AHFS Class:

• HIV Nonnucleoside Reverse Transcriptase Inhibitors 8:18.08.16

Generic Name(s):

• Doravirine

Doravirine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1

Treatment of HIV Infection

Doravirine is used in conjunction with other antiretroviral agents (including as a fixed combination with lamivudine and tenofovir disoproxil fumarate [DF]) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing ≥35 kg who are antiretroviral-naive (have not previously received antiretroviral therapy [ART]) or to replace a current antiretroviral regimen in patients with HIV-1 RNA levels <50 copies/mL (virologically-suppressed) on a stable antiretroviral regiman with no history of treatment failure and no known substitutions associated with resistance to doravirine.1,2,3,4,30,254,350,351,352

Doravirine usually is used in nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimens that include doravirine and 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs); consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral 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.200,201,202

If an NNRTI-based regimen of doravirine, lamivudine, and tenofovir DF is used for the treatment of HIV-1 infection in adults, a fixed-combination preparation containing all 3 drugs (doravirine/lamivudine/tenofovir DF) is commercially available and can be used alone as a complete regimen for the treatment of HIV-1 infection.254

Clinical Experience

Antiretroviral-naive Adults

Efficacy and safety of doravirine in antiretroviral-naive HIV-1-infected adults have been evaluated in two phase 3 randomized studies (DRIVE-FORWARD, NCT02275780; DRIVE-AHEAD, NCT02403674).1,2,3,4 The primary efficacy end point of both studies was the proportion of participants achieving plasma HIV-1 RNA levels <50 copies/mL at 48 weeks.2,3,4 Results of these studies indicated that doravirine in conjunction with 2 NRTIs was noninferior to regimens of ritonavir-boosted darunavir or efavirenz in conjunction with 2 NRTIs for initial treatment in antiretroviral-naive adults.1,2,3

In DRIVE-FORWARD, 766 patients (median age 33 years, median baseline HIV-1 RNA level of 4.4 log₁₀ copies/mL, median baseline CD4⁺ T-cell count of 410 or 393 cells/mm³) were randomized in a 1:1 ratio to receive either doravirine (100 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir and 100 mg of ritonavir) once daily, in conjunction with a dual NRTI selected by the investigator (either emtricitabine and tenofovir DF [emtricitabine/tenofovir DF] or abacavir and lamivudine [abacavir/lamivudine]); 87% of patients received emtricitabine/tenofovir DF and 13% received abacavir/lamivudine.1,4

At 48 weeks, 84% of patients in the doravirine group achieved an HIV-1 RNA level <50 copies/mL, compared to 80% of patients in the ritonavir-boosted darunavir group, showing noninferiority of the doravirine-containing regimen.4 At 96 weeks, 72% of patients in the doravirine group and 65% of those in the ritonavir-boosted darunavir group had plasma HIV-1 RNA levels <50 copies/mL, which again demonstrated noninferiority of doravirine to ritonavir-boosted darunavir in antiretroviral-naive adults.1,350 The mean increase in CD4⁺ T-cell count was 224 cells/mm³ in the doravirine group and 207 cells/mm³ in the ritonavir-boosted darunavir group.1

In DRIVE-AHEAD, 728 patients (median age 31 years, median baseline HIV-1 RNA level of 4.4 log₁₀copies/mL, median baseline CD4⁺ T-cell count of 397 cells/mm³) were randomized in a 1:1 ratio to receive either the fixed combination of doravirine 100 mg, lamivudine 300 mg, and tenofovir DF 300 mg (doravirine/lamivudine/tenofovir DF) once daily or the fixed combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg (efavirenz/emtricitabine/tenofovir DF) once daily.1,2,3,254

At 48 weeks, 84.3% of patients in the doravirine/lamivudine/tenofovir DF group achieved an HIV-1 RNA level <50 copies/mL, compared with 80.8% of patients in the efavirenz/emtricitabine/tenofovir DF group, showing noninferiority of the doravirine-containing regimen.3 At 96 weeks, 77% of patients in the doravirine/lamivudine/tenofovir DF group and 74% of those in the efavirenz/emtricitabine/tenofovir DF group had plasma HIV-1 RNA levels <50 copies/mL, which again demonstrated noninferiority of doravirine/lamivudine/tenofovir DF to efavirenz/emtricitabine/tenofovir DF in antiretroviral-naive adults.1,351 The mean increase in CD4⁺ T-cell count was 238 cells/mm³ in the doravirine/lamivudine/tenofovir DF group and 223 cells/mm³ in the efavirenz/emtricitabine/tenofovir DF group.1

