Nevirapine (nevirapine)
Antiviral-HIV (Antiretroviral) Nonnucleoside RT Inhibitor Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Nevirapine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).
Nevirapine is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI). While the complete mechanism of antiviral activity of nevirapine has not been fully elucidated, the drug inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Nevirapine binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.
The mechanism of action of nevirapine differs from that of HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, lamivudine, stavudine, zidovudine). NRTIs require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5' to 3' phosphodiester linkages. Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase.
The drug binds directly to heterodimeric HIV-1 reverse transcriptase and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme.
The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between the beta sheets of the ''palm'' and at the base of the ''thumb'' subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation.
Nevirapine appears to have no appreciable effect on the rate of or equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate.
Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase, and results of in vitro studies indicate that nevirapine does not appear to inhibit cellular DNA polymerases, including human alpha-, beta-, gamma-, or delta-polymerases.
The pharmacokinetics of nevirapine have been studied in healthy adults, adults with HIV-1 infection, and pediatric patients 14 days of age and older with HIV-1 infection. Studies to date have not revealed clinically important race-related differences in the pharmacokinetics of nevirapine. Studies in adults 18-68 years of age have not revealed any age-related differences in the pharmacokinetics of nevirapine; however, pharmacokinetics of the drug have not been extensively studied to date in geriatric adults older than 55-65 years of age.
Immediate-release tablets containing nevirapine and the oral suspension containing nevirapine hemihydrate are bioequivalent and can be used interchangeably at doses up to 200 mg. Bioavailability of 400 mg of nevirapine administered as extended-release tablets relative to 400 mg administered as conventional (immediate-release) tablets is approximately 75%. Following oral administration of nevirapine immediate-release tablets or oral suspension in healthy or HIV-infected adults, the drug is readily (more than 90%) absorbed.
Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 50-mg immediate-release tablet or 91% following administration of an oral solution of the drug. Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily. Following oral administration of a single 400-mg dose of nevirapine as an extended-release tablet in healthy adults, mean peak plasma concentrations were attained at a median of approximately 24 hours.
In HIV-infected pediatric patients 6 to less than 18 years of age who were switched to nevirapine extended-release tablets after at least 18 weeks of immediate-release nevirapine, overall mean systemic nevirapine exposure at steady-state after 10 days of therapy with the extended-release preparation was similar to that reported for the immediate-release preparation. At steady state, the observed geometric mean ratios of extended-release nevirapine to immediate-release nevirapine were approximately 97% for trough plasma concentrations and 94% for AUCs; the ratio for peak plasma concentrations was lower and consistent with the once-daily extended-release preparation.
Results of a study in 6 individuals indicate that nevirapine is distributed into CSF in concentrations that are 45% of concurrent plasma concentrations; this ratio is approximately equal to the fraction of the drug not bound to plasma proteins. At plasma concentrations of 1-10 mcg/mL, nevirapine is approximately 60% bound to plasma proteins. Nevirapine readily crosses the placenta in humans.
Nevirapine is distributed into human milk.
Nevirapine is extensively converted in vivo to several hydroxylated metabolites via cytochrome P-450 (CYP) oxidative metabolism. In vitro studies using human liver microsomes indicate that metabolism of nevirapine is mediated principally by CYP3A4, but other isoenzymes may also play a role in metabolism of the drug. There is evidence that nevirapine induces CYP3A4 and CYP2B6 enzymes resulting in autoinduction of its own metabolism.
The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2-4 weeks of dosing at a dosage of 200-400 mg daily. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours with a single dose to approximately 25-30 hours following multiple dosing using a dosage of 200-400 mg daily in adults. In a population substudy, women had a 13.8% lower clearance of nevirapine than men.
These results could not be explained by body weight or body mass index differences between men and women. Nevirapine is excreted in urine (81%), mainly as glucuronide conjugates of hydroxylated metabolites, and in feces (10%).
USES: This drug is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life.
Nevirapine belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nevirapine is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor.
Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor. Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Nevirapine should not be used to prevent HIV infection after accidental exposure (such as needle sticks, blood/bodily fluid contact). Different HIV medications are used to prevent infection after exposure.
Generic name: nevirapine
Pronunciation: (ne-VIR-a-peen)
Drug class: Antiviral-HIV (Antiretroviral) Nonnucleoside RT Inhibitor
Therapeutic class: Anti-Infective Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Nevirapine
Indications
The following indications are listed for Nevirapine:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Nevirapine therapy usually should be initiated using a low dosage of immediate-release nevirapine for the first 14 days since this appears to reduce the frequency of rash. Nevirapine extended-release tablets should not be used during the initial 14 days of nevirapine therapy. Patients not currently receiving nevirapine may receive the extended-release tablets after a lead-in period of 14 days of low dosage of immediate-release nevirapine. Patients already receiving usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.
If nevirapine therapy has been interrupted for more than 7 days for any reason and reinitiation of the drug is not contraindicated, the manufacturer states that the drug should be restarted using the recommended low initial dosage of immediate-release nevirapine for the first 14 days.
Dosage of nevirapine in pediatric patients is usually based on body surface area (BSA) calculated using the Mosteller formula.
If mild to moderate rash without constitutional symptoms occurs during the initial 14-day period of low dosage of immediate-release nevirapine, dosage should not be increased until the rash has resolved. The low dosage should not be continued for longer than 28 days; if the rash has not resolved by day 28, nevirapine should be discontinued and an alternative antiretroviral agent selected. If a severe rash or any rash with constitutional symptoms (e.g., fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) occurs, discontinue nevirapine.
Nevirapine is administered orally without regard to food.
Nevirapine conventional (immediate-release) tablets and oral suspension are used in adults and pediatric patients 15 days of age or older.
Nevirapine extended-release tablets are used in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m2or greater.
Store conventional (immediate-release) tablets at 20-25degreesC (excursions permitted to 15-30degreesC). Extended-release tablets should be stored at 20-25degreesC (excursions permitted to 15-30degreesC). Store nevirapine oral suspension at 20-25degreesC (excursions permitted to 15-30degreesC).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Nevirapine 200 Mg Tablet | Maintenance | Take 1 tablet (200 mg) by oral route once daily. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Nevirapine 200 Mg Tablet | Maintenance | Take 1 tablet (200 mg) by oral route once daily. |
Drug interactions
Metabolism of nevirapine is mediated in part by the cytochrome P-450 (CYP) 3A4 and 2B6 isoenzymes, and plasma nevirapine concentrations may be decreased by concomitant use of drugs that induce these isoenzymes (e.g., rifabutin, rifampin) or may be increased by concomitant use of drugs that inhibit these isoenzymes (e.g., cimetidine, macrolides). In addition, nevirapine is an inducer of CYP3A4 and CYP2B6 and may attenuate the therapeutic effects of drugs metabolized by these isoenzymes. While principally an inducer of CYP3A4 and CYP2B6, nevirapine may also inhibit these enzymes; however, the drug may have only a minimal inhibitory effect on other substrates of CYP3A4 at therapeutic concentrations.
