Store at room temperature (15C to 30C).
Control #: 274571
October 3, 2023
PAXLOVID (nirmatrelvir tablets; ritonavir tablets) is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
PAXLOVID is not authorized:
The safety and effectiveness of PAXLOVID have not been established in pediatric patients (<18 years of age).
Clinical studies of PAXLOVID include participants 65 years of age and older and their data contributes to the overall assessment of safety and efficacy (see 14 CLINICAL TRIALS). Of the total number of participants in the pivotal trial randomized to receive PAXLOVID (N=1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.
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 (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).
PAXLOVID is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
PAXLOVID is also contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance (see Table 1 and 9 DRUG INTERACTIONS):
| |||
| Drug Class | Drugs Within Class that are Contraindicated with PAXLOVID | Clinical Comment | |
|---|---|---|---|
| Alpha1-Adrenoreceptor Antagonist | alfuzosin | Potential for serious reactions, such as hypotension (see Table 4). | |
| Antianginal | ranolazine | Potential for serious and/or life-threatening reactions. | |
| Antiarrhythmics | amiodarone, bepridila, dronedarone, flecainide, propafenone, quinidinea | Potential for serious and/or life-threatening reactions, such as cardiac arrhythmias. | |
| Antibiotic | fusidic acid | Potential of increased fusidic acid-associated adverse events, such as hepatitis or bone marrow suppression. | |
| Anticancer | apalutamide | Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of PAXLOVID and potential loss of virologic response. In addition, exposure of apalutamide may increase with co-administration of PAXLOVID that may lead to serious adverse events including seizure and fracture. | |
| neratinib | Potential for serious and/or life-threatening reactions including hepatotoxicity. | ||
| venetoclaxd | Concomitant use of strong CYP3A inhibitors, such as PAXLOVID, and venetoclax may increase the risk of tumor lysis syndrome at the dose initiation and during the ramp-up phase. | ||
| Anticoagulant | rivaroxaban | Potential of increased rivaroxaban plasma concentrations which may lead to risk of increased bleeding. | |
| Anticonvulsants | carbamazepine, phenobarbital, phenytoin | Decreased plasma concentration and reduced clinical effects of nirmatrelvir and ritonavir. | |
| Antifungal | voriconazole | Significant reduction in voriconazole plasma concentrations and possible loss of effect (see Table 4). | |
| Anti-gout | colchicine | Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment (see Table 4). | |
| Antihistamines | astemizolea, | Potential for serious and/or life-threatening reactions, such as cardiac arrhythmias. | |
| Antimycobacterial | rifampin | Decreased plasma concentration and reduced clinical effects of nirmatrelvir and ritonavir. | |
| Antipsychotics | lurasidone | Potential for serious and/or life-threatening reactions. | |
| pimozide | Potential for serious and/or life-threatening reactions, such as cardiac arrhythmias. | ||
| Benign Prostatic Hyperplasia Agents | silodosin | Potential for postural hypotension. | |
| Cardiovascular Agents | eplerenone ivabradine | Potential for hyperkalemia. Potential for bradycardia or conduction disturbances. | |
| Ergot Derivatives | dihydroergotamine, ergonovine, ergotamine, methylergonovinea | Potential for serious and/or life-threatening reactions, such as acute ergot toxicity characterized by vasospasm and tissue ischemia. | |
| GI Motility Agent | cisapridea | Potential for serious and/or life-threatening reactions, such as cardiac arrhythmias. | |
| Herbal Products | St. John’s wort (Hypericum perforatum) | May lead to loss of virologic response and possible resistance to PAXLOVID or to the class of protease inhibitors. | |
| Lipid-modifying Agents | |||
| HMG-CoA Reductase Inhibitors | lovastatin, simvastatin | Potential for serious reactions, such as risk of myopathy including rhabdomyolysis. | |
| Microsomal Triglyceride Transfer Protein (MTTP) Inhibitor | lomitapide | Potential for serious reactions, such as hepatotoxicity. | |
| Long-Acting Beta- Adrenoceptor | salmeterol | May result in potential increased risk of cardiovascular adverse events associated with salmeterol. | |
| Migraine Medications | 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 | Potential for serious adverse reactions. | ||
| Mineralocorticoid Receptor Antagonists | finerenone | Potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia. | |
| Opioid Antagonists | naloxegol | Potential for opioid withdrawal symptoms. | |
| PDE5 Inhibitors | sildenafilb, only when used for the treatment of pulmonary arterial hypertension (PAH) | Potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes, and prolonged erection. | |
| vardenafil, when used for the treatment of erectile dysfunction or PAH | Potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes, and prolonged erection. | ||
| Sedative/Hypnotics | orally administered midazolamc, triazolam | Potential for serious and/or life-threatening reactions, such as prolonged or increased sedation or respiratory depression. | |
| Serotonin Receptor 1A Agonist/Serotonin Receptor 2A Antagonist | flibanserin | Potential for hypotension, syncope, and CNS depression. | |
| Vasopressin Receptor Antagonists | tolvaptan | Potential for dehydration, hypovolemia and hyperkalemia. | |
PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer (see 9 DRUG INTERACTIONS):
Serious Warnings and Precautions
Dosage Modification in Patients with Moderate Renal Impairment
PAXLOVID is a combination of nirmatrelvir tablets co-packaged with ritonavir tablets. The daily dose is two tablets of nirmatrelvir and one ritonavir tablet twice daily. Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment. No dosage adjustment is needed in patients with mild renal impairment (eGFR 60 to <90 mL/min). In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), reduce the dosage of PAXLOVID to one tablet of nirmatrelvir and one tablet ritonavir every 12 hours (see 4 DOSAGE AND ADMINISTRATION, 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING, and 10 CLINICAL PHARMACOLOGY).
PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min).
Drug Interactions
Initiation of PAXLOVID, a 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. Drug-drug interactions leading to potentially serious and/or life-threatening reactions are possible due to the effects of ritonavir on the hepatic metabolism of certain drugs.
Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir will result in plasma levels of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.
The dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together orally twice daily for 5 days. Patients should be advised to complete the full 5-day treatment course.
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. 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 professional’s discretion.
The following medical conditions or other factors place patients at high risk for progression to severe COVID-19:
Other medical conditions or factors (i.e., race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and is not limited to the medical conditions or factors listed above.
Recommended Dose:
The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together orally twice daily for 5 days. PAXLOVID should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 5 days of symptom onset (see 10.3 Pharmacokinetics).
Patients with Renal Impairment:
Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment (see 10.3 Pharmacokinetics, Special Populations and Conditions). No dosage adjustment is needed in patients with mild renal impairment (eGFR 60 to <90 mL/min).
In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), reduce the dosage of PAXLOVID to 150 mg of nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days. Healthcare professionals should counsel patients about renal dosing instructions (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING, and 10.3 Pharmacokinetics).
PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min).
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 hepatic impairment (Child-Pugh Class C); therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment (see Hepatic/Biliary/Pancreatic).
PAXLOVID (both nirmatrelvir; ritonavir tablets) can be taken orally with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.
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.
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.
For management of a suspected drug overdose, contact your regional poison control centre.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Oral (co-packaged for use) | Nirmatrelvir Tablet (pink): 150mg
| Tablet core: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate Film coat: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol and titanium dioxide |
| Ritonavir Tablet (white): 100mg | Tablet core: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. Film coat: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc and titanium dioxide. |
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. It is supplied in two different Dose Packs.
Nirmatrelvir tablets and ritonavir tablets are supplied in separate cavities within the same child resistant blister card.
| Dose Packs | Content | Description |
|---|---|---|
| 300 mg nirmatrelvir; 100 mg ritonavir | Each Carton Contains: | Nirmatrelvir tablets: Oval, pink immediate-release, film‑coated tablets debossed with "PFE" on one side and "3CL" on the other side. |
| Each Blister Carda Contains: | Nirmatrelvir tablets: Oval, pink immediate-release, film‑coated tablets debossed with "PFE" on one side and "3CL" on the other side. | |
| 150 mg nirmatrelvir; 100 mg ritonavir | Each Carton Contains: | Nirmatrelvir tablets: Oval, pink immediate-release, film‑coated tablets debossed with "PFE" on one side and "3CL" on the other side. |
| Each Blister Carda Contains: | Nirmatrelvir tablets: Oval, pink immediate-release, film‑coated tablets debossed with "PFE" on one side and "3CL" on the other side. | |
| ||
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
General
There are limited clinical data available for PAXLOVID. Serious and unexpected adverse events may occur that have not been previously reported with PAXLOVID use.
Risk of Serious Adverse Reactions Due to Drug Interactions
Initiation of PAXLOVID, a 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. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PAXLOVID, respectively.
These interactions may lead to:
See Table 1 and Table 4 for clinically significant drug interactions, including contraindicated drugs. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).
Co-administration of PAXLOVID with calcineurin inhibitors and mTOR inhibitors:
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).
Consultation of a multidisciplinary group (e.g., involving physicians, specialists in immunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle the complexity of this co-administration by closely and regularly monitoring immunosuppressant serum concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see 9 DRUG INTERACTIONS).
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 (see 9 DRUG INTERACTIONS).
Hepatic/Biliary/Pancreatic
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.
Immune
Allergic Reactions/Hypersensitivity reactions have been reported with PAXLOVID including urticaria, angioedema, dyspnea, mild skin eruptions, and pruritus. Cases of anaphylaxis, TEN, and Stevens-Johnson syndrome have also been reported with components of PAXLOVID (refer to NORVIR labeling). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care (see 8.5 Post-Market Adverse Reactions)
Reproductive Health: Female and Male Potential
Women of childbearing potential should use effective contraception during treatment with PAXLOVID. Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with PAXLOVID (see 7.1.1 Pregnant Women and 9 DRUG INTERACTIONS).
Fertility
There are no available human data to evaluate the effect of PAXLOVID on fertility. No effects on fertility were observed in a study performed in rats with nirmatrelvir at systemic exposures (AUC) approximately 8 times higher than clinical exposure at the authorized human dose of PAXLOVID. Ritonavir produced no effects on fertility in rats (see Reproductive and Developmental Toxicity).
Teratogenic risk
There are limited data from the use of PAXLOVID in pregnant women. PAXLOVID should be used during pregnancy only if the potential benefits outweigh the potential risks for the mother and the fetus.
Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower fetal body weights) at systemic exposures (AUC) approximately 10 times higher than clinical exposure at the authorized human dose of PAXLOVID. In an embryo-fetal developmental toxicity study in pregnant rats, there was no nirmatrelvir-related effect on fetal morphology or embryo-fetal viability at systemic exposures (AUC) approximately 8 times higher than the clinical exposure at the authorized human dose of PAXLOVID. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Animal data with ritonavir have shown reproductive toxicity (see Reproductive and Developmental Toxicity).
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 (see 4 DOSAGE AND ADMINISTRATION, 2 CONTRAINDICATIONS, and 9 DRUG INTERACTIONS).
PAXLOVID should not be used in pregnant women unless the potential benefits outweigh the potential risks to the fetus.
There are no available human data on the use of nirmatrelvir during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
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 10 times higher than clinical exposure at the authorized 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 authorized human dose of PAXLOVID (see Reproductive and Developmental Toxicity).
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. Based on prospective reports to the antiretroviral pregnancy registry of approximately 6,900 live births following exposure to ritonavir-containing regimens (including over 3,400 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). The prevalence of birth defects in live births was 2.3% (95% confidence interval [CI]: 1.9% 2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4% 3.6%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.
In animal reproduction studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at doses (based on body surface area conversions) or systemic exposures (AUC) greater than or equal to 3 times higher than clinical doses or exposure at the authorized human dose of PAXLOVID (see Reproductive and Developmental Toxicity).
