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PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets)

7 DRUG INTERACTIONS

7.1 Potential for PAXLOVID to Affect Other Drugs

PAXLOVID (nirmatrelvir co-packaged with ritonavir) is an 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 Contraindications (4) and Table 1]. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 1.

7.2 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.

7.3 Established and Other Potentially Significant Drug Interactions

Table 1 provides listing of clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 1 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. The healthcare provider should consult appropriate references for comprehensive information [see Contraindications (4)].

Table 1: Established and Other Potentially Significant Drug Interactions
Drug ClassDrugs within ClassEffect on ConcentrationClinical Comments
*
See Pharmacokinetics, Drug Interaction Studies Conducted with Nirmatrelvir and Ritonavir (12.3).
Alpha 1-adrenoreceptor antagonistalfuzosin↑ alfuzosinCo-administration contraindicated due to potential hypotension [see Contraindications (4)].
Analgesicspethidine,
piroxicam,
propoxyphene
↑ pethidine
↑ piroxicam
↑ propoxyphene
Co-administration contraindicated due to potential for serious respiratory depression or hematologic abnormalities [see Contraindications (4)].
Antianginalranolazine↑ ranolazineCo-administration contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].
Antiarrhythmicsamiodarone,
dronedarone,
flecainide,
propafenone,
quinidine
↑ antiarrhythmicCo-administration contraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].
Antiarrhythmicsbepridil,
lidocaine (systemic)
↑ antiarrhythmicCaution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics if available.
Anticancer drugsapalutamide↓ nirmatrelvir/ritonavirCo-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
Anticancer drugsabemaciclib,
ceritinib,
dasatinib,
encorafenib,
ibrutinib,
ivosidenib,
neratinib,
nilotinib,
venetoclax,
vinblastine,
vincristine
↑ anticancer drugAvoid 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 individual product label for anticancer drug.
Anticoagulantswarfarin↑↓ warfarinClosely monitor INR if co-administration with warfarin is necessary.
rivaroxaban↑ rivaroxabanIncreased bleeding risk with rivaroxaban. Avoid concomitant use.
Anticonvulsantscarbamazepine*,
phenobarbital,
phenytoin
↓ nirmatrelvir/ritonavir
↑ carbamazepine
↓ phenobarbital
↓ phenytoin
Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
Antidepressantsbupropion↓ bupropion and active metabolite hydroxy-bupropion Monitor for an adequate clinical response to bupropion.
trazodone↑ trazodoneAdverse 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 trazadone product label for further information.
Antifungalsvoriconazole,↓ voriconazoleAvoid concomitant use of voriconazole.
ketoconazole,
isavuconazonium sulfate
itraconazole*
↑ ketoconazole
↑ isavuconazonium sulfate
↑ itraconazole
↑ nirmatrelvir/ritonavir
Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information.
Anti-goutcolchicine↑ colchicineCo-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 inhibitorsamprenavir,
atazanavir,
darunavir,
fosamprenavir,
indinavir,
nelfinavir,
saquinavir,
tipranavir
↑ protease InhibitorFor 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 with concomitant use of these protease inhibitors [see Dosage and Administration (2.4)].
Anti-HIVdidanosine,
delavirdine,
efavirenz,
maraviroc,
nevirapine,
raltegravir,
zidovudine
bictegravir/ emtricitabine/ tenofovir
↑ didanosine
↑ efavirenz
↑ maraviroc
↓ raltegravir
↓ zidovudine
↑ bictegravir
↔ emtricitabine
↑ tenofovir
For further information, refer to the respective anti-HIV drugs prescribing information.
Anti-infectiveclarithromycin,
erythromycin
↑ clarithromycin
↑ erythromycin
Refer to the respective prescribing information for anti-infective dose adjustment.
Antimycobacterialrifampin↓ nirmatrelvir/ritonavirCo-administration contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered [see Contraindications (4)].
Antimycobacterialbedaquiline↑ bedaquilineRefer to the bedaquiline product label for further information.
rifabutin↑ rifabutinRefer to rifabutin product label for further information on rifabutin dose reduction.
Antipsychoticslurasidone,
pimozide,
clozapine
↑ lurasidone
↑ pimozide
↑ clozapine
Co-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Antipsychoticsquetiapine↑ quetiapine If co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations.
Calcium channel blockersamlodipine,
diltiazem,
felodipine,
nicardipine,
nifedipine
↑ calcium channel blockerCaution 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 individual product label for calcium channel blocker for further information.
Cardiac glycosidesdigoxin↑ digoxinCaution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels.
Refer to the digoxin product label for further information.
Endothelin receptor Antagonistsbosentan↑ bosentanDiscontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID.
Refer to the bosentan product label for further information.
Ergot derivativesdihydroergotamine,
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 antiviralselbasvir/grazoprevir,
glecaprevir/pibrentasvir
↑ antiviralIncreased grazoprevir concentrations can result in ALT elevations.
It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir.
ombitasvir/paritaprevir/ritonavir and dasabuvirRefer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information.
sofosbuvir/velpatasvir/voxilaprevirRefer 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 [see Dosage and Administration (2.4)].
Herbal productsSt. John's Wort (hypericum perforatum)↓ nirmatrelvir/ritonavirCo-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
HMG-CoA reductase inhibitorslovastatin,
simvastatin
↑ lovastatin
↑ simvastatin
Co-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)].
Discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID.
HMG-CoA reductase inhibitorsatorvastatin,
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Consider temporary discontinuation of atorvastatin and rosuvastatin during treatment with PAXLOVID.
Hormonal contraceptiveethinyl estradiol↓ ethinyl estradiolAn additional, non-hormonal method of contraception should be considered.
Immunosuppressantscyclosporine,
tacrolimus,
sirolimus
↑ cyclosporine
↑ tacrolimus
↑ sirolimus
Therapeutic concentration monitoring is recommended for immunosuppressants.
Avoid use of PAXLOVID when close monitoring of immunosuppressant serum concentrations is not feasible.
Avoid concomitant use of sirolimus and PAXLOVID.
If co-administered, refer to individual product label for immunosuppressant for further information.
Long-acting beta-adrenoceptor agonistsalmeterol↑ salmeterol Co-administration is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Narcotic analgesicsfentanyl↑ fentanylCareful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with PAXLOVID.
methadone↓ methadoneMonitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
PDE5 inhibitorsildenafil (Revatio®) when used for pulmonary arterial hypertension↑ sildenafilCo-administration contraindicated due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope [see Contraindications (4)].
Sedative/hypnotics triazolam,
oral midazolam
↑ triazolam
↑ midazolam
Co-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4)].
Sedative/hypnoticsmidazolam (administered parenterally)↑ midazolamCo-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 product label for further information.
Systemic corticosteroidsbetamethasone,
budesonide,
ciclesonide,
dexamethasone,
fluticasone,
methylprednisolone,
mometasone,
prednisone,
triamcinolone
↑ corticosteroidIncreased risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone should be considered.
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