Nevirapine does not appear to affect plasma concentrations of drugs that are substrates of other CYP isoenzymes (e.g., 1A2, 2D6, 2A6, 2E1, 2C9, 2C19).
The following drug interactions are based on studies using nevirapine conventional (immediate-release) tablets and are expected to also apply to nevirapine extended-release tablets.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Anti-Retrovirals/Atidarsagene Autotemcel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.
CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.
DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)
Anti-Retrovirals/Elivaldogene Autotemcel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.
CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.
DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)
Anti-Retrovirals/Etuvetidigene Autotemcel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Etuvetidigene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating HIV-based lentiviral vector. Antiretrovirals may interfere with the manufacturing of the apheresed cells.
CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of etuvetidigene autotemcel.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients should not take antiretrovirals for at least one month prior to mobilization and until at least 7 days after etuvetidigene autotemcel infusion.(1) If a patient requires antiretroviral agents for HIV post-exposure prophylaxis, etuvetidigene autotemcel treatment should be delayed until HIV testing is negative at 6 months post-exposure.(1)
DISCUSSION: Antiretroviral medications may interfere with the manufacturing of etuvetidigene autotemcel therapy.(1)
Anti-Retrovirals/Lovotibeglogene Autotemcel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.
CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1)
DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)
Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)
CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.
DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)
Cyp3a4 Inducers/Lumateperone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)
DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)
Cyp3a4 Inducers/Zuranolone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)
DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Delavirdine; Nevirapine/St. John's Wort
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: St. John's wort may induce the metabolism of delavirdine and nevirapine by CYP3A4.(1-3)
CLINICAL EFFECTS: The concurrent administration of delavirdine or nevirapine and St. John's wort may result in decreased levels and clinical effects of delavirdine and nevirapine.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturers of delavirdine(2) and nevirapine(3) state that these agents should not be administered with St. John's wort. Patients receiving both of these medications should be alerted to the the possibility of decreased effects of the NNRTI.(1) Consider monitoring blood levels of the NNRTI, as well as the CD4 count and viral load during concurrent therapy. The dosage of the NNRTI may need to be adjusted if St. John's wort is added to or discontinued from concurrent therapy. St. John's wort may need to be discontinued.
DISCUSSION: In a study of 5 patients who had been receiving concurrent nevirapine and St. John's wort for several months, concurrent St. John's wort increased nevirapine clearance by 35% compared to periods when the patients were not receiving St. John's wort.(4) St. John's wort is expected to lower concentrations of delavirdine(2) as well.
Efavirenz; Nevirapine/Asunaprevir
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Efavirenz and nevirapine may induce the metabolism of asunaprevir via CYP3A4. Efavirenz may also decrease asunaprevir absorption via the P-glycoprotein (P-gp) transporter.(1,2)
CLINICAL EFFECTS: The combination of asunaprevir with efavirenz or nevirapine may not be effective for the treatment of hepatitis C.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Because of the risk for treatment failure, the manufacturer of asunaprevir states that concomitant use with efavirenz and nevirapine is contraindicated.(1)
DISCUSSION: A study of 20 healthy subjects found that rifampin (a strong CYP3A4 inducer and OATP1B1 inhibitor) 600 mg daily decreased the maximum concentration (Cmax) and area-under-curve (AUC) of asunaprevir (600 mg twice daily) by 5% and 21%, respectively. The expected decrease in asunaprevir concentrations was thought to be attenuated by the inhibition of liver uptake by OATP1B1. Hepatic asunaprevir exposure was thought to be significantly reduced.(3) There have been no studies with the concurrent use of asunaprevir and efavirenz or nevirapine. Unlike rifampin, neither efavirenz nor nevirapine inhibit OATP1B1, and they are expected to lower asunaprevir plasma levels.
Efavirenz; Nevirapine/Elvitegravir
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Efavirenz and nevirapine may induce the metabolism of elvitegravir by CYP3A4. Efavirenz may also decrease the absorption of elvitegravir by P-glycoprotein (P-gp).(1,2)
CLINICAL EFFECTS: Concurrent use of efavirenz or nevirapine may result in altered and/or suboptimal pharmacokinetics of elvitegravir.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Elvitegravir should not be used with efavirenz or nevirapine.(1)
DISCUSSION: Concurrent use of elvitegravir with efavirenz or nevirapine may result in altered and/or suboptimal pharmacokinetics of elvitegravir.(1,2)
Etravirine; Nevirapine/Rifampin; Rifapentine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Rifampin may induce the metabolism of etravirine(1) and nevirapine by CYP3A4.(2-4)
CLINICAL EFFECTS: Concurrent use of rifampin may result in decreased levels and clinical effectiveness of etravirine(1) and nevirapine.(2-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of etravirine states that it should not be used with rifampin or rifapentine.(1) The Australian, UK, and US manufacturers of nevirapine state that rifampin should not be coadministered with nevirapine.(2-4) The Canadian manufacturer of nevirapine states that nevirapine should only be used in combination with rifampin if clearly indicated and with careful monitoring.(5) Rifabutin may be an alternative to rifampin.(2-4)
DISCUSSION: In a study in 14 subjects, concurrent nevirapine and rifampin decreased nevirapine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of nevirapine by 58%, 50%, and 68%, respectively.(3) There were no significant changes to rifampin Cmax or AUC. (3,4) In a study in 10 HIV-positive tuberculosis patients, concurrent rifampin and nevirapine decreased nevirapine AUC and Cmax by 31% and by 36%, respectively. There was a non-statistically significant decrease in nevirapine Cmin by 21%.(6)
Nevirapine/Atazanavir
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nevirapine is a weak inducer of CYP3A and CYP2B6 and atazanavir is a moderate inhibitor of CYP3A and a weak inhibitor of CYP2C8.(1)
CLINICAL EFFECTS: Concurrent use of atazanavir and nevirapine may result in decreased atazanavir levels and effectiveness. The possibility exists for increased toxicity to nevirapine based on increase exposure.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturers of atazanavir(2) and nevirapine(1) state that these agents should not be given together because of the decreased in atazanavir levels and the potential for virologic failure. Increased exposure to nevirapine with concurrent atazanavir use may lead to increased hepatic and skin reactions.