There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the breastfed infant, or the effects on milk production. A transient decrease in body weight was observed in the nursing offspring of rats exposed to nirmatrelvir at maternal systemic exposure (AUC) approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID (see Reproductive and Developmental Toxicity). Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition.
The safety and effectiveness of PAXLOVID have not been established in pediatric patients.
Clinical studies of PAXLOVID include subjects 65 years of age and older and their data contributes to the overall assessment of safety and efficacy (see 14 CLINICAL TRIALS). Of the total number of subjects in EPIC-HR randomized to receive PAXLOVID (N=1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful for identifying and approximating rates of adverse drug reactions in real-world use.
The safety of PAXLOVID is based on data from Study C4671005 (EPIC-HR), a Phase 2/3 randomized, placebo-controlled trial in non hospitalized adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection (see 14 CLINICAL TRIALS). A total of 2,224 symptomatic adult subjects 18 years of age and older who are at high risk of developing severe COVID-19 illness received at least one dose of either PAXLOVID (n=1,109) or placebo (n=1,115). Adverse events were those reported while subjects were on study medication and through Day 34 after initiating study treatment. PAXLOVID [300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir] or matching placebo were to be taken twice daily for 5 days.
Adverse events (all grades regardless of causality) in the PAXLOVID group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), hypertension (1% and <1%), and myalgia (1% and <1%).
The proportions of subjects who discontinued treatment due to an adverse event were 2% in the PAXLOVID group and 4% in the placebo group.
| |||
PAXLOVID | Placebo | ||
|---|---|---|---|
Nervous system disorders Dysgeusia Headache |
5.6 1.4 |
0.3 1.3 |
|
Gastrointestinal Diarrhoea Vomiting |
3.1 1.1 |
1.6 0.8 |
|
The following adverse reactions have been identified during post-authorization use of PAXLOVID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious Drug Interactions
Initiation of PAXLOVID, a 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.
Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PAXLOVID, respectively. These interactions may lead to:
See Table 4 for clinically significant drug interactions, including contraindicated drugs. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).
Potential for PAXLOVID to Affect Other Drugs
PAXLOVID is a strong inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. 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 (see 2 CONTRAINDICATIONS). Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 4.
Potential for Ritonavir to Affect Other Drugs
When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted (see Table 4).
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 the therapeutic effect of PAXLOVID.
Established or Potentially Significant Drug Interactions
Table 4 provides listing of clinically significant drug interactions, including contraindicated drugs. The drugs listed in Table 4 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. Table 5 summarizes the effects of co-administration of PAXLOVID with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and Cmax.
| |||
| Concomitant Drug Class: Drug Name | Effect on Concentration of PAXLOVID or Concomitant Drug | Clinical Comment | |
|---|---|---|---|
Alpha1-adrenoreceptor Antagonist: | |||
alfuzosin | ↑ alfuzosin | Based on results of a drug interaction study with ketoconazole, another potent inhibitor of CYP3A4, a significant increase in alfuzosin exposure is expected in the presence of ritonavir (600 mg twice daily). Therefore, alfuzosin is contraindicated with PAXLOVID (see 2 CONTRAINDICATIONS). | |
tamsulosin | ↑tamsulosin | Avoid concomitant use with PAXLOVID. | |
Analgesics, Narcotic: | |||
fentanyl, hydrocodone, oxycodone, meperidine, | ↑fentanyl ↑hydrocodone ↑oxycodone ↑meperidine | Ritonavir inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of fentanyl, tramadol, and propoxyphene. Use tramadol and propoxyphene with caution, as dose reduction of these drugs may be needed. | |
tramadol propoxyphenea | ↑tramadol ↑propoxyphene |
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. | |
| methadone | ↓methadone | Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Dosage increase of methadone may be considered. | |
Anesthetic: | |||
meperidine | ↓ meperidine ↑ normeperidine (metabolite) | Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). | |
Antianginal: | |||
ranolazine | ↑ ranolazine | Co-administration contraindicated due to potential for serious and/or life threatening reactions (see 2 CONTRAINDICATIONS). | |
Antiarrhythmics: | |||
disopyramide, lidocaine (systemic), mexiletine | ↑ antiarrhythmics | Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
amiodarone, bepridila, dronedarone, flecainide, propafenone, quinidinea | ↑ antiarrhythmics | Co-administration may lead to serious and/or life-threatening reactions, such as cardiac arrhythmias. Therefore, use of these antiarrhythmics with PAXLOVID is contraindicated (see 2 CONTRAINDICATIONS). | |
Antibacterial: | |||
fusidic acid | ↑ fusidic acid ↑ ritonavir | Coadministration of protease inhibitors, including ritonavir with fusidic acid is expected to increase fusidic acid, as well as the protease inhibitor concentration in plasma (see 2 CONTRAINDICATIONS). | |
Anticancer agents: | |||
| apalutamide | ↓nirmatrelvir/ritonavir | Co-administration is contraindicated (see 2 CONTRAINDICATIONS). | |
abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, vincristine, vinblastine | ↑ anticancer agents | Serum concentrations increase when co-administered with ritonavir resulting in the potential for increased incidence of adverse events, some of which may be serious. Coadministration of ritonavir with ibrutinib is not recommended due to expected increase in ibrutinib exposure that could potentially result in a risk of tumor lysis syndrome. Coadministration of ritonavir with dasatinib should be avoided due to expected increase in dasatinib exposure. If the co-administration is unavoidable, close monitoring for toxicity and a dasatinib dose reduction should be considered (see SPRYCEL Product Monograph). Coadministration of encorafenib or ivosidenib with ritonavir should be avoided due to potential risk of serious adverse events such as QT interval prolongation. If coadministration cannot be avoided, modify encorafenib dose as recommended in the encorafenib Product Monograph. Coadministration of ritonavir with nilotinib should be avoided due to expected increase in nilotinib exposure. If the co-administration is unavoidable, close monitoring for the QT interval prolongation is recommended (see TASIGNA Product Monograph). Coadministration of ritonavir with abemaciclib should be avoided due to expected increase in abemaciclib exposure. If the co-administration is unavoidable, close monitoring for toxicity and abemaciclib dose reduction should be considered (see VERZENIO Product Monograph). Coadministration of ritonavir with neratinib is contraindicated due to expected increase in neratinib exposure (see 2 CONTRAINDICATIONS). Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects | |
