Pifeltro (doravirine)

No dosing information is available for this tab.

Doravirine is administered orally once daily without regard to food.

Doravirine must be used in conjunction with other antiretrovirals for the treatment of HIV-1 infection.

Single-entity doravirine (Pifeltro(R)) is commercially available as tablets.

Doravirine also is commercially available in fixed-combination tablets containing doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF; Delstrigo(R)).

Store doravirine tablets in the original bottle at 20-25degreesC (excursions permitted to 15-30degreesC); protect from moisture and do not remove the desiccant.

No dosing information is available for this tab.

Doravirine is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A. In vitro, doravirine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and is not likely to induce CYP1A2, 2B6, or 3A4. In vitro, doravirine does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1. Based on in vitro studies, doravirine is not likely to inhibit the P-glycoprotein (P-gp) transport system, organic anion transport polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE) 1, or MATE2K.

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)

Doravirine/Strong Cyp3a4 Inducers

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: Strong inducers of CYP3A4 are expected to increase the metabolism of doravirine.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of doravirine.(3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with doravirine is contraindicated. A washout period of 4 weeks for the CYP3A4 inducer is recommended prior to initiation of doravirine.(1)

DISCUSSION: Doravirine is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 10 subjects, rifampin (600 mg daily), a strong inducer of CYP3A4, decreased the area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 88%, 57%, and 97% respectively.(1) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(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)

Doravirine/Efavirenz;Etravirine;Nevirapine

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)

Doravirine/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inducers are expected to increase the metabolism of doravirine.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of doravirine.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Recommendations for concurrent use of moderate CYP3A4 inducers with doravirine vary depending on the reference. The manufacturer of the fixed dose combination of doravirine-islatravir states concurrent use with moderate CYP3A4 inducers is not recommended.(3) The DHHS HIV guidelines state when coadministering doravirine with bosentan, dexamethasone, and eslicarbazepine (moderate CYP3A4 inducers): consider an alternative antiretroviral or alternative drug to the moderate CYP3A4 inducer. It would be prudent to consider alternative drugs to other moderate CYP3A4 inducers. If co-administration is necessary monitor virologic response.(4) The University of Liverpool HIV Drug Interactions Database states concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, dose adjustment of doravirine to 100 mg twice daily is recommended and should be maintained for at least 2 weeks following cessation of the moderate CYP3A4 inducer. If a patient is on eslicarbazepine, doravirine should not be coadministered.(5) The manufacturer of single ingredient doravirine and the fixed dose combination of doravirine-lamivudine-tenofovir does not have a recommendation for concurrent use with moderate CYP3A4 inducers.(1,3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate CYP3A4 inducers are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3-4)

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.

Doravirine/Rifabutin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifabutin may induce the metabolism of doravirine by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of doravirine.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If concurrent therapy is necessary, increase doravirine dosage to one tablet twice daily for the duration of coadministration with rifabutin.(1) Patients on the fixed-dose combination of doravirine-lamivudine-tenofovir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-lamivudine-tenofovir for the duration of rifabutin co-administration.(2) Patients on the fixed-dose combination of doravirine-islatravir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-islatravir for the duration of rifabutin co-administration.(3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate inducers of CYP3A4 such as rifabutin are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate inducer of CYP3A4, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) In a study of 15 patients, doravirine 100 mg twice daily given concurrently with rifabutin 300 mg once daily resulted in similar doravirine levels and exposure as doravirine 100 mg once daily alone.(3)

Doravirine/Tecovirimat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tecovirimat may induce the metabolism of doravirine via CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of tecovirimat may result in decreased levels and effectiveness of doravirine, as well as the development of resistance.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of doravirine with tecovirimat should be approached with caution. Some experts state that dose adjustment of either drug is not necessary while others suggest the following dosage change: For adult and pediatric patients weighing at least 35 kg, consider increasing doravirine to 100 mg twice daily during treatment with tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)

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) In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of midazolam by 39% and 32%, respectively.(2-3)

*Concomitant use of doravirine and potent inducers of cytochrome P-450 (CYP) isoenzyme 3A (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, enzalutamide, rifampin, rifapentine, mitotane, St. John's wort (Hypericum perforatum)) is contraindicated. Concomitant use with such drugs may result in substantially decreased doravirine plasma concentrations and may decrease the effectiveness of doravirine.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• Viral hepatitis B

The most common adverse effects of doravirine (>=5%; all grades) include nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams.

Less Frequent

• Hyperbilirubinemia
• Increased alanine transaminase
• Increased aspartate transaminase

Rare or Very Rare

• Autoimmune hepatitis
• DRESS syndrome
• Graves' disease
• Guillain-barre syndrome
• Hepatitis
• Polymyositis
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Diarrhea
• Dizziness
• Dream disorder
• Fatigue
• Headache disorder
• Nausea
• Sleep disorder

Less Frequent

• Altered consciousness
• Drowsy
• Lethargy
• Skin rash
• Syncope

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Safety and efficacy of doravirine have been established in pediatric patients weighing >=35 kg.

The use of doravirine in pediatric patients with HIV infection weighing >=35 kg is supported by well-controlled studies in adults and an additional open-label study in antiretroviral naive and experienced pediatric patients 12 to <18 years of age. The safety, efficacy, and pharmacokinetics of doravirine in this patient population were similar to that in adults.

The safety and efficacy of doravirine have not been established in pediatric patients weighing <35 kg.

In pediatric patients weighing at least 35 kg and less than 45 kg receiving doravirine 100 mg daily, AUC and peak plasma concentrations were 25 and 36% higher, respectively, compared to adults; however, these differences are not considered clinically important.

Antiretroviral Pregnancy Registry at 800-258-4263 or https://www.apregistry.com/.

Human data are not adequate to establish whether or not doravirine poses a risk to pregnancy outcomes.

In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered to rabbits or rats at exposures that were 8 or 9 times higher, respectively, than human exposures at the recommended human dosage. In rabbits and rats, doravirine crossed the placenta resulting in fetal plasma concentrations up to 40 and 52%, respectively, of maternal concentrations observed on gestation day 20.

It is not known whether doravirine is distributed into human milk, affects human milk production, or affects the breast-fed infant.

Doravirine was distributed into the milk of lactating rats following oral administration (milk concentrations were approximately 1.5 times higher than maternal plasma concentrations at 2 hours after a dose on lactation day 14).

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.

The manufacturer makes no specific dosage recommendations for doravirine in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently to doravirine than younger adults.

Doravirine should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

The pharmacokinetics of doravirine in adults are not substantially affected by age in those 18-78 years of age.