DISCUSSION: In a study in 23 subjects, concurrent nevirapine (200 mg twice daily) with atazanavir/ritonavir (300/100 mg daily) decreased atazanavir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 28%, 42%, an 72%, respectively.(1,2) Nevirapine Cmax, AUC, and Cmin increased 17%, 25%, and 32%, respectively.(2) In a study in 23 subjects, concurrent nevirapine (200 mg twice daily) with atazanavir/ritonavir (400/100 mg daily) decreased atazanavir AUC and Cmin by 19% and 59%, respectively.(1,2) Nevirapine Cmax, AUC, and Cmin increased 21%, 26%, and 35%, respectively.(2)
Nevirapine/Levoketoconazole
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nevirapine may induce the metabolism of levoketoconazole by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent administration of nevirapine and levoketoconazole may result in decreased levels of levoketoconazole, resulting in a loss of efficacy.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of levoketoconazole states that concurrent administration with CYP3A4 inducers should be used with caution.(1)
DISCUSSION: In a study in 21 HIV-infected patients, the concurrent administration of nevirapine (200 mg twice daily) and ketoconazole (400 mg once daily) resulted in decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of ketoconazole by 72% and 44%, respectively.(2)
Nnrtis/Cobicistat-Elvitegravir
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Cobicistat inhibits CYP2D6, CYP3A4, BCRP, OATP1B1 and OATP1B3. Elvitegravir induces CYP2C9. Efavirenz may induce the metabolism of cobicistat via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors (NNRTIs) may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir should not be used with non-nucleoside reverse transcriptase inhibitors.(1)
DISCUSSION: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Anti-Retrovirals/Marnetegragene Autotemcel
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Marnetegragene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of transduced cells.
CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of marnetegragene autotemcel.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the antiretrovirals) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.(1)
DISCUSSION: Antiretroviral medications may interfere with the manufacturing of marnetegragene autotemcel.(1)
Cyp3a4 Inducers/Erlotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)
DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)
Efavirenz; Etravirine;Nevirapine/Selected Hepatitis C Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Efavirenz, etravirine, and nevirapine may induce the metabolism of boceprevir,(1,2) telaprevir,(2,3) simeprevir,(4) velpatasvir(5,6) voxilaprevir, glecaprevir(7), and pibrentasvir(7) via CYP3A4. Efavirenz may also decrease absorption of these agents through the P-glycoprotein (P-gp) transporter.
CLINICAL EFFECTS: Concurrent use of efavirenz, etravirine, or nevirapine(1,2) may result in decreased levels and effectiveness of boceprevir,(3,4) telaprevir,(4,5) simeprevir,(6) velpatasvir,(6,7) voxilaprevir,(8) glecaprevir,(9) and pibrentasvir(9).
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of boceprevir and efavirenz.(3,4) The concurrent use of efavirenz, etravirine, or nevirapine(1,2) with simeprevir,(6) velpatasvir,(6,7) voxilaprevir,(8) glecaprevir,(9) and pibrentasvir(9) is not recommended. If concurrent therapy is warranted, monitor patients for decreased response to boceprevir,(3,4) telaprevir,(4,5) simeprevir,(6) velpatasvir,(6,7) voxilaprevir,(8) glecaprevir,(9) and pibrentasvir(9). The Swedish manufacturer of telaprevir recommends that the dose of telaprevir be increased to 1125 mg every 8 hours when used concurrently with efavirenz.(10)
DISCUSSION: In a study, concurrent efavirenz (600 mg daily for 16 days) decreased the the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of boceprevir (800 mg 3 times daily for 6 days) by 8%, 19%, and 44%, respectively. Efavirenz Cmax and AUC increased by 11% and 20%, respectively.(3,4) In a study in 21 subjects, efavirenz (600 mg daily for 20 days) decreased the Cmax, AUC, and Cmin of telaprevir (750 mg every 8 hours for 10 days) by 9%, 26%, and 47%, respectively. The Cmax, AUC, and Cmin of efavirenz decreased by 16%, 7%, and 2%, respectively.(4,5) In a study in 15 subjects, concurrent telaprevir (1125 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) decreased telaprevir Cmax, AUC, and Cmin by 14%, 18%, and 25%, respectively. Efavirenz Cmax, AUC, and Cmin decreased by 24%, 18%, and 10%, respectively.(5) In a study in 16 subjects, concurrent telaprevir (1500 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) decreased telaprevir Cmax, AUC, and Cmin by 3%, 20%, and 48%, respectively. Efavirenz Cmax, AUC, and Cmin decreased by 20%, 15%, and 11%, respectively.(5) In a study in 23 subjects, efavirenz (600 mg daily for 14 days) decreased the Cmax, AUC, and Cmin of simeprevir (150 mg daily for 14 days) by 51%, 71%, and 91%, respectively.(4,6) In a study in 23 subjects, simeprevir (150 mg daily for 14 days) decreased the AUC and Cmin of efavirenz (600 mg daily for 14 days) by 10% and 13%, respectively.(4) In an interaction study, efavirenz 600 mg daily (in combination with emtricitabine-tenofovir DF) decreased velpatasvir Cmax, AUC, and Cmin 47%, 53% and 57% respectively.(7,8)
Efavirenz; Nevirapine/Hormonal Contraceptive Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Efavirenz(1) and nevirapine(2,3) may induce the metabolism of hormonal contraceptives via CYP3A4.
CLINICAL EFFECTS: Concurrent administration of efavirenz(1) or nevirapine(2,3) with a hormonal contraceptive agent may result in decreased plasma concentrations and clinical effectiveness of the contraceptive agent.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturers of efavirenz(1) and nevirapine(2) state that hormonal contraceptives should not be used as the sole method of contraception in women taking these agents. A reliable method of barrier contraception must be used in addition to hormonal contraception in women taking efavirenz.(1) Alternative or additional methods of contraception should be considered in women taking nevirapine.(2) Because of the long half-life of efavirenz, women should continue to use a barrier method of contraception in addition to hormonal contraception for 12 weeks after discontinuing efavirenz.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.(4) Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.
