Paxlovid Drug Information
Generic name: NIRMATRELVIR AND RITONAVIR
Uses of Paxlovid
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.
Dosage & Administration of Paxlovid
Important Dosage and Administration Information PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are three different dose packs available: • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg. • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment. • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg (Day 1) and 150 mg;100 mg (Days 2-5) for patients with severe renal impairment. Nirmatrelvir must be co-administered with ritonavir.
Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2.
The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider's discretion. If the patient misses a dose of PAXLOVID 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. PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food.
The tablets should be swallowed whole and not chewed, broken, or crushed.
Recommended Dosage
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.
Providers should counsel patients about renal dosing instructions. No dosage adjustment is recommended in patients with mild renal impairment. In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min) or with severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis, the dosage of PAXLOVID should be reduced as shown in Table 1.
On days patients with severe renal impairment undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis. Table 1: Recommended Dose and Regimen for Patients with Renal Impairment
Use in Patients with Hepatic Impairment
No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment; therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment.
| Abbreviation: eGFR=estimated glomerular filtration rate. | ||
| Renal Function | Days of Treatment | Dose and Dose Frequency PAXLOVID should be administered at approximately the same time each day for 5 days. |
| Moderate renal impairment (eGFR ≥30 to <60 mL/min) | Days 1-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily |
| Severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis. | Day 1 | 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once |
| Days 2-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily | |
| Abbreviation: eGFR=estimated glomerular filtration rate. | ||
| Renal Function | Days of Treatment | Dose and Dose Frequency PAXLOVID should be administered at approximately the same time each day for 5 days. |
| Moderate renal impairment (eGFR ≥30 to <60 mL/min) | Days 1-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily |
| Severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis. | Day 1 | 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once |
| Days 2-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily | |
Side Effects of Paxlovid
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. 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.
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
Warnings & Cautions for Paxlovid
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).
See Table 2 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.
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.
Drug Interactions with Paxlovid
Potential for PAXLOVID to Affect Other Drugs
PAXLOVID (nirmatrelvir co-packaged with ritonavir) is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID 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 such drugs and increase the risk of adverse events. Co-administration of PAXLOVID 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.
Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 2.
Potential for Other Drugs to Affect PAXLOVID Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect.
Established and Other Potentially Significant Drug Interactions Table 2 provides a listing of 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. 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 such as ritonavir.
Table 2: Established and Other Potentially Significant Drug Interactions Co-administration contraindicated due to potential hypotension. Co-administration contraindicated due to potential for serious and/or life-threatening reactions. Antiarrhythmics amiodarone, dronedarone, flecainide, propafenone, quinidine ↑ antiarrhythmic Co-administration contraindicated due to potential for cardiac arrhythmias.
Co-administration contraindicated due to potential loss of virologic response and possible resistance. dabigatran See Pharmacokinetics, Clinical Drug Interaction Studies. Alternate antimycobacterial drugs such as Co-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias. Co-administration contraindicated due to potential for postural hypotension. is contraindicated due to potential for hyperkalemia. ivabradine ↑ ivabradine Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances.
Co-administration contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. HMG-CoA reductase inhibitors lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration contraindicated due to potential for myopathy including rhabdomyolysis. Co-administration contraindicated due to potential for acute and/or chronic nephrotoxicity.
Immunosuppressants calcineurin inhibitors: cyclosporine, tacrolimus ↑ cyclosporine ↑ tacrolimus Avoid concomitant use of calcineurin inhibitors with PAXLOVID when close monitoring of immunosuppressant concentrations is not feasible. Obtain expert consultation to appropriately manage the complexity of this co-administration. Co-administration contraindicated due to potential for hepatotoxicity and gastrointestinal adverse reactions.
Migraine medications eletriptan ↑ eletriptan Co-administration of eletriptan within at least 72 hours of PAXLOVID is contraindicated due to potential for serious adverse reactions including cardiovascular and cerebrovascular events. ubrogepant ↑ ubrogepant Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions. Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia. Opioid antagonists naloxegol ↑ naloxegol Co-administration contraindicated due to the potential for opioid withdrawal symptoms.
