Monitor plasma concentrations of immunosuppressive agent; avoid concomitant use if monitoring of immunosuppressive agent concentrations not feasible If co-administered, dosage adjustments of the immunosuppressant and monitoring for immunosuppressant concentrations and associated adverse effects is recommended Sirolimus, everolimus: Avoid concomitant use |
|
Ivabradine |
Possible increased ivabradine concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for bradycardia or conduction disturbances |
|
Lomitapide |
Possible increased lomitapide concentrations and increased risk of hepatotoxicity and GI adverse effects |
Concomitant use contraindicated |
|
Macrolides (clarithromycin, erythromycin |
Possible increased macrolide concentrations |
Refer to the individual macrolide product label for additional information |
|
Meperidine |
Possible increased meperidine concentrations |
Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals |
|
Methadone |
Possible decreased methadone concentrations |
Closely monitor for opiate withdrawal since some patients may need adjustment of methadone maintenance dosage |
|
Naloxegol |
Possible increased naloxegol concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for opioid withdrawal symptoms |
|
Ombitasvir |
Increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir and dasabuvir |
|
|
Oxycodone |
Possible increased concentrations of oxycodone |
Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals |
|
Paritaprevir |
Possible increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir/dasabuvir |
|
|
Ranolazine |
Possible increased ranolazine concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated |
|
Rimegepant |
Possible increased rimegepant concentrations |
Avoid concomitant use |
|
Riociguat |
Possible increased riociguat concentrations |
Dosage adjustment of riociguat recommended |
|
Salmeterol |
Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, and sinus tachycardia |
Avoid concomitant use |
|
Saxagliptin |
Possible increased saxagliptin concentrations |
Dosage adjustment of saxagliptin is recommended |
|
Sildenafil |
Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope) |
Concomitant use with sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH) contraindicated Dosage adjustment recommended for sildenafil used for erectile dysfunction |
|
Silodosin |
Possible increased silodosin concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated because of the potential for postural hypotension |
|
Sofosbuvir |
Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations |
Refer to the product label for sofosbuvir/velpatasvir/voxilaprevir for additional information |
|
St. John’s wort (Hypericum perforatum) |
Possible decreased nirmatrelvir and ritonavir concentrations, and possible loss of virologic response and development of resistance |
Concomitant use contraindicated; do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of St. John's wort due to delayed offset of St. John's wort |
|
Suvorexant |
Possible increased concentrations of suvorexant |
Avoid concomitant use |
|
Tadalafil |
Possible increased tadalafil concentrations |
Avoid concomitant use of tadalafil for pulmonary hypertension Dosage adjustment recommended for tadalafil used for erectile dysfunction |
|
Tamsulosin |
Possible increased tamsulosin concentrations |
Avoid concomitant use |
|
Tenofovir alafenamide |
Fixed combination of bictegravir, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF): Possible increased TAF concentrations if used with ritonavir-boosted nirmatrelvir |
|
|
Ticagrelor |
Possible increased concentrations of ticagrelor |
Avoid concomitant use |
|
Tofacitinib |
Possible increased concentrations of tofacitinib |
Dosage adjustment of tofacitinib is recommended |
|
Tolvaptan |
Possible increased tolvaptan concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for dehydration, hypovolemia, and hyperkalemia |
|
Trazodone |
Possible increased trazodone concentrations and increased risk of nausea, dizziness, hypotension, syncope |
Consider reduced trazodone dosage; refer to trazodone product labeling |
|
Ubrogepant |
Possible increased ubrogepant concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated |
|
Upadacitinib |