DISCUSSION: In a study in 21 subjects, concurrent efavirenz (600 mg daily for 14 days) and ethinyl estradiol/norgestimate (0.035/0.25 mg for 14 days) had no effect on ethinyl estradiol levels. The maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of norelgestromin decreased by 46%, 64%, and 82%, respectively. The Cmax, AUC, and Cmin of levonorgestrel decreased by 80%, 83%, and 86%, respectively.(1) There have been reports of contraceptive failure in patients with etonogestrel implants who were receiving efavirenz.(1) In a study in 10 subjects taking Ortho-Novum 1/35, nevirapine decreased the AUC of ethinyl estradiol by 20% and the AUC and Cmax of norethindrone by 19% and 16%, respectively.(2) In a study in 16 HIV-positive females, concurrent nevirapine (200 mg daily, Days 2-15; 200 mg twice daily, Days 16-29) and ethinyl estradiol with norethindrone decreased the AUCs of ethinyl estradiol and norethindrone by 29% and 18%, respectively.(3) A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(5)
Efavirenz;Etravirine;Nevirapine/Cobicistat-Boosted Darunavir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Efavirenz, etravirine, and nevirapine may induce the metabolism of darunavir and cobicistat via CYP3A4.(1,2)
CLINICAL EFFECTS: Concurrent use of efavirenz, etravirine, or nevirapine may may result in altered and/or suboptimal pharmacokinetics of cobicistat, resulting in subtherapeutic levels of darunavir.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Cobicistat boosted darunavir should not be coadministered with efavirenz, etravirine, or nevirapine.(1,2) Note that there is no clinically significant interaction between ritonavir-boosted darunavir and efavirenz, etravirine, or nevirapine, and no dose adjustments are recommended.(2,3)
DISCUSSION: Concurrent use of efavirenz, etravirine, or nevirapine with cobicistat boosted darunavir may result in altered and/or suboptimal pharmacokinetics of cobicistat(1,2) In a study of 30 HIV-positive patients, darunavir 800 mg once daily and cobicistat 150 mg once daily administered with etravirine 400 mg once daily resulted in no change to darunavir AUC and Cmax but a 56 % decrease in Cmin. Cobicistat AUC, Cmax, and Cmin decreased 30 %, 14 % and 66 %, respectively.(4)
Efavirenz;Etravirine;Nevirapine/Doravirine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Efavirenz, etravirine, and nevirapine may induce the metabolism of doravirine via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of efavirenz, etravirine, or nevirapine may result in subtherapeutic levels of doravirine.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Coadministration of doravirine with efavirenz, etravirine, or nevirapine is not recommended.(1)
DISCUSSION: In a study in 17 healthy subjects, coadministration of efavirenz (600 mg daily) with a single dose of doravirine (100 mg) decreased doravirine's area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) by 62%, 35%, and 85%, respectively.(1)
Etravirine; Efavirenz; Nevirapine/Dolutegravir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Etravirine, efavirenz, and nevirapine may induce the metabolism of dolutegravir via CYP3A4.(1,2) Efavirenz and etravirine may also induce dolutegravir metabolism via UGT enzymes.
CLINICAL EFFECTS: Concurrent use of etravirine, efavirenz, or nevirapine and dolutegravir may result in decreased levels of and clinical effectiveness of dolutegravir.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of dolutegravir states that dolutegravir should not be used with etravirine without atazanavir/ritonavir (ATVr), darunavir/ritonavir (DRVr), or lopinavir/ritonavir (LPVr).(1) The Canadian(3) and UK(4) manufacturers of dolutegravir state that INSTI-naive patients may use etravirine concurrently with dolutegravir at an increased dose of 50 mg twice daily. In pediatric patients, the weight-based once daily dose should be given twice daily. No dose adjustment for dolutegravir is needed when used with etravirine along with concurrent ATVr, DRVr, or LPVr.(1,3-5) When used with efavirenz in patients without INSTI resistance, the dosage of dolutegravir should be 50 mg twice daily.(1,2) When using the combination abacavir-dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product.(2) Alternative combinations that do not induce metabolic inducers should be considered when possible for patients with certain INSTI-associated resistance or clinically suspected INSTI resistance. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation.(1) Although the US(1) and Canadian(3) manufacturers of dolutegravir recommend avoiding concurrent use of nevirapine, the US Department of Health and Human Services HIV guidelines recommend standard doses of dolutegravir when administered concurrently with nevirapine.(5) The UK manufacturer of dolutegravir recommends increasing the dose of dolutegravir to 50 mg twice daily when used concurrently with nevirapine.(4)
DISCUSSION: In a study in 12 subjects, the administration of efavirenz with dolutegravir (50 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 39%, 57%, and 75%, respectively.(1) In a study in 16 subjects, the administration of etravirine with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 52%, 71%, and 88%, respectively.(1) In a study in 9 subjects, the administration of etravirine and darunavir/ritonavir (200 mg and 600/100 mg BID) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 12%, 25%, and 37%, respectively.(1) In a study in 8 subjects, the administration of efavirenz and lopinavir/ritonavir (200 mg and 400/100 mg BID) with dolutegravir (50 mg daily) increased the Cmax, AUC, and Cmin of dolutegravir by 7%, 11%, and 28%, respectively.(1)
Moderate Cyp3a4 Inducers/Bictegravir-Lenacapavir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of bictegravir-lenacapavir for HIV treatment states that concurrent use of moderate CYP3A4 inducers is not recommended.(1)
DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, elagolix, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, rifapentine, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Lenacapavir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1-3)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(1-3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lenacapavir for HIV treatment states that concurrent use of moderate CYP3A4 inducers is not recommended.(1-3)
DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, rifapentine, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)
Nevirapine/Itraconazole; Ketoconazole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Nevirapine may induce the metabolism of itraconazole or ketoconazole by CYP3A4.(1,2,3) Ketoconazole may inhibit the metabolism of nevirapine at CYP3A4.(1)
CLINICAL EFFECTS: The concurrent administration of nevirapine and either itraconazole or ketoconazole may result in decreased levels of itraconazole or ketoconazole, resulting in a loss of efficacy.(1) Ketoconazole may increase levels of nevirapine, although the clinical significance of this is unknown.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Recommendations differ: - The manufacturer of nevirapine states that nevirapine should not be administered with itraconazole or ketoconazole.(1) - The manufacturer of oral ketoconazole states concomitant administration with nevirapine is not recommended.(2) - The manufacturer of itraconazole states concomitant treatment with nevirapine is not recommended.(3) - US guidelines for the use of antiretroviral agents in adults and adolescents recommend the following(4): Ketoconazole should not be used with nevirapine. Avoid concomitant use of nevirapine and itraconazole if possible. If co-administered, monitor itraconazole concentration and adjust dose accordingly. The US manufacturer of itraconazole states that concurrent administration with nevirapine is not recommended two weeks before and during itraconazole treatment.(3)
DISCUSSION: In a study in 21 HIV-infected patients, the concurrent administration of nevirapine (200 mg twice daily) and ketoconazole (400 mg once daily) resulted in decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of ketoconazole by 72% and 44%, respectively.(1)
Nevirapine/Selected Protease Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown.
CLINICAL EFFECTS: Concurrent administration of nevirapine with the protease inhibitors amprenavir, fosamprenavir, indinavir, nelfinavir, or saquinavir may decrease plasma concentrations of the protease inhibitor.(1-8) Decreased plasma concentrations of the protease inhibitor may result in decreased effectiveness and the development of resistance.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The exact clinical significance is unknown. Patients receiving concurrent therapy should be closely monitored. The US manufacturers of fosamprenavir(4) and nevirapine(2) state that concurrent use of nevirapine with fosamprenavir without ritonavir is not recommended. No dosage adjustment is required when nevirapine is given with fosamprenavir in combination with ritonavir twice daily.(2,4) The combination of nevirapine with fosamprenavir/ritonavir once daily has not been studied.(4) One set of investigators recommends that a dose of 1000 mg of indinavir every eight hours be considered in patients receiving concurrent therapy with nevirapine.(1) The manufacturers of indinavir(8) and nevirapine(2) state that the appropriate doses for this combination have not been established. Appropriate doses of the combinations of nevirapine with nelfinavir(2,5) or with saquinavir/ritonavir(6) have not been determined.