Pulmonary hypertension agents (PDE5 inhibitors) sildenafil (Revatio ® ) ↑ sildenafil Co-administration of sildenafil with PAXLOVID is contraindicated for use in pulmonary hypertension due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope. Co-administration contraindicated due to potential for extreme sedation and respiratory depression. Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression.
Vasopressin receptor antagonists tolvaptan ↑ tolvaptan Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia.
| Drug Class | Drugs within Class | Effect on Concentration | Clinical Comments |
|---|---|---|---|
| Alpha 1- adrenoreceptor antagonist | alfuzosin | ↑ alfuzosin | Co-administration contraindicated due to potential hypotension [see Contraindications (4) ]. |
| Alpha 1- adrenoreceptor antagonist | tamsulosin | ↑ tamsulosin | Avoid concomitant use with PAXLOVID. |
| Antianginal | ranolazine | ↑ ranolazine | Co-administration contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ]. |
| Antiarrhythmics | amiodarone, dronedarone, flecainide, propafenone, quinidine | ↑ antiarrhythmic | Co-administration contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ]. |
| Antiarrhythmics | lidocaine (systemic), disopyramide | ↑ antiarrhythmic | Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics if available. |
| Anticancer drugs | apalutamide, enzalutamide | ↓ nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4) ]. |
| Anticancer drugs | abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine | ↑ anticancer drugs | Avoid co-administration of encorafenib or ivosidenib due to potential risk of serious adverse events such as QT interval prolongation. Avoid use of neratinib, venetoclax or ibrutinib. Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects. For further information, refer to the individual product prescribing information for anticancer drug. |
| Anticoagulants | warfarin | ↑↓ warfarin | Closely monitor international normalized ratio (INR) if co-administration with warfarin is necessary. |
| rivaroxaban | ↑ rivaroxaban | Increased bleeding risk with rivaroxaban. Avoid concomitant use. | |
| dabigatran See Pharmacokinetics, Clinical Drug Interaction Studies (12.3). | ↑ dabigatran | Increased bleeding risk with dabigatran. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran prescribing information for further information. | |
| apixaban | ↑ apixaban | Combined P-gp and strong CYP3A inhibitors increase blood levels of apixaban and increase the risk of bleeding. Dosing recommendations for co-administration of apixaban with PAXLOVID depend on the apixaban dose. Refer to the apixaban prescribing information for more information. | |
| Anticonvulsants | carbamazepine, phenobarbital, primidone, phenytoin | ↓ nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4) ]. |
| Anticonvulsants | clonazepam | ↑ anticonvulsant | A dose decrease may be needed for clonazepam when co-administered with PAXLOVID and clinical monitoring is recommended. |
| Antidepressants | bupropion | ↓ bupropion and active metabolite hydroxy-bupropion | Monitor for an adequate clinical response to bupropion. |
| trazodone | ↑ trazodone | Adverse reactions of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. Refer to the trazadone prescribing information for further information. | |
| Antifungals | voriconazole | ↓ voriconazole | Avoid concomitant use of voriconazole. |
| ketoconazole, isavuconazonium sulfate, itraconazole | ↑ ketoconazole ↑ isavuconazonium sulfate ↑ itraconazole | Refer to the ketoconazole, isavuconazonium sulfate, and itraconazole prescribing information for further information. | |
| ↑ nirmatrelvir/ritonavir | A nirmatrelvir/ritonavir dose reduction is not needed. | ||
| Anti-gout | colchicine | ↑ colchicine | Co-administration contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4) ]. |
| Anti-HIV protease inhibitors | atazanavir, darunavir, tipranavir | ↑ protease inhibitor | For further information, refer to the respective protease inhibitors' prescribing information. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or protease inhibitor adverse events. |
| Anti-HIV | efavirenz, maraviroc, nevirapine, zidovudine, bictegravir/ emtricitabine/ tenofovir | ↑ efavirenz ↑ maraviroc ↑ nevirapine ↓ zidovudine ↑ bictegravir ↔ emtricitabine ↑ tenofovir | For further information, refer to the respective anti-HIV drugs prescribing information. |
| Anti-infective | clarithromycin, erythromycin | ↑ clarithromycin ↑ erythromycin | Refer to the respective prescribing information for anti-infective dose adjustment. |
| Antimycobacterial | rifampin, rifapentine | ↓ nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered [see Contraindications (4) ]. |