venetoclax | ↑ venetoclax | Concomitant use of strong CYP3A inhibitors, such as ritonavir, and venetoclax may increase the risk of tumor lysis syndrome at the dose initiation and during the ramp-up phase (see 2 CONTRAINDICATIONS). For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (see VENCLEXTA Product Monograph). | |
Anticoagulants: | |||
| apixaban | ↑apixaban | Combined P-gp and strong CYP3A4 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 product label for more information. | |
| dabigatran | ↑ dabigatran | Co-administration with PAXLOVID results in increased dabigatran exposure and an increased risk of bleeding. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran product label for further information. | |
rivaroxaban | ↑ rivaroxaban | A study has shown that co-administration of ritonavir and rivaroxaban resulted in increased exposure of rivaroxaban which may lead to risk of increased bleeding. Co-administration of PAXLOVID and rivaroxaban is contraindicated (see 2 CONTRAINDICATIONS). | |
warfarin | ↓ R-warfarin ↓ ↑ S-warfarin | Initial frequent monitoring of the INR (International Normalized Ratio) during ritonavir and warfarin co-administration is indicated. | |
Anticonvulsants: | |||
clonazepam ethosuximide divalproex lamotrigine | ↑ clonazepam ↑ ethosuximide ↓ divalproex ↓ lamotrigine | Plasma concentrations of clonazepam and ethosuximide are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed and clinical monitoring is recommended. Plasma concentrations of divalproex and lamotrigine are expected to decrease by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose increase of these drugs may be needed. | |
carbamazepine, phenobarbital, phenytoin, primidone, | ↑ carbamazepine ↓ phenytoin ↓nirmatrelvir/ ritonavir | Co-administration of PAXLOVID with carbamazepine, phenobarbital, phenytoin or primidone is contraindicated (see 2 CONTRAINDICATIONS)
| |
Antidepressants: | |||
amitriptyline, clomipramine, fluoxetine, imipramine, maprotilinea, nefazodonea, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine, | ↑ antidepressants | Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
| bupropion | ↓ bupropion and active metabolite hydroxy bupropion | Bupropion is primarily metabolized by CYP2B6. Concurrent administration of bupropion with repeated doses of ritonavir decreases bupropion levels. Monitor for an adequate clinical response to bupropion. | |
| desipramine | ↑ desipramine | A study has shown that co-administration of ritonavir and desipramine resulted in increased exposure of desipramine. Dosage reduction and concentration monitoring of desipramine is recommended. | |
trazodone | ↑ trazodone | Concomitant use of ritonavir and trazodone increases concentrations of trazodone. Adverse events of nausea, dizziness, hypertension, and syncope have been observed. If trazodone is used with a CYP3A4 inhibitor, such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. | |
Antiemetics: | |||
dronabinola | ↑ dronabinol | Plasma concentrations of dronabinol are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of dronabinol may be needed. | |
Antifungal: | |||
ketoconazole, | ↑ ketoconazole ↑isavuconazonium sulfate ↑ itraconazole ↑nirmatrelvir/ ritonavir | High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended. Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information. | |
| voriconazole | ↓voriconazole | Avoid concomitant use of voriconazole. | |
Antigout: | |||
colchicine | ↑ colchicine | For patients with renal and/or hepatic impairment:
For patients with normal renal and/or hepatic function:
| |
Anti-infective: | |||
clarithromycin erythromycin | ↑ clarithromycin ↑erythromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. Refer to the respective prescribing information for anti-infective dose adjustment. | |
Antimycobacterial: | |||
rifabutin | ↑ rifabutin and rifabutin metabolite ↓ ritonavir | Dosage reduction of rifabutin by at least three- quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or 3 times a week). Further dosage reduction may be necessary. | |
rifampin | ↓ ritonavir ↓nirmatrelvir | Co-administration of PAXLOVID with rifampin is contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered (see 2 CONTRAINDICATIONS). | |
Antiparasitics: | |||
atovaquone | ↓ atovaquone | Plasma concentrations of atovaquone are expected to decrease by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose increase of atovaquone may be needed. | |
quinine | ↑ quinine | Plasma concentrations of quinine are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of quinine may be needed. | |
Anxiolytics/Sedative/Hypnotics: | |||
triazolam midazolam orala | ↑triazolam ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Co-administration contraindicated due to potential for extreme sedation and respiratory depression (see 2 CONTRAINDICATIONS). | |
midazolam parenteralb | ↑ midazolam | Concomitant use of parenteral midazolam with ritonavir may increase plasma concentrations of midazolam. Coadministration 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. | |
buspirone, clorazepate, diazepam, estazolama, flurazepam, zolpidem | ↑Anxiolytics/Sedatives/ Hypnotics | Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
Benign prostatic hyperplasia agents | |||
silodosin | ↑silodosin | Co-administration contraindicated due to potential for postural hypotension (see 2 CONTRAINDICATIONS). | |
Beta-blockers: | |||
metoprolol, timolol | ↑ beta-blockers | Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
Bronchodilator: | |||
theophylline | ↓ theophylline | Increased dosage of theophylline may be required; therapeutic monitoring should be considered. | |
Calcium channel blockers: | |||
| amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil | ↑ calcium channel blockers | Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
Cardiovascular agents | |||
eplerenone | ↑ eplerenone | Co-administration with eplerenone is contraindicated due to potential for hyperkalemia (see 2 CONTRAINDICATIONS). | |
ivabradine | ↑ ivabradine | Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances (see 2 CONTRAINDICATIONS). | |
aliskiren, ticagrelor, vorapaxar, clopidogrel | ↑ aliskiren ↑ ticagrelor ↑ vorapaxar ↓ clopidogrel active metabolite | Avoid concomitant use with PAXLOVID. | |
Corticosteroids: | |||
budesonide, fluticasone propionate, triamcinolone | ↑ fluticasone ↑ budesonide ↑ triamcinolone | Concomitant use of ritonavir and inhaled, injectable, or intranasal fluticasone propionate, budesonide, triamcinolone, or other glucocorticoids that are metabolized by CYP3A4 are not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects, including Cushing’s syndrome and adrenal suppression. Concomitant use of ritonavir and fluticasone propionate, budesonide or triamcinolone can significantly increase fluticasone propionate, budesonide or triamcinolone plasma concentrations and reduce serum cortisol concentrations. Consider alternatives to fluticasone propionate, budesonide, or triamcinolone particularly for long-term use. | |
dexamethasone prednisone | ↑dexamethasone ↓ ritonavir
↑ prednisone | Dexamethasone, which increases CYP3A activity, would be expected to increase the clearance of ritonavir resulting in decreased ritonavir plasma concentrations. Plasma concentrations of dexamethasone and prednisone are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose adjustment of these drugs may be needed. | |
digoxin | ↑ digoxin | A literature report has shown that co-administration of ritonavir (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administrating ritonavir and digoxin, with appropriate monitoring of serum levels. | |
Cystic fibrosis transmembrane conductance regulator potentiators: | |||
lumacaftor/ivacaftor | ↓nirmatrelvir/ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance (see 2 CONTRAINDICATIONS). | |
ivacaftor | ↑ivacaftor | Reduce dosage when co-administered with PAXLOVID. Refer to individual product labels for more information. | |
| elexacaftor/ tezacaftor/ivacaftor | ↑elexacaftor/ tezacaftor/ivacaftor | ||
| tezacaftor/ivacaftor | ↑tezacaftor/ivacaftor | ||
Dipeptidyl peptidase 4 (DPP4) inhibitors: | |||
saxagliptin | ↑saxagliptin | Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin product label for more information. | |
Endothelin receptor antagonist: | |||
bosentan | ↑ bosentan | Discontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID. Refer to the bosentan product label for further information. | |
Ergot derivatives: | |||
dihydroergotamine, ergotamine, methylergonovinea | ↑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 2 CONTRAINDICATIONS). | |
Gonadotropin releasing hormone (GnRH) receptor antagonist | |||
elagolix | ↑ elagolix | Coadministration of elagolix with ritonavir could increase elagolix exposure due to inhibition of CYP3A and P-gp. Known serious adverse events for elagolix include suicidal ideation and hepatic transaminase elevations. In addition, elagolix is a weak/moderate inducer of CYP3A, which may decrease exposure of ritonavir. Refer to the elagolix label for dosing information with strong CYP3A4 inhibitors. | |
HCV-Antiviral Agents | |||
HCV Combination Drug: | |||
elbasvir/grazoprevir, glecaprevir/pibrentasvir ombitasvir/paritaprevir/ ritonavir with or without dasabuvira sofosbuvir/velpatasvir/voxilaprevir | ↑antiviral | Increased grazoprevir concentrations can result in ALT elevations. Coadministration with ritonavir is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure. Avoid concomitant use of glecaprevir/pibrentasvir with PAXLOVID. Refer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information. Refer to the sofosbuvir/velpatasvir/voxilaprevir product label 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. | |
HCV Protease Inhibitors: | |||
simeprevira | ↑ simeprevir | A pharmacokinetic study demonstrated that concomitant administration of simeprevir 200 mg once daily with ritonavir 100 mg twice daily resulted in an increase in simeprevir concentrations. It is not recommended to co-administer PAXLOVID with simeprevir. | |
Herbal products | |||
St. John’s Wort (hypericum perforatum) | ↓nirmatrelvir/ ritonavir | Co-administration contraindicated due to potential loss of virologic response and possible resistance use (see 2 CONTRAINDICATIONS). | |
HIV-Antiretroviral Agents | |||
HIV Protease Inhibitors: | |||
fosamprenavir | ↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin) | Refer to the fosamprenavir Product Monograph for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily or fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily. | |
atazanavir | ↑ atazanavir (↑ AUC, ↑ Cmax, ↑ Cmin) | Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. Refer to the atazanavir Product Monograph for details on co-administration of atazanavir 300 mg once daily, with ritonavir 100 mg once daily. | |
darunavir | ↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin) | Refer to the darunavir Product Monograph for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily. | |
indinavira | ↑ indinavir (↑ AUC, ↑ Cmax, ↑ Cmin) | Alterations in concentrations are noted when reduced doses of indinavir are co-administered with reduced dose of ritonavir. The safety and efficacy of this combination have not yet been established. The risk of nephrolithiasis may be increased when doses of indinavir equal to or greater than 800 mg twice daily are given with ritonavir. Adequate hydration and monitoring of the patients is warranted. | |
nelfinavir | ↑ M8 (major active metabolite of nelfinavir) | Ritonavir increases the concentrations of nelfinavir major active metabolite, M8. This interaction is likely to involve cytochrome P450 inhibition and induction. | |
saquinavir | ↑ saquinavir (↑ AUC, ↑ Cmax, ↑ Cmin) | The recommended dosage regimen is saquinavir 1000 mg with ritonavir 100 mg twice daily taken within 2 hours after a meal. Dose adjustment may be needed if other HIV-protease inhibitors are used in combination with saquinavir and ritonavir. Saquinavir and ritonavir should not be given together with rifampin due to risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the 3 drugs are given together. In some cases, co-administration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis, and liver disorders, especially in patients with pre- existing liver disease. Refer to the saquinavir Product Monograph for prescribing information. | |