DISCUSSION: In a study in 17 subjects, concurrent nevirapine (200 mg twice daily) and fosamprenavir (1400 mg twice daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of amprenavir by 25%, 33%, and 35%, respectively.(2,4) Nevirapine Cmax, AUC, and Cmin increased by 25%, 29%, and 34%, respectively.(4) In a study in 17 subjects, concurrent nevirapine (200 mg twice daily) with fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) decreased the AUC and Cmin of amprenavir by 11% and 19%, respectively.(2,4) Nevirapine Cmax, AUC, and Cmin increased by 13%, 14%, and 22%, respectively.(4) In a study in 19 HIV-infected patients, the concurrent administration of nevirapine with indinavir (800 mg every 8 hours) decreased indinavir AUC, Cmax, and Cmin, by 31%, 15%, and 44%, respectively.(2) There was a non-significant effect on nevirapine levels.(1) In a study in 23 HIV-infected patients, the concurrent administration of nevirapine (200 mg daily for 14 days, then 200 mg twice daily) with nelfinavir (750 mg 3 times daily) decreased the Cmin of nelfinavir by 32%. The AUC, Cmax, and Cmin of the M8-metabolite of nelfinavir decreased by 62%, 59%, and 66%, respectively.(2) In a study in 14 HIV-infected patients, the concurrent administration of nevirapine and ritonavir (600 mg twice daily) did not affect the AUC or Cmax of ritonavir.(2) There was no effect on nevirapine pharmacokinetics.(1) In a study in 23 HIV-infected patients, the concurrent administration of nevirapine with saquinavir (600 mg three times daily) decreased saquinavir AUC and Cmax by 38% and 32%, respectively.(2) There was no effect on the pharmacokinetics of nevirapine.(1)
Nevirapine/Selected Strong Cyp3a4 Inducers
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of nevirapine.(1)
CLINICAL EFFECTS: Concurrent use of nevirapine with strong CYP3A4 inducers may result in sub-therapeutic levels of nevirapine and the development of resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs).
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The University of Liverpool's HIV Drug Interactions database advises not coadministering most strong CYP3A4 inducers with nevirapine, except for carbamazepine and phenytoin, which should be used with caution and monitored for virologic response and drug levels.(2) The US Department of Health and Human Services HIV guidelines recommend considering alternative therapies to carbamazepine, phenytoin, and phenobarbital for patients on nevirapine. If concurrent use is necessary, monitor nevirapine levels and virologic response.(3) The US manufacturer of nevirapine states that concurrent use of carbamazepine (a strong CYP3A4 inducer) should be approached with caution and monitored for virologic response and anticonvulsant levels.(1)
DISCUSSION: In a study in 14 subjects, concurrent nevirapine and rifampin decreased nevirapine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of nevirapine by 58%, 50%, and 68%, respectively. There were no significant changes to rifampin Cmax or AUC.(1) In a study in 10 HIV-positive tuberculosis patients, concurrent rifampin and nevirapine decreased nevirapine AUC and Cmax by 31% and by 36%, respectively. There was a non-statistically significant decrease in nevirapine Cmin by 21%.(4) In an open label pharmacokinetic study of 36 healthy, HIV-negative women, the effects of several CYP3A4 inducers on plasma nevirapine levels after a single-dose of nevirapine 200 mg was determined. Phenobarbital 200 mg did not produce therapeutic levels and did not have an effect on nevirapine levels. Carbamazepine 400 mg and phenytoin 184 mg for 3 days and for 7 days lowered nevirapine half-life from 46.3 hours to 33.8 hours, 27.1 hours, and 34.5 hours, respectively. Time to undetectable nevirapine levels decreased from 14 days to 12 days with carbamazepine and 8.5 days with both phenytoin regimens.(5) A study in 158 HIV+ pregnant women examined the effect of single-dose carbamazepine 400 mg on plasma concentrations of nevirapine and development of nevirapine resistance mutations after single-dose nevirapine 200 mg administered at delivery. Nevirapine levels at 1 week post-partum were 36% lower in the patients who received carbamazepine, and there was a trend towards fewer nevirapine resistance mutations.(6) A pharmacokinetic study in 73 HIV+ pregnant women confirmed that phenytoin 184 mg for 7 days decreases the half-life of single-dose nevirapine. Nevirapine half-life was 25.5 hours in the phenytoin group and 63.2 hours in the control group.(7) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(8)
Selected Protease Inhibitors And Nnrtis/Garlic
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown. Garlic may induce the metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) by CYP3A4. P-glycoproteins may also be involved.(1,2)
CLINICAL EFFECTS: Concurrent use of garlic and a protease inhibitor or NNRTI may result in decreased levels and effectiveness of the protease inhibitor or NNRTI therapy.(2-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients taking a protease inhibitor or NNRTI should avoid taking garlic supplements. Garlic from food sources is not likely to cause a problem, although there may be some concern if patients are ingesting a large quantity of garlic on a regular basis.
DISCUSSION: A study in nine HIV-negative subjects examined the effects of the concurrent use of a garlic supplement (taken twice daily) on saquinavir (1200 mg twice daily). Concurrent use resulted in a decrease in saquinavir area-under-curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to the administration of saquinavir alone. Following a garlic washout period, saquinavir levels only returned to 60-70% of baseline.(2) In a study in 10 healthy subjects, the administration of garlic (10 mg twice daily) for four days had no significant effects on a single dose of ritonavir (400 mg). Ritonavir AUC and Cmax decreased by 17% and by 25%, respectively. However, the authors cautioned that their results should not be extrapolated to steady-state conditions.(4)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Efavirenz; Nevirapine/Caspofungin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Efavirenz and nevirapine may induce the metabolism of caspofungin via induction of unspecified hepatic CYP enzymes.(1)
CLINICAL EFFECTS: The concurrent administration of caspofungin with either efavirenz or nevirapine may result in decreased levels and clinical effectiveness of caspofungin.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: In adult patients receiving concurrent therapy with efavirenz or nevirapine, the US manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg (following the usual 70 mg loading dose) be considered.(1) In pediatric patients receiving concurrent therapy with efavirenz or nevirapine, the US manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the usual 70 mg/m2 loading dose) be considered.(1)
DISCUSSION: Regression analyses of patient pharmacokinetic data suggests that administration of caspofungin with inducers and or mixed inducers/ inhibitors of drug clearance may result in clinically significant decreases in caspofungin concentrations. Therefore, the manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg (following the usual 70 mg loading dose) be considered in patients receiving concurrent therapy with efavirenz or nevirapine. The efficacy of a 70 mg daily dose in patients who are not responding to the 50 mg daily dose is not known, but limited safety data suggests that it is well tolerated.(1)
Efavirenz; Nevirapine/Levomethadone; Methadone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Efavirenz(1-4) and nevirapine(4-6) may induce the metabolism of methadone by CYP2B6. Levomethadone is an enantiomer of methadone.(7)
CLINICAL EFFECTS: Concurrent use of efavirenz or nevirapine may result in decreased levels and effectiveness of methadone and withdrawal symptoms.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving efavirenz or nevirapine should be monitored for decreased effectiveness of methadone and symptoms of methadone withdrawal. The dosage of methadone may need to be adjusted.
