PIFELTRO

Doravirine is an

HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) intended to be administered in combination with other antiretroviral medicines. 5, 4 Doravirine is available by itself or as a of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg).

Doravirine is formally indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, further expanding the possibility and choice of therapeutic treatments available for the management of HIV-1 infection.

Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history.

It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

In a clinical phase 2 trial evaluating a dose range of 0.25-2x the recommended dose of doravirine (in combination with emtricitabine/tenofovir) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.

Furthermore, at a dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose, doravirine does not prolong the QT interval to any clinically relevant extent.

The absolute bioavailability of doravirine is 64% with a T max of 2 hours.

Following oral doravirine administration, all of the administered dose was recovered and the agent is considered to be well absorbed.

Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies.

The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L.

Following absorption, unchanged parent drug is the major circulating component in plasma.

M9 metabolite.

• a product of cytochrome P450 3A4/5 mediated oxidative metabolism.

• is the most abundant doravirine metabolite in the circulation.

Hover over products below to view reaction partners Doravirine Doravirine M9 Metabolite.

The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism. 5, 1, 2 Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces.

The elimination half-life determined of doravirine is 15 hours.

The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively.

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No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18-78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B).

The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown.

No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes.

It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant.

Because of the potential for

HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV positive infants), and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine.

The safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age.

Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

In general, caution should be exercised in the administration of doravirine in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy.

No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment.

Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients.

No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to and 7 times, respectively, the human exposures at the RHD.

A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls.

Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.

There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD.

is contraindicated when co-administered with: drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of IDVYNSO. lamivudine (3TC) or emtricitabine (FTC) as significant decreases in islatravir-triphosphate (ISL-TP) concentrations may occur, which may decrease the effectiveness of IDVYNSO.

IDVYNSO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of IDVYNSO.

IDVYNSO is contraindicated when co-administered with lamivudine (3TC) or emtricitabine (FTC), which are deoxycytidine kinase (dCK) substrates, as a decrease in islatravir-triphosphate (ISL-TP) levels may occur, which may decrease the effectiveness of IDVYNSO.

Recommended dosage

One tablet taken orally once daily with or without food in adults.

Dosage adjustment with rifabutin

Take one tablet of IDVYNSO once daily, followed by one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of IDVYNSO. 2.1 Recommended Dosage The recommended dosage of IDVYNSO is one tablet taken orally once daily with or without food.

One tablet of

IDVYNSO contains 100 mg doravirine and 0.25 mg islatravir. 2.2 Dosage Adjustment with Rifabutin If IDVYNSO is co-administered with rifabutin, take one tablet of IDVYNSO once daily as recommended, followed by one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of IDVYNSO for the duration of rifabutin co-administration.

IDVYNSO tablet contains 100 mg of doravirine and 0.25 mg of islatravir, is pink, oval-shaped and film-coated, and is debossed with on one side and plain on the other side.

Each bottle contains 30 tablets (NDC 0006-5092-01) with desiccant and is closed with a child-resistant closure.

IDVYNSO in the original bottle.

Keep the bottle tightly closed to protect from moisture.

Do not remove the desiccant.

IDVYNSO at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to IDVYNSO during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary There are insufficient human data on the use of IDVYNSO during pregnancy to inform a drug-associated risk of birth defects and miscarriage.

In animal reproduction studies, no developmental effects were observed when the components of IDVYNSO were administered separately at exposures (AUC) at least 8 (doravirine) and 500 (islatravir) times the exposure at the recommended human dose (RHD) of these components in IDVYNSO The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%.

Methodological limitations of the APR include the use of MACDP as the external comparator group.

MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.

Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on Gestation Days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD to 20 and separately from GD to Lactation/Postpartum Day 20).

No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD.

Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20.

Islatravir was administered orally to pregnant rabbits (up to 10 mg/kg/day on GD to 20) and rats (up to 50 mg/kg/day on GD to 20 and separately up to 10 mg/kg from GD to Lactation/Postpartum Day 20).

No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 500 times (rats) and 1300 times (rabbits) the exposure in humans at the RHD.

In rats, islatravir was transferred to the fetus through the placenta in rats, with fetal plasma concentrations of up to 88% that of maternal concentrations observed on GD 20.

The safety and effectiveness of

IDVYNSO have not been established in pediatric patients less than 18 years of age.

Clinical trials in virologically-suppressed participants who received IDVYNSO (Trial and Trial 052) included 81 (11%) participants aged 65 years and older, including 10 (1%) aged 75 years and older.

No overall differences in safety or effectiveness were observed between these participants and younger participants, but greater sensitivity of some older individuals cannot be ruled out.