| Antimycobacterial | bedaquiline | ↑ bedaquiline | Refer to the bedaquiline prescribing information for further information. |
| rifabutin | ↑ rifabutin | Refer to the rifabutin prescribing information for further information on rifabutin dose reduction. | |
| Antipsychotics | lurasidone, pimozide | ↑ lurasidone ↑ pimozide | Co-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. |
| Antipsychotics | quetiapine | ↑ quetiapine | If co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations. |
| clozapine | ↑ clozapine | If co-administration is necessary, consider reducing the clozapine dose and monitor for adverse reactions. | |
| Benign prostatic hyperplasia agents | silodosin | ↑ silodosin | Co-administration contraindicated due to potential for postural hypotension [see Contraindications (4) ]. |
| Calcium channel blockers | amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil | ↑ calcium channel blocker | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PAXLOVID. If co-administered, refer to the individual product prescribing information for calcium channel blocker for further information. |
| Cardiac glycosides | digoxin | ↑ digoxin | Caution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels. Refer to the digoxin prescribing information for further information. |
| Cardiovascular agents | eplerenone | ↑ eplerenone | Co-administration with eplerenone is contraindicated due to potential for hyperkalemia [see Contraindications (4) ]. |
| ivabradine | ↑ ivabradine | Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances [see Contraindications (4) ]. | |
| Cardiovascular agents | aliskiren, ticagrelor, vorapaxar clopidogrel | ↑ aliskiren ↑ ticagrelor ↑ vorapaxar ↓ clopidogrel active metabolite | Avoid concomitant use with PAXLOVID. |
| cilostazol | ↑ cilostazol | Dosage adjustment of cilostazol is recommended. Refer to the cilostazol prescribing information for more information. | |
| mavacamten | ↑ mavacamten | Co-administration with mavacamten may increase mavacamten plasma concentration and increase the risk of heart failure. Discontinue mavacamten for the duration of PAXLOVID treatment. Resumption of mavacamten within 5 days of completing PAXLOVID may result in higher exposure of mavacamten. Refer to the mavacamten prescribing information for more information. | |
| Corticosteroids primarily metabolized by CYP3A | betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone | ↑ corticosteroid | Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. However, the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A inhibitor is low. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone should be considered. |
| Cystic fibrosis transmembrane conductance regulator potentiators | lumacaftor/ivacaftor | ↓ nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4) ]. |
| Cystic fibrosis transmembrane conductance regulator potentiators | ivacaftor elexacaftor/tezacaftor/ ivacaftor tezacaftor/ivacaftor | ↑ ivacaftor ↑ elexacaftor/tezacaftor/ ivacaftor ↑ tezacaftor/ivacaftor | Reduce dosage when co-administered with PAXLOVID. Refer to the individual product prescribing information for more information. |
| Dipeptidyl peptidase 4 (DPP4) inhibitors | saxagliptin | ↑ saxagliptin | Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin prescribing information for more information. |
| Endothelin receptor antagonists | bosentan | ↑ bosentan ↓ nirmatrelvir/ritonavir | Discontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID. Refer to the bosentan prescribing information for further information. |
| Ergot derivatives | dihydroergotamine, ergotamine, methylergonovine | ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine | Co-administration contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4) ]. |
| Hepatitis C direct acting antivirals | elbasvir/grazoprevir | ↑ antiviral | Increased grazoprevir concentrations can result in alanine transaminase (ALT) elevations. |
| glecaprevir/pibrentasvir | Avoid concomitant use of glecaprevir/pibrentasvir with PAXLOVID. | ||
| ombitasvir/paritaprevir/ritonavir and dasabuvir | Refer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information. | ||
| sofosbuvir/velpatasvir/voxilaprevir | Refer to the sofosbuvir/velpatasvir/voxilaprevir prescribing information for further information. Patients on ritonavir-containing HCV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or HCV drug adverse events with concomitant use. | ||
| Herbal products | St. John's Wort ( hypericum perforatum ) | ↓ nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4) ]. |
| HMG-CoA reductase inhibitors | lovastatin, simvastatin | ↑ lovastatin ↑ simvastatin | Co-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ]. If treatment with PAXLOVID is considered medically necessary, discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID, during the 5 days of PAXLOVID treatment, and for 5 days after completing PAXLOVID. |
