Nirmatrelvir, ritonavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Overview
Nirmatrelvir, ritonavir is a strong CYP3A inhibitor, that is FDA approved for the treatment of PAXLOVID is a nirmatrelvir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor,that is FDA approved for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.. Common adverse reactions include Most common adverse reactions (incidence ≥1% and greater incidence than in the placebo group) are dysgeusia and diarrhea..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- PAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.
- Limitations of Use
PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19. The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily in the morning and at bedtime for 5 days.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nirmatrelvir, ritonavir in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nirmatrelvir, ritonavir in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nirmatrelvir, ritonavir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nirmatrelvir, ritonavir in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nirmatrelvir, ritonavir in pediatric patients.
Contraindications
- PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome] to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product.
- PAXLOVID is contraindicated with drugs that are primarily metabolized by CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions and drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. There are certain other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, interruption, or therapeutic monitoring is recommended. Drugs listed in this section are a guide and not considered a comprehensive list of all drugs that may be contraindicated with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor like PAXLOVID.
- Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions.
- Alpha 1-adrenoreceptor antagonist: alfuzosin.
- Antianginal: ranolazine.
- Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
- Anti-gout: colchicine (in patients with renal and/or hepatic impairment.
- Antipsychotics: lurasidone, pimozide.
- Benign prostatic hyperplasia agents: silodosin
- Cardiovascular agents: eplerenone, ivabradine
- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use:
- Immunosuppressants: voclosporin.
- Microsomal triglyceride transfer protein inhibitor: lomitapide.
- Migraine medications: eletriptan, ubrogepant.
- Mineralocorticoid receptor antagonists: finerenone.
- Opioid antagonists: naloxegol.
- PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH).
- Sedative/hypnotics: triazolam, oral midazolam.
- Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin.
- Vasopressin receptor antagonists: tolvaptan.
- Drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer.
- Anticancer drugs: apalutamide, enzalutamide.
- Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin.
- Antimycobacterials: rifampin, rifapentine.
- Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor.
- Herbal products: St. John's Wort (hypericum perforatum).
- Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions.
Warnings
- Risk of Serious Adverse Reactions Due to Drug Interactions
- Initiation of PAXLOVID, which contains ritonavir, a strong CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:
- Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
- Loss of therapeutic effect of PAXLOVID and possible development of viral resistance.
- Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (e.g., tacrolimus, cyclosporine), followed by calcium channel blockers.
- Prior to prescribing PAXLOVID, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors). for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID.
- Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed.
- Initiation of PAXLOVID, which contains ritonavir, a strong CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:
- Hypersensitivity Reactions
- Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID .If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.
- Hepatotoxicity
- Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.
- Risk of HIV-1 Resistance Development
- Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.*The safety of PAXLOVID is based on two Phase 2/3 randomized, placebo-controlled trials in symptomatic adult subjects 18 years of age and older with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Subjects in both studies received PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo every 12 hours for 5 days for the treatment of mild-to-moderate COVID-19 within 5 days of symptom onset.
- Trial C4671005 (EPIC-HR) enrolled subjects who were at high risk for progression to severe disease.
- Trial C4671002 (EPIC-SR) enrolled subjects who were at standard risk for progression to severe disease (previously unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease).
- Adverse reactions were those reported while subjects were on study medication and through 28 days after the last dose of study treatment.
- In Trial C4671005 (EPIC-HR), 1,038 subjects received PAXLOVID and 1,053 subjects received placebo. The most common adverse reactions (≥1% incidence in the PAXLOVID group and occurring at a greater frequency than in the placebo group) were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively).
- Among vaccinated or unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease in Trial C4671002 (EPIC-SR), 540 subjects received PAXLOVID and 528 subjects received placebo. The adverse reactions observed were consistent with those observed in EPIC-HR.
- Trial C4671028 (EPIC-SRI) was a Phase 1, open-label trial that evaluated the effects of severe renal impairment on the pharmacokinetics, safety, and tolerability of PAXLOVID in non-hospitalized adult participants with COVID-19 and severe renal impairment. A total of 15 subjects with severe renal impairment were enrolled in this trial, with 12 subjects receiving intermittent hemodialysis and 3 subjects not on hemodialysis. Subjects received nirmatrelvir/ritonavir 300 mg/100 mg once on Day 1 followed by nirmatrelvir/ritonavir 150 mg/100 mg once daily from Days 2-5. The safety profile of PAXLOVID in subjects with severe renal impairment, including those requiring hemodialysis, was consistent with the safety profile observed in the Phase 2/3 randomized, placebo-controlled trials.
- Emergency Use Authorization Experience in Subjects with COVID-19.
The following adverse reactions have been identified during use of PAXLOVID under Emergency Use Authorization.
- Immune System Disorders: Anaphylaxis, hypersensitivity reactions.
- Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome.
- Nervous System Disorders: Headache
- Vascular Disorders: Hypertension.
- Gastrointestinal Disorders: Abdominal pain, nausea, vomiting.
- General Disorders and Administration Site Conditions: Malaise
Postmarketing Experience
There is limited information regarding Nirmatrelvir, ritonavir Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Nirmatrelvir, ritonavir Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Nirmatrelvir, ritonavir in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nirmatrelvir, ritonavir in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nirmatrelvir, ritonavir during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in geriatric settings.
Gender
There is no FDA guidance on the use of Nirmatrelvir, ritonavir with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nirmatrelvir, ritonavir with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nirmatrelvir, ritonavir in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Nirmatrelvir, ritonavir in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Nirmatrelvir, ritonavir Administration in the drug label.
Monitoring
There is limited information regarding Nirmatrelvir, ritonavir Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Nirmatrelvir, ritonavir and IV administrations.
Overdosage
There is limited information regarding Nirmatrelvir, ritonavir overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Nirmatrelvir, ritonavir Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Nirmatrelvir, ritonavir Mechanism of Action in the drug label.
Structure
There is limited information regarding Nirmatrelvir, ritonavir Structure in the drug label.
Pharmacodynamics
There is limited information regarding Nirmatrelvir, ritonavir Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Nirmatrelvir, ritonavir Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Nirmatrelvir, ritonavir Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Nirmatrelvir, ritonavir Clinical Studies in the drug label.
How Supplied
There is limited information regarding Nirmatrelvir, ritonavir How Supplied in the drug label.
Storage
There is limited information regarding Nirmatrelvir, ritonavir Storage in the drug label.
Images
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Patient Counseling Information
There is limited information regarding Nirmatrelvir, ritonavir Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Nirmatrelvir, ritonavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Nirmatrelvir, ritonavir Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Nirmatrelvir, ritonavir Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.