DISCUSSION: In a study, efavirenz (600 mg daily) given for 3 weeks led to a decrease of levomethadone maximum concentration (Cmax) and area-under-curve (AUC) of 48 % and 57 %, respectively.(7) In a study of 11 patients receiving methadone maintenance therapy, the addition of efavirenz to their regimen decreased methadone Cmax and AUC by 45% and by 52%, respectively. Nine patients experienced withdrawal symptoms beginning at Day 8 of concurrent therapy.(1) The manufacturer of efavirenz states that concurrent use resulted in decreased methadone levels and signs of withdrawal. Subjects required an average methadone dosage increase of 22% to relieve symptoms.(2) There are case reports of methadone withdrawal symptoms in patients receiving efavirenz.(8,9) In a study in 20 HIV-positive patients receiving methadone maintenance therapy, the addition of nevirapine to their regimen decreased methadone AUC by 41%. Reductions in AUC were similar for racemic methadone (37%) and (R)-methadone (44%). Changes in AUC ranged from mild increases in three patients to decreases of up to 70%. Fourteen subjects experienced withdrawal symptoms and required methadone dosage adjustments. The median dosage adjustment was 15%.(5) In a study in 8 HIV-positive patients receiving methadone maintenance therapy, the addition of nevirapine resulted in withdrawal symptoms after 5-10 days of concurrent therapy.(6) In a study in 9 patients receiving methadone, the addition of nevirapine (200 mg daily for 14 days, then 200 mg twice daily for at least 7 days) increased the clearance of methadone by 3-fold and withdrawal symptoms. Dosage adjustments were required in 7 patients.(10) There are several case reports of methadone withdrawal following the addition of nevirapine.(11-15)
Efavirenz; Nevirapine/Lopinavir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Efavirenz(1-3) and nevirapine(1,2,4) may induce the metabolism of lopinavir via CYP3A4.
CLINICAL EFFECTS: The concurrent administration of efavirenz(1-3) or nevirapine(1,2,4) with lopinavir may result in decreased levels and clinical effectiveness of lopinavir.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Lopinavir/ritonavir should not be administered once daily in combination with either efavirenz or nevirapine. Administration of lopinavir/ritonavir with either efavirenz or nevirapine in patients less than 6 months of age is not recommended.(1) The US manufacturer of lopinavir/ritonavir states that the dose of lopinavir/ritonavir tablets should be 500/125 mg (two 200/50 mg tablets and one 100/25 mg tablet) twice daily in adults receiving concurrent efavirenz.(1) The US manufacturer of efavirenz states that a dosage increase to 600/150 mg of lopinavir/ritonavir twice daily may be considered in treatment-experienced patients receiving combination therapy in whom decreased susceptibility to lopinavir is suspected.(3) The US manufacturers of lopinavir/ritonavir(1) and nevirapine(4) states that the dose of lopinavir/ritonavir tablets should be 500/125 mg (two 200/50 mg tablets and one 100/25 mg tablet) twice daily in adults receiving concurrent nevirapine. The dose of lopinavir/ritonavir oral solution should be 520/130 mg (6.5 ml) twice daily in adults receiving concurrent efavirenz or nevirapine.(1,4) The US manufacturer of lopinavir/ritonavir states that pediatric patients aged 6 months to 18 years receiving efavirenz or nevirapine require a dosage increase to 300/75 mg/m2 of oral solution twice daily (not to exceed the recommended adult dose).(1) If weight-based dosing is preferred, patients weighing less than 15 kg should receive 13/3.25 mg/kg of lopinavir/ritonavir oral solution twice daily with food and patients weighing 15 kg to 45 kg should receive 11/2.75 mg/kg of lopinavir/ritonavir oral solution twice daily with food.(1,4) Refer to the current Kaletra tablet labeling for information on dosing Kaletra tablets in pediatric patients who can swallow tablets.(1)
DISCUSSION: A study in 11 subjects examined the effects of concurrent administration of efavirenz (600 mg daily) with lopinavir/ritonavir (400/100 mg twice daily). When compared to 7 controls, concurrent administration resulted in decreases in the area-under-curve (AUC) and and minimum concentration (Cmin) lopinavir by 19% and 39%, respectively. Efavirenz AUC and Cmin decreased 16% and 16%, respectively.(1-3) There was no effect on ritonavir levels.(3) In a study in 19 subjects, concurrent efavirenz (600 mg daily) with lopinavir/ritonavir (500/125 mg twice daily) increased lopinavir maximum concentration (Cmax) and AUC by 12% and 6%, respectively, and decreased lopinavir Cmin by 10% when compared to lopinavir/ritonavir 400/100 mg twice daily alone.(1) In a study in 23 subjects, concurrent efavirenz (600 mg daily) with lopinavir/ritonavir (600/150 mg twice daily) increased lopinavir Cmax, AUC, and Cmin by 36%, 36%, and 32%, respectively, when compared to lopinavir/ritonavir (400/100 mg twice daily) without concurrent efavirenz.(1) A study compared 22 subjects taking concurrent nevirapine (200 mg twice daily) with lopinavir/ritonavir (400/100 mg twice daily) with 19 subjects taking lopinavir/ritonavir alone. Concurrent therapy decreased lopinavir Cmax, AUC, and Cmin by 19%, 27%, and 51%, respectively. Another study compared 12 subjects taking concurrent nevirapine (7 mg/kg or 4 mg/kg daily for 2 weeks, twice daily for 1 week) and lopinavir/ritonavir (300/75 mg/m2) with 15 subjects taking lopinavir/ritonavir alone. Concurrent therapy decreased lopinavir Cmax, AUC, and Cmin by 14%, 22%, and 55%, respectively.(4) Another study compared 5 subjects taking concurrent nevirapine (200 mg daily for 14 days, twice daily for 6 days) with 6 subjects taking lopinavir/ ritonavir alone. Concurrent therapy increased nevirapine Cmax, AUC, and Cmin by 5%, 8%, and 15% respectively.(1-3) In pediatric patients aged 6 months to 12 years, administration of 230/57.5 mg/m2 twice daily of lopinavir/ritonavir without nevirapine and 300/73 mg/m2 twice daily of lopinavir/ritonavir with nevirapine provided similar lopinavir plasma concentrations.(1)
Lopinavir; Nelfinavir; Nevirapine; Ritonavir/Warfarin Derivs
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Lopinavir, nelfinavir, nevirapine, and ritonavir may induce the metabolism of acenocoumarol and warfarin. The more potent S-enantiomer of warfarin is metabolized by CYP2C9 while the weaker R-enantiomer of warfarin is metabolized by CYP3A4 and CYP1A2. Although protease inhibitors can induce or inhibit multiple CYP450 pathways depending upon the drug and time course of therapy, all antiviral agents linked to this monograph are inducers of CYP2C9.