Possible increased concentrations of upadacitinib |
Dosing recommendations for upadacitinib depend on the indication; refer to the product label for additional information |
|
Vardenafil |
Possible increased concentrations of vardenafil |
Dosage adjustment of vardenafil recommended |
|
Velpatasvir |
Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations if ritonavir-boosted nirmatrelvir is used with fixed combination of sofosbuvir, velpatasvir, and voxilaprevir |
|
|
Voclosporin |
Possible increased voclosporin concentrations and increased risk of serious and/or life-threatening adverse effects |
Concomitant use contraindicated due to potential for acute and/or chronic nephrotoxicity |
|
Vorapaxar |
Possible increased concentrations of vorapaxar |
Avoid concomitant use |
|
Voxilaprevir |
Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations if ritonavir-boosted nirmatrelvir is used with fixed combination of sofosbuvir, velpatasvir, and voxilaprevir |
|
|
Zolpidem |
Possible increased concentrations of zolpidem |
Dosage reduction may be necessary for zolpidem; monitor for adverse effects |
Nirmatrelvir and Ritonavir Pharmacokinetics
Absorption
Bioavailability
Following oral administration of ritonavir-boosted nirmatrelvir, systemic exposure of nirmatrelvir increases in a less than dose proportional manner up to 750 mg (single dose) and up to 500 mg twice daily. Following administration of ritonavir-boosted nirmatrelvir twice daily for 10 days, steady-state concentrations of nirmatrelvir are attained on day 2 with approximately 2-fold accumulation.
Following oral administration of a single 300-mg dose of nirmatrelvir with 100 mg of ritonavir in healthy individuals, peak plasma concentrations of nirmatrelvir and ritonavir are achieved in 3 and 3.98 hours, respectively.
Food
Following coadministration of a suspension formulation of nirmatrelvir and ritonavir tablets with a high fat meal, mean peak plasma concentrations increased by approximately 15% and mean AUC increased by 1.6% relative to administration in a fasted state.
Distribution
Extent
Nirmatrelvir: Not known whether nirmatrelvir is distributed into human or animal milk.
Ritonavir: Limited published data indicate that ritonavir is present in human milk.
Plasma Protein Binding
Nirmatrelvir (when given with ritonavir) or ritonavir is 69 or 98–99% bound to plasma proteins, respectively.
Elimination
Metabolism
Nirmatrelvir is a CYP3A4 substrate but metabolic clearance is minimal when coadministered with ritonavir. Ritonavir is primarily metabolized by CYP3A4 and, by a lesser extent, CYP2D6.
Elimination Route
Following oral administration of a radiolabeled dose of nirmatrelvir suspension and ritonavir, 49.6% of the nirmatrelvir dose recovered in urine and 35.3% of the dose recovered in feces.
Half-Life
Nirmatrelvir: Following a single 300-mg dose of nirmatrelvir administered in conjunction with 100 mg of ritonavir, mean elimination half-life of nirmatrelvir is 6.05 hours in healthy individuals.
Ritonavir: Following a single 300-mg dose of nirmatrelvir administered in conjunction with 100 mg of ritonavir, mean elimination half-life of ritonavir is 6.15 hours in healthy individuals.
Specific Populations
Effects of age and sex on the pharmacokinetics of ritonavir-boosted nirmatrelvir not established.
Pharmacokinetics of ritonavir-boosted nirmatrelvir not evaluated in pediatric patients.
Based on adults with similar body weight to pediatric patients weighing ≥40 kg in the EPIC-HR clinical trial, the EUA-recommended dosage of ritonavir-boosted nirmatrelvir is expected to result in plasma concentrations in pediatric patients ≥12 years of age weighing ≥40 kg that are comparable to those observed in adults.
Systemic exposure is decreased in Japanese individuals compared with individuals from Western countries; however, the difference is not clinically significant.
Stability
Storage
Oral
Tablets
Blister packs containing nirmatrelvir and ritonavir tablets: 20–25°C (excursions permitted between 15–30ºC).
Actions
-
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro) (also referred to as 3C-like protease [3CLpro] or nsp5 protease).
-
Following binding of nirmatrelvir directly to the SARS-CoV-2 Mpro active site, inhibition of SARS-CoV-2 Mpro prevents viral replication.
