Doravirine (Monograph)

Brand name: Pifeltro
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors

Medically reviewed by Drugs.com on Dec 15, 2023. Written by ASHP.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Doravirine

Treatment of HIV Infection

Used in conjunction with other antiretroviral agents (including as a fixed combination with lamivudine and tenofovir disoproxil fumarate [TDF]) for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥35 kg who are antiretroviral-naive (have not previously received antiretroviral therapy) or to replace a current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) with no history of treatment failure and no known substitutions associated with resistance to doravirine.

Commonly used in NNRTI-based regimens that include doravirine and 2 HIV NRTIs; consult guidelines for the most current information on recommended regimens.

Selection of an initial ARV regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.

Doravirine Dosage and Administration

General

Pretreatment Screening

Consider potential for drug interactions prior to, and during treatment with doravirine. Review concomitant medications to assess for drug interactions.

Administration

Oral Administration

Administer orally once daily without regard to food.

Must use single-entity doravirine in conjunction with other antiretrovirals.

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

Dosage

Pediatric Patients

HIV Infection

Oral

Pediatric patients ≥35 kg: 100 mg once daily.

Pediatric patients ≥35 kg receiving concomitant rifabutin: 100 mg twice daily (12 hours apart).

Adults

HIV Infection

Oral

100 mg once daily.

In patients receiving concomitant rifabutin, increase dosage to 100 mg twice daily (12 hours apart).

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild, moderate, or severe renal impairment: Dosage adjustments not needed.

Not adequately studied in patients with end-stage renal disease; not studied in those receiving dialysis.

Geriatric Patients

No specific dosage recommendations; use with caution.

Cautions for Doravirine

Contraindications

Concomitant use with potent CYP3A inducers (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, enzalutamide, rifampin, rifapentine, mitotane, St. John’s wort [Hypericum perforatum]).

Warnings/Precautions

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

Concomitant use with certain drugs may result in known or potentially clinically important drug interactions, some of which may lead to loss of therapeutic effect of doravirine and possible development of resistance.

Consider potential for drug interactions prior to and during doravirine therapy; review concomitant drugs during therapy and monitor for adverse effects.

Immune Reconstitution Syndrome

Immune reconstitution syndrome reported in HIV-infected patients receiving multiple-drug antiretroviral therapy. During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii], tuberculosis); such responses may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) also reported in the setting of immune reconstitution; however, time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Data insufficient to determine if doravirine poses a risk to pregnancy outcomes.

No adverse developmental effects observed in animal studies.

Lactation

Not known whether doravirine distributes into human milk, affects human milk production, or affects the breast-fed infant.

Distributed into milk of lactating rats.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission, risk of developing viral resistance in HIV-positive infants, and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy established in pediatric patients weighing ≥35 kg. Safety and efficacy not established in pediatric patients weighing <35 kg.

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether they respond differently than younger adults.

Use 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.

Hepatic Impairment

No clinically important differences in pharmacokinetics in patients with moderate hepatic impairment (Child-Pugh class B); dosage adjustments not needed in those with mild or moderate hepatic impairment (Child-Pugh class A or B).

Not studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Based on population pharmacokinetic analysis, renal function does not have a clinically important effect on pharmacokinetics; dosage adjustments not needed in those with mild, moderate, or severe renal impairment.

Not adequately studied in patients with end-stage renal disease; not studied in those receiving dialysis.

Common Adverse Effects

Most common adverse effects (≥5%): nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, abnormal dreams.

Drug Interactions

Primarily metabolized by CYP3A. Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; not likely to induce CYP1A2, 2B6, or 3A4.

Does not inhibit UGT1A1. Not likely to inhibit P-glycoprotein (P-gp), 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.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Concomitant use with CYP3A inducers may decrease doravirine plasma concentrations and may reduce efficacy.

Concomitant use with CYP3A inhibitors may increase doravirine concentrations.

Not likely to have a clinically important effect on exposures of drugs metabolized by CYP isoenzymes.