tipranavir | ↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin) | Refer to the tipranavir Product Monograph for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. | |
Nucleoside Reverse Transcriptase Inhibitors: | |||
didanosinea | ↓ didanosine | Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility. | |
tenofovir | ↑ tenofovir | Lopinavir/ritonavir has been shown to increase tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir- associated adverse events, including renal disorders. Patients receiving ritonavir and tenofovir disoproxil fumarate should be monitored for tenofovir-associated adverse events. Refer to the tenofovir Product Monograph for more information. | |
zidovudine, emtricitabine | ↓zidovudine ↔emtricitabine | For further information, refer to the respective anti-HIV drugs prescribing information. | |
Non-Nucleoside Reverse Transcriptase Inhibitors: | |||
delavirdinea | ↑ ritonavir ↔ delavirdine | When used in combination with delavirdine, a dose reduction of ritonavir should be considered. Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be affected by ritonavir. The safety and efficacy of this combination (delavirdine/ ritonavir) have not been established. | |
efavirenz | ↑ efavirenz | In healthy volunteers receiving 500 mg ritonavir twice daily with efavirenz 600 mg once daily, the steady state AUC was increased by 21%. An associated increase in the AUC of ritonavir of 17% was observed. | |
nevirapine | ↑nevirapine | For further information, refer to the respective anti-HIV drugs prescribing information. | |
Integrase Inhibitor: | |||
raltegravir | ↓ raltegravir | A pharmacokinetic study showed that co-administration of ritonavir 100 mg twice daily and raltegravir 400 mg single dose resulted in a reduction in raltegravir plasma concentration. | |
bictegravir | ↑ bictegravir | For further information, refer to the respective anti-HIV drugs prescribing information. | |
CCR5 Antagonist: | |||
maraviroc | ↑ maraviroc (↑ AUC, ↑ Cmax, ↑ Cmin) | When co-administered with reduced doses of ritonavir plasma levels of maraviroc increases. The dose of maraviroc should be decreased during co-administration with ritonavir. Refer to the maraviroc Product Monograph for details on co-administration of maraviroc 150 mg twice daily with ritonavir. | |
Hypolipidemics, HMG-CoA Reductase Inhibitors: | |||
lovastatin, simvastatin | ↑lovastatin, | The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis (see 2 CONTRAINDICATIONS). 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. | |
lomitapide | ↑ lomitapide | Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated (see 2 CONTRAINDICATIONS). | |
atorvastatin, | ↑atorvastatin, rosuvastatin | Caution must also be exercised, and reduced doses should be considered if ritonavir is used concurrently with atorvastatin, which is metabolized to a lesser extent by CYP3A4. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration. Atorvastatin and rosuvastatin do not need to be discontinued prior to or after completing PAXLOVID. Use the lowest doses of atorvastatin or rosuvastatin with careful monitoring for signs and symptoms of myopathy or rhabdomyolysis. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended. | |
Immunosuppressants: | |||
Calcineurin inhibitors cyclosporine, tacrolimus,
mTOR inhibitors everolimus, sirolimusa | ↑ immunosuppressants ↑ cyclosporine ↑ tacrolimus
↑ everolimus ↑ sirolimus | Avoid concomitant use of calcineurin inhibitors or mTOR inhibitors during treatment with PAXLOVID. Dose adjustment of the immunosuppressant and close and regular monitoring for immunosuppressant concentrations and immunosuppressant-associated adverse reactions are recommended during and after treatment with PAXLOVID. Refer to the individual immunosuppressant product label and latest guidelines for further information and obtain expert consultation of a multidisciplinary group (see 7 WARNINGS AND PRECAUTIONS). | |
Janus kinase (JAK) inhibitors | |||
tofacitinib | ↑tofacitinib | Dosage adjustment of tofacitinib is recommended. Refer to the tofacitinib product label for more information. | |
upadacitinib | ↑upadacitinib | Dosing recommendations for co‑PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib product label for more information. | |
Kinase inhibitors (also see Anticancer agents above): | |||
fostamatinib | ↑ fostamatinib | Coadministration of fostamatinib with ritonavir could increase fostamatinib metabolite R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Monitor for toxicities of fostamatinib that may require fostamatinib dose modification (see fostamatinib Product Monograph). | |
Long-acting beta adrenoceptor agonist | |||
salmeterol | ↑salmeterol | Co-administration is not recommended. 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. | |
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 2 CONTRAINDICATIONS. | |
ubrogepant | ↑ubrogepant | Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions (see 2 CONTRAINDICATIONS). | |
Mineralocorticoid receptor antagonists: | |||
finerenone | ↑ finerenone | Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia (see 2 CONTRAINDICATIONS). | |
Muscarinic receptor antagonists: | |||
darifenacin | ↑ darifenacin | The darifenacin daily dose should not exceed 7.5 mg when co-administered with PAXLOVID. Refer to the darifenacin product label for more information. | |
Neuroleptics/Antipsychotics: | |||
clozapine | ↑clozapine | If co-administration is necessary, consider reducing the clozapine dose and monitor for adverse reactions. | |
lurasidone | ↑ lurasidone | Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected to increase. Co-administration of lurasidone with PAXLOVID is contraindicated (see 2 CONTRAINDICATIONS). | |
perphenazine, | ↑ neuroleptics | Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
pimozide | ↑ pimozide | Co-administration of PAXLOVID with pimozide is contraindicated as it may lead to serious and/or life-threatening reactions, such as cardiac arrhythmias (see 2 CONTRAINDICATIONS). | |
quetiapine | ↑ quetiapine | Due to inhibition of CYP3A by PAXLOVID (ritonavir), co-administration of PAXLOVID with quetiapine may result in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions have been reported with CYP3A inhibitors. PAXLOVID should not be used in combination with quetiapine. Monitoring and dose reduction may be required if necessary. | |
Neuropsychiatric agents: | |||
suvorexanta | ↑suvorexant | Avoid concomitant use of suvorexant with PAXLOVID.