| HMG-CoA reductase inhibitors | atorvastatin | ↑ atorvastatin | Consider temporary discontinuation of atorvastatin during treatment with PAXLOVID. Atorvastatin does not need to be withheld prior to or after completing PAXLOVID. |
| Hormonal contraceptive | ethinyl estradiol | ↓ ethinyl estradiol | An additional, non-hormonal method of contraception should be considered during the 5 days of PAXLOVID treatment and until one menstrual cycle after stopping PAXLOVID. |
| Immunosuppressants | voclosporin | ↑ voclosporin | Co-administration contraindicated due to potential for acute and/or chronic nephrotoxicity [see Contraindications (4) ]. |
| Immunosuppressants | calcineurin inhibitors: cyclosporine, tacrolimus | ↑ cyclosporine ↑ tacrolimus | Avoid concomitant use of calcineurin inhibitors with PAXLOVID when close monitoring of immunosuppressant concentrations is not feasible. If co-administered, dose adjustment of the immunosuppressant and close and regular monitoring for immunosuppressant concentrations and adverse reactions are recommended during and after treatment with PAXLOVID. Obtain expert consultation to appropriately manage the complexity of this co-administration [see Warnings and Precautions (5.1) ]. |
| mTOR inhibitors: everolimus, sirolimus | ↑ everolimus ↑ sirolimus | Avoid concomitant use of everolimus and sirolimus and PAXLOVID. Refer to the individual immunosuppressant prescribing information and latest guidelines for further information. | |
| Janus kinase (JAK) inhibitors | tofacitinib | ↑ tofacitinib | Dosage adjustment of tofacitinib is recommended. Refer to the tofacitinib prescribing information for more information. |
| upadacitinib | ↑ upadacitinib | Dosing recommendations for co-administration of upadacitinib with PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib prescribing information for more information. | |
| Long-acting beta-adrenoceptor agonist | salmeterol | ↑ salmeterol | Avoid concomitant use with PAXLOVID. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Microsomal triglyceride transfer protein (MTTP) inhibitor | lomitapide | ↑ lomitapide | Co-administration contraindicated due to potential for hepatotoxicity and gastrointestinal adverse reactions [see Contraindications (4) ]. |
| Migraine medications | eletriptan | ↑ eletriptan | Co-administration of eletriptan within at least 72 hours of PAXLOVID is contraindicated due to potential for serious adverse reactions including cardiovascular and cerebrovascular events [see Contraindications (4) ]. |
| ubrogepant | ↑ ubrogepant | Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions [see Contraindications (4) ]. | |
| Migraine medications | rimegepant | ↑ rimegepant | Avoid concomitant use with PAXLOVID. |
| Mineralocorticoid receptor antagonists | finerenone | ↑ finerenone | Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia [see Contraindications (4) ]. |
| Muscarinic receptor antagonists | darifenacin | ↑ darifenacin | The darifenacin daily-dose should not exceed 7.5 mg when co-administered with PAXLOVID. Refer to the darifenacin prescribing information for more information. |
| Narcotic analgesics | fentanyl, hydrocodone, oxycodone, meperidine | ↑ fentanyl ↑ hydrocodone ↑ oxycodone ↑ meperidine | Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl, hydrocodone, oxycodone, or meperidine is concomitantly administered with PAXLOVID. If concomitant use with PAXLOVID is necessary, consider a dosage reduction of the narcotic analgesic and monitor patients closely at frequent intervals. Refer to the individual product prescribing information for more information. |
| methadone | ↓ methadone | Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly. | |
| Neuropsychiatric agents | suvorexant | ↑ suvorexant | Avoid concomitant use of suvorexant with PAXLOVID. |
| aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin | ↑ aripiprazole ↑ brexpiprazole ↑ cariprazine ↑ iloperidone ↑ lumateperone ↑ pimavanserin | Dosage adjustment of aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, and pimavanserin is recommended. Refer to the individual product prescribing information for more information. | |
| Non-opioid analgesic (selective blocker of Na v 1.8 sodium channels) | suzetrigine | ↑ suzetrigine and active metabolite M6‑SUZ | Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions [see Contraindications (4) ]. |
| Opioid antagonists | naloxegol | ↑ naloxegol | Co-administration contraindicated due to the potential for opioid withdrawal symptoms [see Contraindications (4) ]. |