Specific Drugs

Drug	Interaction	Comments
Abacavir	No in vitro evidence of antagonistic antiretroviral effects
Antacids	Antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone: No clinically important pharmacokinetic interactions
Anticonvulsants	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Decreased doravirine concentrations expected; possible decreased doravirine efficacy	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use contraindicated; do not initiate doravirine until ≥4 weeks after anticonvulsant discontinued
Antimycobacterials ( rifamycins)	Rifabutin: Decreased doravirine AUC; peak plasma concentrations not affected Rifampin: Decreased doravirine AUC and peak plasma concentrations; possible decreased efficacy of doravirine Rifapentine: Decreased doravirine concentrations expected; possible decreased efficacy of doravirine	Rifabutin: Increase dosage of doravirine to 100 mg twice daily Rifampin, rifapentine: Concomitant use contraindicated; do not initiate doravirine until ≥4 weeks after rifampin or rifapentine discontinued
Atorvastatin	No clinically important pharmacokinetic interactions
Darunavir	No in vitro evidence of antagonistic antiretroviral effects
Delavirdine	No in vitro evidence of antagonistic antiretroviral effects
Didanosine	No in vitro evidence of antagonistic antiretroviral effects
Dolutegravir	No clinically important effect on pharmacokinetics of either drug
Efavirenz	On day 1 of doravirine therapy (and after discontinuance of efavirenz), doravirine exposures and peak plasma concentrations decreased by 62 and 35%, respectively; on day 14 of doravirine therapy (and after discontinuance of efavirenz), doravirine exposures and peak plasma concentrations decreased by 32 and 14%, respectively No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
Elbasvir and grazoprevir	No clinically important pharmacokinetic interactions
Emtricitabine	No in vitro evidence of antagonistic antiretroviral effects
Enfuvirtide	No in vitro evidence of antagonistic antiretroviral effects
Enzalutamide	Decreased doravirine concentrations expected; possible decreased doravirine efficacy	Concomitant use contraindicated; do not initiate doravirine until ≥4 weeks after enzalutamide discontinued
Etravirine	Decreased doravirine concentrations expected No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
Indinavir	No in vitro evidence of antagonistic antiretroviral effects
Ketoconazole	Increased doravirine exposures and peak plasma concentrations; not considered clinically important
Lamivudine	No clinically important pharmacokinetic interactions No in vitro evidence of antagonistic antiretroviral effects
Ledipasvir and sofosbuvir	No clinically important pharmacokinetic interactions
Maraviroc	No in vitro evidence of antagonistic antiretroviral effects
Metformin	No clinically important effects on metformin concentrations
Methadone	No clinically important effect on pharmacokinetics of either drug
Midazolam	No clinically important pharmacokinetic interactions
Mitotane	Decreased doravirine concentrations expected; possible decreased doravirine efficacy	Concomitant use contraindicated; do not initiate doravirine until ≥4 weeks after mitotane discontinued
Nevirapine	Decreased doravirine concentrations expected No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
Oral contraceptives (ethinyl estradiol and levonorgestrel)	No clinically important pharmacokinetic interactions
Pantoprazole	No clinically important pharmacokinetic interactions when doravirine used concomitantly
Raltegravir	No in vitro evidence of antagonistic antiretroviral effects
Rilpivirine	No in vitro evidence of antagonistic antiretroviral effects
Ritonavir	Increased doravirine exposures and peak plasma concentrations; not considered clinically important
St. John's wort (Hypericum perforatum)	Decreased doravirine concentrations expected; possible decreased efficacy of doravirine	Concomitant use contraindicated; do not initiate doravirine until ≥4 weeks after St. John's wort discontinued
Tenofovir	Tenofovir DF: No clinically important pharmacokinetic interactions with doravirine Tenofovir DF: No in vitro evidence of antagonistic antiretroviral effects with doravirine
Zidovudine	No in vitro evidence of antagonistic antiretroviral effects

Doravirine Pharmacokinetics

Absorption

Bioavailability

64%.

Food

Relative to fasting state, administration with high-fat meal increases AUC, peak plasma concentrations, and trough plasma concentrations by 16, 3, and 36%, respectively.

Effect of food not considered clinically important.

Plasma Concentrations

Peak plasma concentrations occur 2 hours after oral administration. Steady-state concentrations achieved after 2 days.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

76%.

Elimination

Metabolism

Metabolized primarily by CYP3A.

Elimination Route

Approximately 6% of oral dose eliminated in urine as unchanged doravirine; unchanged drug also eliminated to a minor extent by biliary and/or fecal routes.

Half-life

15 hours.

Special Populations

Moderate hepatic impairment (Child-Pugh class B): No clinically important effect on doravirine pharmacokinetics.

Severe renal impairment: Doravirine exposures increased by 43%.

Based on population pharmacokinetic analysis, renal function does not have a clinically important effect on doravirine pharmacokinetics.

No clinically relevant differences in pharmacokinetics based on age (adults), race, BMI, or sex.

In pediatric patients weighing ≥35 kg and <45 kg receiving doravirine 100 mg daily, AUC and peak plasma concentrations were 25 and 36% higher, respectively, compared to adults; however, not considered clinically important.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Store in original bottle. Protect from moisture; do not remove desiccant and keep bottle tightly closed.

Actions and Spectrum

Doravirine is a pyridinone HIV NNRTI antiretroviral. Inhibits replication of HIV-1 by interfering with viral polymerase activities of reverse transcriptase.
Inhibits polymerization reaction by noncompetitive, non-active site binding to reverse transcriptase causing conformational changes within active site that result in an inactive conformation.
Does not inhibit human cellular α- and β-DNA polymerases or mitochondrial γ-DNA polymerase.
Active against wild-type HIV-1, including certain strains resistant to other NNRTIs (i.e., those with K103N and/or Y181C substitutions).
HIV-1 strains resistant to doravirine have been produced in vitro and have emerged during doravirine therapy.
Cross-resistance occurs among HIV NNRTIs (e.g., efavirenz, etravirine, nevirapine, rilpivirine). Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to other NNRTIs; however, treatment-emergent doravirine resistance-associated substitution Y318F does not appear to confer reduced susceptibility to efavirenz, etravirine, or rilpivirine.

Advice to Patients

Advise patients to take doravirine once every day at a regularly scheduled time with or without food.
Advise patients not to miss or skip doses since this can result in development of resistance. If a patient forgets to take doravirine, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time.
Advise patients that doravirine may interact with certain other drugs. For patients receiving rifabutin, importance of taking one 100-mg tablet of doravirine twice daily (approximately 12 hours apart).
Inform patients that signs and symptoms of inflammation from other previous infections may occur soon after initiation of antiretroviral therapy in some patients with advanced HIV infection (AIDS). These symptoms may be due to an improvement in immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to immediately inform a clinician if any symptoms of infection occur.
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to doravirine. Advise HIV-infected women not to breast-feed because HIV-1 can be passed to the baby in breast milk.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.