| |
aripiprazole, | ↑aripiprazole | Dosage adjustment of aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, and pimavanserin is recommended. Refer to individual product label for more information. | |
Opioid antagonists: | |||
naloxegol | ↑naloxegol | Co-administration contraindicated due to the potential for opioid withdrawal symptoms (see 2 CONTRAINDICATIONS). | |
Oral Contraceptive or Patch Contraceptive: | |||
ethinyl estradiol | ↓ ethinyl estradiol | Co-administration with ritonavir results in reduced ethinyl estradiol concentrations. Dosage increase or alternate contraceptive measures should be considered. 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. | |
PDE5 Inhibitors (erectile dysfunction agents): | |||
sildenafil, | ↑ sildenafil | Particular caution should be used when prescribing PDE5 inhibitors for the treatment of erectile dysfunction in patients receiving PAXLOVID. Co-administration of PAXLOVID with these drugs is expected to substantially increase their concentrations and may result in increase in associated adverse events, such as hypotension, syncope, visual changes, and prolonged erection.
Use of PDE5 Inhibitors for Erectile Dysfunction
Sildenafil may be used with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Tadalafil may be used with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. Vardenafil should not be used with PAXLOVID (see 2 CONTRAINDICATIONS).
Coadministration of PAXLOVID and tadalafil for the treatment of pulmonary arterial hypertension is not recommended. The use of sildenafil or vardenafil is contraindicated with PAXLOVID (see 2 CONTRAINDICATIONS). | |
PDE5 Inhibitors (pulmonary hypertension agents): | |||
sildenafil | ↑sildenafil | Co-administration of sildenafil with PAXLOVID is contraindicated due to the potential for sildenafil associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope (see 2 CONTRAINDICATIONS). | |
tadalafil | ↑tadalafil | Avoid concomitant use of tadalafil with PAXLOVID. | |
sGC stimulators (pulmonary hypertension agents): | |||
riociguat | ↑riociguat | Dosage adjustment is recommended for riociguat. Refer to the riociguat product label for more information. | |
Serotonin receptor 1A agonist/ serotonin receptor 2A antagonist: | |||
flibanserin | ↑flibanserin | Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression (see 2 CONTRAINDICATIONS). | |
Stimulants: | |||
Methamphetamine | ↑methamphetamine | Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed. | |
Vasopressin receptor antagonists: | |||
tolvaptan | ↑tolvaptan | Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia (see 2 CONTRAINDICATIONS). | |
Co-administered Drug | Dose (Schedule) | N | Percent Ratio of Nirmatrelvira PK Parameters (90% CI); No Effect=100 | ||
|---|---|---|---|---|---|
Co-administered Drug | Nirmatrelvir/ ritonavir | Cmax | AUCb | ||
carbamazepinec | 300 mg twice daily | 300 mg/100 mg once daily (2 doses) | 10 | 56.82 (47.04, 68.62) | 44.50 (33.77, 58.65) |
itraconazole | 200 mg once daily | 300 mg/100 mg twice daily | 11 | 118.57 (112.50, 124.97) | 138.82 (129.25, 149.11) |
Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; Cmax= observed maximum plasma concentrations; PK=pharmacokinetic. a. Percent ratio of test (i.e., carbamazepine or itraconazole in combination with nirmatrelvir/ritonavir)/reference (i.e., nirmatrelvir/ritonavir alone). b. For carbamazepine, AUC=AUCinf, for itraconazole, AUC=AUCtau. c. Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7). | |||||
The effects of co-administration of PAXLOVID with midazolam (CYP3A4 substrate) or dabigatran (P-gp substrate) on the midazolam and dabigatran AUC and Cmax, respectively, are summarized in Table 6.
Co-administered drug | Dose (schedule) | N | Percent ratioa of test/reference of geometric means (90% CI); no effect=100 | ||
|---|---|---|---|---|---|
Co-administered | Nirmatrelvir/ | Cmax | AUCb | ||
midazolamc | 2 mg | 300 mg/100 mg twice daily (9 doses)b | 10 | 368.33 (318.91, 425.41) | 1430.02 (1204.54, 1697.71) |
dabigatranc | 75 mg | 300 mg/100 mg twice daily | 24 | 233.06 (172.14, 315.54) | 194.47 (155.29, 243.55) |
Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; Cmax=maximum plasma concentrations; P gp=p glycoprotein. a. Percent ratio of test (i.e., midazolam or dabigatran in combination with nirmatrelvir/ritonavir)/reference (i.e., midazolam or dabigatran alone). b. AUC=AUCinf for both midazolam and dabigatran. c. For midazolam, Test=nirmatrelvir/ritonavir plus midazolam, Reference=midazolam. Midazolam is an index substrate for CYP3A4. For dabigatran, Test=nirmatrelvir/ritonavir plus dabigatran, Reference=dabigatran. Dabigatran is an index substrate for P-gp. | |||||
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 3C-like protease main protease (Mpro), also referred to as 3CLpro or NSP5 protease. Inhibition of the SARS-CoV-2 3CL protease renders it incapable of processing polyprotein precursors, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS CoV-2 3CL protease in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 3CL protease active site by X-ray crystallography.
Ritonavir is an HIV-1 protease inhibitor but is not active against the SARS-CoV-2 3CL protease. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.
Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans.
The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy subjects and in participants with mild to moderate COVID-19.
Ritonavir is administered with nirmatrelvir as a pk (pharmacokinetic) enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir. In healthy participants in the fasted state, the mean half‑life (t1/2) of a single dose of 150 mg nirmatrelvir administered alone was approximately 2 hours compared to 7 hours after administration of a single dose of 250 mg/100 mg nirmatrelvir/ritonavir thereby supporting a twice daily administration regimen.
Upon administration of single dose of nirmatrelvir/ritonavir 250 mg/100 mg to healthy participants in the fasted state, the geometric mean (CV%) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUClast) was 2.88 ug/mL (25%) and 27.6 ug*hr/mL (13%), respectively.
Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.. The pharmacokinetic properties of nirmatrelvir; ritonavir are displayed in Table 7.
| Nirmatrelvir (When Given with Ritonavir) | Ritonavir |
|---|---|---|
Absorption |
|
|
Tmax (h), median | 3.00a | 3.98a |
Food effect | Test/Reference (fed/fasted) ratios of geometric means (90% Confidence Interval) AUClast and Cmax for nirmatrelvir were 120.9 (109.3 – 133.7) and 161.0 (139.1 – 186.4), respectivelyb | |
Distribution |
|
|
% bound to human plasma proteins | 69% | 98-99% |
Blood-to-plasma ratio | 0.60 | 0.14d |
Vz/F (L), mean | 104.7 c | 112.4 c |
Elimination |
|
|
Major route of elimination | Renal eliminatione | Hepatic metabolism |
Half-life (t1/2) (hr), mean | 6.05a | 6.15a |
Oral clearance (CL/F), mean | 8.99c | 13.92c |
Metabolism |
|
|
Metabolic pathways | Minimale | Major CYP3A4, Minor CYP2D6 |
Excretion |
|
|
% drug-related material in feces | 35.3%f | 86.4%g |
% drug-related material in urine | 49.6%f | 11.3%g |
a. Represents data after a single dose of 300 mg nirmatrelvir (2 x 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects. b. Following a single oral dose of nirmatrelvir 300 mg boosted with ritonavir 100 mg at -12 hours, 0 hours, and 12 hours, administered under fed (high fat, high calorie meal) (Test) or fasted (Reference) conditions. c. 300 mg nirmatrelvir (oral suspension formulation) and 100 mg ritonavir (tablet formulation) administered together twice a day for 3 days. d. Red blood cell to plasma ratio. e. Nirmatrelvir is a CYP3A4 substrate but when dosed with ritonavir metabolic clearance is minimal. f. Determined by 19F-NMR analysis following 300 mg oral suspension enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours. g. Determined by 14C analysis following 600 mg 14C-ritonavir oral solution.
| ||
The Single dose pharmacokinetic data of PAXLOVID in healthy subjects is depicted below in Table 8.
PK Parameter (units) | Nirmatrelvir (N=12) |
|---|---|
Cmax (µg/mL) | 2.21 (33) |
AUCinf (µg*hr/mL) | 23.01 (23) |
Tmax (hr) | 3.00 (1.02-6.00) |
T1/2 (hr) | 6.05 ± 1.79 |
Represents data from 2 x 150 mg tablets of nirmatrelvir. Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for T1/2. | |
Absorption
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) Cmax and area under the plasma concentration-time curve from 0 to infinity (AUCinf) was 2.21 µg/mL (33) and 23.01 µg*hr/mL (23), respectively. The median (range) time to Cmax (Tmax) was 3.00 hrs (1.02-6.00). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (1.8) hours. Following oral administration of nirmatrelvir /ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir (CV%) Cmax and AUCinf was 0.36 µg/mL (46) and 3.60 µg*hr/mL (47), respectively. The median (range) time to Cmax (Tmax) was 3.98 hrs (1.48-4.20). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (2.2) hours.
Effect of food on oral absorption:
In healthy subjects, administration of a single oral dose of nirmatrelvir 300 mg (2 x 150 mg tablets) boosted with ritonavir 100 mg (1 x 100 mg tablet) at -12 hours, 0 hours, and 12 hours, under fed conditions (high fat and high calorie meal) increased the exposure of nirmatrelvir relative to fasting conditions. There was an approximate 61% increase in nirmatrelvir mean Cmax and a 21% increase in nirmatrelvir mean AUClast relative to fasting conditions. There was a delay in the median Tmax by 0.21 hours when dosed with the high fat, high calorie meal compared to fasting conditions. PAXLOVID can be taken orally with or without food.
Distribution
The protein binding of nirmatrelvir in human plasma is approximately 69%. The protein binding of ritonavir in human plasma is approximately 98-99%.
Metabolism
In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolized by CYP3A4. Nirmatrelvir is not an inducer or substrate of other CYP enzymes. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only drug-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the feces and urine.
In vitro studies utilising human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M-2.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolized by CYP3A4) and other protease HIV inhibitors may influence the pharmacokinetics of ritonavir.
Elimination
The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and feces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug related entity quantifiable was unchanged nirmatrelvir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
Special Populations and Conditions
| Normal Hepatic Function (n=8) | Moderate Hepatic Impairment (n=8) |
|---|---|---|
Cmax (µg/mL) | 1.89 (20) | 1.92 (48) |
AUCinf (µg*hr/mL) | 15.24 (36) | 15.06 (43) |
Tmax (hr) | 2.0 (0.6 - 2.1) | 1.5 (1.0 - 2.0) |
T1/2 (hr) | 7.21 ± 2.10 | 5.45 ± 1.57 |
Values are presented as geometric mean (geometric % CV) except Median (Range) for Tmax and arithmetic mean ± SD for t1/2.
| Normal Renal Function (n=8) | Mild Renal Impairment (n=8) | Moderate Renal Impairment (n=8) | Severe Renal Impairment (n=8) |
|---|---|---|---|---|
Cmax (µg/mL) | 1.60 (31) | 2.08 (29) | 2.21 (17) | 2.37 (38) |
AUCinf (µg*hr/mL) | 14.46 (20) | 17.91 (30) | 27.11 (27) | 44.04 (33) |
Tmax (hr) | 2.0 (1.0 - 4.0) | 2.0 (1.0 – 3.0) | 2.50 (1.0 – 6.0) | 3.0 (1.0 - 6.1) |
T1/2 (hr) | 7.73 ± 1.82 | 6.60 ± 1.53 | 9.95 ± 3.42 | 13.37 ± 3.32 |
Values are presented as geometric mean (geometric % CV) except Median (Range) for Tmax and arithmetic mean ± SD for t1/2.
Store at room temperature (15C to 30C).
Control #: 274571
October 3, 2023
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