| Pulmonary hypertension agents (PDE5 inhibitors) | sildenafil (Revatio ® ) | ↑ sildenafil | Co-administration of sildenafil with PAXLOVID is contraindicated for use in pulmonary hypertension due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope [see Contraindications (4) ]. |
| Pulmonary hypertension agents (PDE5 inhibitors) | tadalafil (Adcirca ® ) | ↑ tadalafil | Avoid concomitant use of tadalafil with PAXLOVID for pulmonary hypertension. |
| Pulmonary hypertension agents (sGC stimulators) | riociguat | ↑ riociguat | Dosage adjustment is recommended for riociguat when used for pulmonary hypertension. Refer to the riociguat prescribing information for more information. |
| Erectile dysfunction agents (PDE5 inhibitors) | avanafil | ↑ avanafil | Do not use PAXLOVID with avanafil because a safe and effective avanafil dosage regimen has not been established. |
| sildenafil, tadalafil, vardenafil | ↑ sildenafil ↑ tadalafil ↑ vardenafil | Dosage adjustment is recommended for use of sildenafil, tadalafil or vardenafil with PAXLOVID when used for erectile dysfunction. Refer to the individual product prescribing information for more information. | |
| Sedative/hypnotics | triazolam, oral midazolam | ↑ triazolam ↑ midazolam | Co-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4) ]. |
| Sedative/hypnotics | buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem | ↑ sedative/hypnotic | A dose decrease may be needed for these drugs when co-administered with PAXLOVID and monitoring for adverse events. |
| midazolam (administered parenterally) | ↑ midazolam | Co-administration of midazolam (parenteral) should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Refer to the midazolam prescribing information for further information. | |
| Serotonin receptor 1A agonist/ serotonin receptor 2A antagonist | flibanserin | ↑ flibanserin | Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression [see Contraindications (4) ]. |
| Vasopressin receptor antagonists | tolvaptan | ↑ tolvaptan | Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia [see Contraindications (4) ]. |
Pregnancy Safety for Paxlovid
Pregnancy Risk Summary Available data on the use of nirmatrelvir during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug associated risk of miscarriage (see Data ).
There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ). In an embryo-fetal development study with nirmatrelvir, reduced fetal body weights following oral administration of nirmatrelvir to pregnant rabbits were observed at systemic exposures (AUC) approximately 11 times higher than clinical exposure at the approved human dose of PAXLOVID. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures (AUC) greater than or equal to 3 times higher than clinical exposure at the approved human dose of PAXLOVID (see Data ).
In embryo-fetal developmental studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at systemic exposures (AUC) 5 (rat) or 8 (rabbits) times higher than clinical exposure at the approved human dose of PAXLOVID (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk 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. Data Human Data Ritonavir Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,500 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Animal Data Nirmatrelvir Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis. No biologically significant developmental effects were observed in the rat EFD study.
At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC 24 ) in rats was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed up to the highest dose tested, 1,000 mg/kg/day.
No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC 24 ) approximately 3 times higher than clinical exposures at the approved human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 showed no adverse findings. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir-treated versus control animals, a decrease in the body weight of offspring was observed on Postnatal Day (PND) 17 (8% decrease) and PND 21 (up to 7% decrease) in the absence of maternal toxicity.
No significant differences in offspring body weight were observed from PND 28 to PND 56. No body weight changes in the offspring were noted at 300 mg/kg/day, where maternal systemic exposure (AUC 24 ) was approximately 6 times higher than clinical exposures at the approved human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures (AUC) approximately 10 times higher than exposure at the approved human dose of PAXLOVID.
In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8 times higher than exposure at the approved human dose of PAXLOVID. In a PPND study in rats, administration of mg/kg/day ritonavir from GD 6 through PND 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10 times the exposure at the approved human dose of PAXLOVID.