CLINICAL EFFECTS: Concurrent use warfarin derivatives and lopinavir, nelfinavir, nevirapine, and/or ritonavir may result in decreased levels and effectiveness of the anticoagulant, which may increase the risk of clotting.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on acenocoumarol or warfarin when initiating or titrating lopinavir, nelfinavir, nevirapine, or ritonavir. Patients maintained on these agents may require higher dosages of the anticoagulant beginning approximately 1-2 weeks after starting the antiviral. If the antiviral is discontinued, enzyme induction will gradually decrease and the anticoagulant concentration is expected to increase over time. Monitor the INR as the anticoagulant dose may need to be lowered. Also monitor INR closely when initiating warfarin in patients on current therapy or titrating doses of lopinavir, nelfinavir, nevirapine, and ritonavir.
DISCUSSION: In a study in 12 subjects, ritonavir (400mg every 12 hours for 12 days) increased the area-under-curve (AUC) of S-warfarin by 9% and decreased the AUC of R-warfarin by 33%, from a single dose of warfarin (5 mg). The maximum concentration (Cmax) of S-warfarin was decreased 9% and unchanged for R-warfarin. In a case-control study, use of ritonavir (200 mg daily) was associated with an increased warfarin maintenance dose of 3.9 mg. There have been case reports of increased acenocoumarol and warfarin requirements in patients taking lopinavir-ritonavir, nelfinavir, nevirapine, and/or ritonavir. In a retrospective study in 29 patients, INR levels were evaluated with concurrent use of nirmatrelvir-ritonavir and warfarin. In patients treated with nirmatrelvir-ritonavir, the first posttreatment INR was lower than baseline (median INR decrease of 0.40). Following completion of the 5-day course of nirmatrelvir-ritonavir, the measured INR was lower than the pretreatment nirmatrelvir-ritonavir INR (median INR decrease of 0.50). No thrombotic events occurred during the study period after nirmatrelvir-ritonavir use.
Moderate And Weak Cyp3a4 Inducers/Tacrolimus
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)
DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)
Moderate And Weak Cyp3a4 Inducers/Ubrogepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)
DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Moderate Cyp3a4 Inducers/Lenacapavir (Prep)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lenacapavir for PrEP states that concurrent use of moderate CYP3A inducers requires supplemental doses of lenacapavir. Moderate CYP3A inducers may be initiated anytime after the first dose of lenacapavir. Recommendations for supplemental doses of lenacapavir state: -On the day moderate CYP3A inducer is initiated: Supplement with 463.5 mg subcutaneously. -If the moderate CYP3A inducer is coadministered longer than 6 months: Every 6 months after CYP3A inducer is initiated, supplement lenacapavir as above. After a moderate CYP3A inducer is stopped, continue the scheduled continuation doses of lenacapavir every 6 months.(1)
DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Nevirapine/Daclatasvir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inducers of CYP3A4 (e.g. nevirapine) may induce the metabolism of daclatasvir.(1)
CLINICAL EFFECTS: Concurrent use of nevirapine without a dosage adjustment of daclatasvir is expected to reduce levels and effectiveness of daclatasvir.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of daclatasvir should be increased to 90 mg once daily in patients receiving nevirapine.(1)
DISCUSSION: Inducers of CYP3A4 have been shown to decrease the the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of daclatasvir. Efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of daclatasvir by 17%, 32%, and 59%, respectively.(1)
Nnrtis/Clarithromycin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Efavirenz, etravirine, and nevirapine may induce the metabolism of clarithromycin via CYP3A4. Clarithromycin may inhibit the metabolism of etravirine by CYP3A4. Also, delavirdine may inhibit the metabolism of clarithromycin by CYP3A4.
CLINICAL EFFECTS: Concurrent use of clarithromycin with efavirenz, etravirine, or nevirapine may alter blood levels of clarithromycin and its active metabolite, 14-OH-clarithromycin, resulting in decreased effectiveness and/or toxicity. Concurrent use of clarithromycin may increase etravirine levels. Concurrent use of clarithromycin with delavirdine may increase the levels and toxicities of clarithromycin.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturers of efavirenz,(1,2) etravirine,(3) and nevirapine(4) state that concurrent use with clarithromycin is not recommended and that alternative antibiotic agents, such as azithromycin, should be considered. If concurrent therapy is warranted, monitor patients closely for efficacy and adverse effects. No dosage adjustment of efavirenz(2) or the combination of efavirenz/emtricitabine/tenofovir(3) is recommended. The US manufacturer of delavirdine recommends that the dose of clarithromycin be reduced by 50% in patients with a CrCl of 30 ml/min to 60 ml/min. For patients with a CrCl of less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. No adjustment is necessary in patients with normal renal function.(5)
DISCUSSION: In a study in 11 subjects, concurrent efavirenz (400 mg) and clarithromycin (500 mg twice daily) decreased the maximum concentration (Cmax), AUC, and minimum concentration (Cmin) by 26%, 39%, and 53%, respectively. The Cmax, AUC, and Cmin of 14-OH-clarithromycin increased by 49%, 34%, and 26%, respectively. The Cmax of efavirenz increased by 11%. In uninfected subjects, 46% developed a rash during concurrent therapy.(1,2) In a study in 15 subjects, concurrent clarithromycin (500 mg twice daily) increased the Cmax, AUC, and Cmin of etravirine (dosage not stated) by 46%, 42%, and 46%, respectively. The Cmax, AUC, and Cmin of clarithromycin decreased by 34%, 39%, and 53%, respectively. The Cmax, AUC, and Cmin of 14-OH-clarithromycin increased by 33%, 21%, and 5%, respectively.(3) In a study in 15 subjects, concurrent nevirapine (200 mg daily for 14 days, then 200 mg twice daily for 14 days) and clarithromycin (500 mg twice daily) decreased the Cmax, AUC, and Cmin of clarithromycin by 23%, 31%, and 56%, respectively. The Cmax and AUC of 14-OH-clarithromycin increased by 47% and 42 %, respectively.(4) Although 14-OH-clarithromycin is an active metabolite, it has reduced activity against Mycobacterium avium-intracellulare complex.(4) In a study in 6 subjects, concurrent delavirdine (300 mg 3 times daily) with clarithromycin (500 mg 3 times daily) increased the area-under-curve (AUC) of clarithromycin by 100%. There was no effect on delavirdine levels.(5)
Selected Moderate-Weak Cyp3a4 Inducers/Exemestane
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.
DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Strong Ugt Inducers; Nevirapine/Artesunate
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase (UGT) and nevirapine may increase the metabolism of dihydroartemisinin (DHA, the active metabolite of artesunate).(1)
CLINICAL EFFECTS: Concurrent use of carbamazepine, efavirenz, etravirine, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, or ritonavir may result in decreased levels and effectiveness of DHA.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If coadministration of strong UGT inducers or nevirapine with artesunate is necessary, monitor for possible reduced antimalarial efficacy.(1)
DISCUSSION: In a study, nevirapine decreased the maximum concentration (Cmax) and area-under-curve (AUC) of DHA by 59% and 68%, respectively.(1) In a study of healthy volunteers, ritonavir (100 mg twice daily for 7 days) decreased the Cmax and AUC of DHA by 27% and 38%, respectively.(1,2) A study of healthy subjects who were coadministered lopinavir-ritonavir 400 mg-100 mg twice daily for 14 days) and artesunate-mefloquine found that artesunate Cmax and AUC decreased by 37% and 45%, respectively, compared to artesunate-mefloquine alone.(3) Agents linked to this monograph include: carbamazepine, efavirenz, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.
Weak Cyp3a4 Inducers/Atogepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.
DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)
Contraindications
*Moderate or severe hepatic impairment (Child-Pugh class B or C).
*Do not use for postexposure prophylaxis following occupational exposure to HIV (PEP) or postexposure prophylaxis following nonoccupational exposure to HIV (nPEP).
- Drug-induced hepatitis
- Hepatic failure
- Acute renal failure
- Chronic hepatitis B
- Chronic hepatitis C
- Disease of liver
- Rhabdomyolysis
There are no moderate contraindications for this drug.
Adverse reactions
The most frequently reported adverse effect in patients receiving nevirapine is rash, developing in 15% of adult patients receiving nevirapine compared to 6% of those receiving placebo. In adults receiving nevirapine, 2% of rashes were reported as grade 3/4, compared to less than 1% in patients receiving placebo. During a lead-in period with immediate-release nevirapine, the development of grade 2 or higher rash in adults occurred in 3% of adult patients. After the lead-in period, the incidence of grade 2 or higher rash occurred in 3% of adults taking extended-release nevirapine.
In pediatric patients, the incidence of rash with immediate-release nevirapine was 21% (all causality). The incidence of grade 2 or higher rash was 1% in pediatric patients taking extended-release nevirapine.
Less Frequent
- Aphthous stomatitis
- Fever
- Hepatitis
- Stevens-johnson syndrome
Rare or Very Rare
- Abnormal hepatic function tests
- Acute hepatic failure
- Anaphylaxis
- Anemia
- Angioedema
- Bullous dermatitis
- Cholestatic hepatitis
- Conjunctivitis
- DRESS syndrome
- Eosinophilia
- Granulocytopenic disorder
- Graves' disease
- Guillain-barre syndrome
- Hepatic necrosis
- Hepatomegaly
- Hypersensitivity drug reaction
- Hypophosphatemia
- Jaundice
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Lymphadenopathy
- Polymyositis
- Rhabdomyolysis
- Toxic epidermal necrolysis
- Urticaria
More Frequent
- Nausea
- Skin rash
Less Frequent
- Acute abdominal pain
- Diarrhea
- Fatigue
- Headache disorder
- Lipodystrophy associated with human immunodeficiency virus infection
- Myalgia
Rare or Very Rare
- Arthralgia
- Drowsy
- Facial edema
- Paresthesia
- Vomiting
Precautions
No enhanced messaging available.
Safety and pharmacokinetics of nevirapine oral suspension have been evaluated in HIV-infected infants 15 days to less than 3 months of age. Safety, pharmacokinetics, and efficacy of nevirapine immediate-release tablets and oral suspension have been evaluated in pediatric patients 3 months to 18 years of age.
Nevirapine extended-release tablets can be used for treatment of HIV-1 infection in pediatric patients 6 years of age or older based on pharmacokinetic, safety, and antiretroviral activity data from an open-label trial evaluating the drug in pediatric patients 3 to less than 18 years of age and efficacy data from adults. The extended-release tablets are not recommended in pediatric patients 3 to less than 6 years of age because pharmacokinetic data are insufficient to support use in this age group; the tablets are not recommended in those less than 3 years of age because of inability to swallow tablets.
The most frequently reported adverse effects in children were similar to those observed in adults; however, granulocytopenia occurred more frequently in children than in adults. Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome has occurred rarely in children receiving nevirapine. Rash and allergic reaction, including anaphylaxis, also have been reported. Anemia has been observed in children during postmarketing surveillance; whether anemia was due to nevirapine or concomitant drug therapy has not been determined.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including nevirapine, the Antiretroviral Pregnancy Registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents.
Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for nevirapine compared with the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data include over 2600 reports of nevirapine exposures during pregnancy resulting in live births, including over 1100 first-trimester exposures to the drug. The prevalence of birth defects in live births was 3% following first-trimester exposures to nevirapine-containing regimens and 3.3% following second- or third-trimester exposures to nevirapine-containing regimens compared with the background rate of 2.7% in the reference population of the MACDP.
Literature reports indicate that minimum nevirapine plasma concentrations are decreased up to 29% in pregnancy with the use of immediate-release nevirapine; however, this reduction is not considered clinically meaningful and dosage adjustment is not considered necessary.
Severe hepatic events, including fatalities, have been reported in HIV-infected pregnant women receiving long-term nevirapine therapy as part of multiple-drug antiretroviral treatment. Because women (including pregnant women) with baseline CD4+ T-cell counts exceeding 250 cells/mm3 appear to be at higher risk of nevirapine-associated symptomatic and potentially fatal rash and hepatic toxicity, the drug should not be initiated in such women and only when potential benefits outweigh risks. It is not clear if pregnancy augments the risk of rash and hepatic toxicity observed in non-pregnant women.
Nevirapine is distributed into human milk. The effects of nevirapine on the breast-fed infant are unclear, and the effects on milk production are not known.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Clinical studies of nevirapine to date have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults. In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
ICD codes
| Code | Type | Description |
|---|---|---|
| HIV infection | ||
| B20 | ICD10CM | Human immunodeficiency virus [HIv] disease |
| B97.35 | ICD10CM | Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere |
| O98.7 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, childbirth and the puerperium |
| O98.71 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy |
| O98.711 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, first trimester |
| O98.712 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, second trimester |
| O98.713 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, third trimester |
| O98.719 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating pregnancy, unspecified trimester |
| O98.72 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating childbirth |
| O98.73 | ICD10CM | Human immunodeficiency virus [HIv] disease complicating the puerperium |
| Z21 | ICD10CM | Asymptomatic human immunodeficiency virus [HIv] infection status |
ICD code information from First Databank (FDB).
Formulary status
Search health-plan coverage for this drug by ZIP code.
Choose the first character of a health plan name.
Last reviewed · Source: First Databank (FDB) drug data
On this page
Actions
Sign in to save favorites
Saving this drug requires a free Physicians Office Resource account.