-
Nirmatrelvir had similar cell culture antiviral activity (EC50 values 3-fold or less relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1621), and Omicron (B.1.1.529/BA.1) variants.
-
Among patients included in the EPIC-HR trial with available sequence analysis data, the following treatment-emergent SARS-CoV-2 Mpro substitutions were detected more commonly among patients treated with ritonavir-boosted nirmatrelvir: A7S/T/V, L30F, M82I/R, G109E/R/V, P132L/S, C145F/R/Y, D153H/Y, E166V, T196A/K/M/R, W207L/S/del, A260D/T/V, D263E, A266P/V, and V297A/F/del. The following Mpro ORFlab cleavage site substitutions were also detected: Q5324H/R, A5328P/S, and T6449I/P. None of these substitutions occurred in patients treated with ritonavir-boosted nirmatrelvir who were also hospitalized; clinical significance of these substitutions is not known.
-
Limited SARS-CoV-2 sequencing data are available to characterize nirmatrelvir resistance in clinical trials. The SARS-CoV-2 Mpro substitutions A260V or A260T emerged in 4% (4/97) of patients receiving ritonavir-boosted nirmatrelvir in the EPIC-HR clinical trial with available sequence analysis data.
-
Cross-resistance not expected between nirmatrelvir and anti-SARS-CoV-2 monoclonal antibodies or remdesivir.
Advice to Patients
-
Advise patients to read the Patient Information.
-
Inform patients to take ritonavir-boosted nirmatrelvir with or without food as instructed. Advise patients to swallow tablets whole and not to chew, break, or crush the tablets. Advise the patient of the importance of completing the full 5-day treatment course. If the patient misses a dose within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.
-
Inform patients that anaphylaxis, serious skin reactions, and other hypersensitivity reactions have been reported, even following a single dose of ritonavir-boosted nirmatrelvir. Advise patients to immediately discontinue the drug and to inform their healthcare provider at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
-
To ensure appropriate dosing in patients with moderate renal impairment, instruct such patients that they will be taking one 150-mg nirmatrelvir tablet with one 100-mg ritonavir tablet together twice daily for 5 days. In the event that the 150 mg/100 mg dose pack is unavailable, the pharmacist should refer to the provided instructions entitled “Important Paxlovid EUA dispensing information for patients with moderate renal impairment” for dispensing of ritonavir-boosted nirmatrelvir to patients with moderate renal impairment and patients should be informed that their daily blister card has been altered to ensure they receive the correct dose.
-
Inform patients or parent/caregivers that FDA authorized the emergency use of nirmatrelvir for use in pediatric patients (12 years of age and older and weighng at least 40 kg) with mild to moderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death.
-
Inform patients or parent/caregivers about the significant known and potential risks and benefits of ritonavir-boosted nirmatrelvir, and the extent to which such risks and benefits are unknown.
-
Advise females of reproductive potential that ritonavir may decrease the effectiveness of hormonal contraceptives and that an effective alternative contraceptive method or an additional barrier method should be used during treatment.
-
Ritonavir-boosted nirmatrelvir may interact with certain drugs, and is contraindicated for use with certain drugs. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
-
Advise patients of other important precautionary information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
|
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
|---|---|---|---|---|
|
Oral |
Kit |
150 mg nirmatrelvir; 100 mg ritonavir dose pack Each blister card contains 2 tablets: 1 tablet, nirmatrelvir 150 mg 1 tablet, ritonavir 100 mg 300 mg nirmatrelvir; 100 mg ritonavir dose pack Each blister card contains 3 tablets: 2 tablets, nirmatrelvir 150 mg 1 tablet, ritonavir 100 mg |
Paxlovid™ (each carton contains 20 tablets divided in 10 blister cards) |
Pfizer |
|
Paxlovid™ (each carton contains 30 tablets divided in 10 blister cards) |
Pfizer |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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