Pediatric Use of Paxlovid
Pediatric Use The optimal dose of PAXLOVID has not been established in pediatric patients.
Contraindications for Paxlovid
- PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions 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
- Non-opioid analgesic (selective blocker of Na v 1.8 sodium channels): suzetrigine
- 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 )
- History of clinically significant hypersensitivity reactions to the active ingredients (nirmatrelvir or ritonavir) or any other components.
- Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
- Co-administration with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
Overdosage Information for Paxlovid
Treatment of overdose with PAXLOVID should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with PAXLOVID.
Clinical Studies of Paxlovid
Efficacy in Subjects at High Risk of Progression to Severe COVID-19 (EPIC-HR) EPIC-HR (NCT04960202) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Subjects with COVID-19 symptom onset of ≤5 days were included in the study.
The trial excluded individuals with a history of prior COVID-19 infection or vaccination and excluded individuals taking any medications with clinically significant drug interactions with PAXLOVID. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set, the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days).
A total of 2,113 subjects were randomized to receive either PAXLOVID or placebo. The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups. The proportions of subjects who discontinued treatment due to an adverse event were 2.0% in the PAXLOVID group and 4.2% in the placebo group.
Table 9 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for PAXLOVID compared to placebo was Table 9: COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 in Non-Hospitalized Adults with COVID-19 (mITT1 Analysis Set): EPIC-HR Consistent results were observed in the mITT and mITT2 analysis populations. Similar trends have been observed across subgroups of subjects (see Figure 1 ).
Figure 1: Subgroup Analysis of Adults with COVID-19 Dosed within 5 Days of Symptom Onset with COVID-19 Related Hospitalization or Death from Any Cause Through Day 28: EPIC-HR Abbreviations: BMI=body mass index; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT=modified intent-to-treat; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. Figure 1
Trial in Unvaccinated Subjects Without a Risk Factor for Progression to Severe COVID-19 or Subjects Fully Vaccinated Against COVID-19 With at Least One Factor for Progression to Severe COVID-19 (EPIC-SR) PAXLOVID is not indicated for the treatment of COVID-19 in patients without a risk factor for progression to severe COVID-19. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e., completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR.
The primary endpoint in this trial, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among PAXLOVID versus placebo recipients, was not met. In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction relative to placebo for the secondary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 was observed.
Post-Exposure Prophylaxis Trial PAXLOVID is not indicated for the post-exposure prophylaxis of COVID-19. In a double-blind, double-dummy, placebo-controlled trial, the efficacy of PAXLOVID when administered for 5 or 10 days as post-exposure prophylaxis of COVID-19 was evaluated. Eligible subjects were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at baseline and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2.
The primary endpoint for this trial was not met. The primary endpoint was the risk reduction between the 5-day and 10-day PAXLOVID regimens versus placebo in the proportion of subjects who developed RT-PCR or RAT-confirmed symptomatic SARS-CoV-2 infection through Day 14 who had a negative SARS-CoV-2 RT-PCR result at baseline. There was not a statistically significant risk reduction versus placebo for either the 5-day or 10-day PAXLOVID regimen.
| PAXLOVID (N=977) | Placebo (N=989) | |
|---|---|---|
| Abbreviations: CI=confidence interval; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT1=modified intent-to-treat 1 (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment). The determination of primary efficacy was based on a planned interim analysis of 754 subjects in mITT population. The estimated risk reduction was -6.5% with a 95% CI of (-9.3%, -3.7%) and 2-sided p-value <0.0001. | ||
| COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 | ||
| n (%) | 9 (0.9%) | 64 (6.5%) |
| Reduction Relative to Placebo The estimated cumulative proportion of subjects hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalization and death status through Day 28 were censored at the time of study discontinuation. (95% CI), % | -5.6 (-7.3, -4.0) | |
| COVID-19 Related Hospitalization Through Day 28, % | 9 (0.9%) | 63 (6.4%) |
| All-cause Mortality Through Day 28 For the secondary endpoint of all-cause mortality through Week 24, there were 0 and 15 (1%) events in the PAXLOVID arm and placebo arm, respectively., % | 0 | 12 (1.2%) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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