Antiretroviral-experienced Adults

Efficacy of switching antiretroviral-experienced HIV-1-infected adults from a stable baseline regimen to the fixed combination containing doravirine (doravirine/lamivudine/tenofovir DF) was evaluated in a phase 3, open-label, active-controlled, noninferiority trial (DRIVE-SHIFT; NCT02397096).1,29 Results indicated that switching to doravirine/lamivudine/tenofovir DF in virologically suppressed HIV-1-infected adults was noninferior to continuing treatment on a stable baseline antiretroviral regimen.30 Patients enrolled in DRIVE-SHIFT had to be virologically suppressed (plasma HIV-1 RNA levels <50 copies/mL) on their baseline regimen for at least 6 months prior to trial entry and have no history of virologic failure.1,30 Stable baseline regimens consisted of 2 NRTIs in conjunction with a cobicistat-boosted or ritonavir-boosted HIV protease inhibitor (atazanavir, darunavir, lopinavir), cobicistat-boosted elvitegravir, or an NNRTI (efavirenz, nevirapine, or rilpivirine).1,30 Patients were randomized 2:1 to switch to doravirine/lamivudine/tenofovir DF on day 1 (immediate-switch group; 447 patients) or stay on their baseline regimen and switch to doravirine/lamivudine/tenofovir DF at week 24 (delayed-switch group; 223 patients).30 The primary efficacy end point was the proportion of participants with plasma HIV-1 RNA levels <50 copies/mL at 48 weeks (immediate-switch group) or 24 weeks (delayed-switch group).30 Patient characteristics were similar between treatment groups (median age 43 years, median baseline CD4+ T-cell count of 628 cells/mm³).1

At 24 or 48 weeks, 94 or 91%, respectively, of patients in the immediate-switch group had plasma HIV-1 RNA levels <50 copies/mL.1,30 In the delayed-switch group, 95% had plasma HIV-1 RNA levels <50 copies/mL at 24 weeks (baseline regimen) and at 48 weeks (24 weeks after switching to doravirine/lamivudine/tenofovir DF).1,30

Pediatric Patients

Doravirine in combination with lamivudine and tenofovir DF (doravirine/lamivudine/tenofovir DF) was evaluated in a phase 1/2 open-label trial (IMPAACT 2014, NCT03332095) in pediatric patients (12 to <18 years of age weighing ≥35 kg).1,254,352 Cohort 1 evaluated the pharmacokinetics of a single dose of doravirine in virologically-suppressed pediatric patients.1 Cohort 2 enrolled patients (median age 15 years, median baseline CD4⁺ T-cell count of 713 cells/mm³) who were either naïve to antiretroviral therapy (2 patients) or virologically-suppressed on a stable regimen (43 patients).1 All patients in cohort 2 were started on or switched to doravirine/lamivudine/tenofovir DF.1 At week 24, 95% of virologically-suppressed patients maintained HIV-1 RNA levels <50 copies/mL.1 Of the 2 antiretroviral-naïve patients, 1 achieved an HIV-1 RNA level <50 copies/mL at week 24; the second patient met the criteria for virologic failure (HIV-1 RNA levels ≥200 copies/mL at week 24), due to nonadherence to treatment.1,352

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from one of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the two drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral 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.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), ARV regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other antiinfective regimens.200

Doravirine, an NNRTI, is commonly used with a dual-NRTI “backbone” in a fully suppressive regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, doravirine is included in various antiretroviral regimens.200 These doravirine-containing regimens are listed among recommended initial regimens in certain clinical situations and include the following regimens: doravirine/lamivudine/tenofovir DF, and doravirine plus either tenofovir DF/emtricitabine or tenofovir alafenamide [TAF]/emtricitabine.200

In the 2023 HHS pediatric HIV treatment guideline, doravirine is included in various antiretroviral regimens.201 Doravirine plus a dual-NRTI “backbone” is recommended as an alternative NNRTI-based regimen for initial treatment of HIV in children and adolescents weighing ≥35 kg.201

In the 2023 HHS perinatal HIV treatment guideline, doravirine is described as having insufficient data for use as an initial regimen before or during pregnancy.202 Doravirine may be continued if pregnancy occurs as part of a fully suppressive, well-tolerated regimen with frequent monitoring of viral load; consider switching to a different regimen due to insufficient data on use of doravirine during pregnancy.202

General

Pretreatment Screening

• Consider potential for drug interactions prior to, and during treatment with doravirine.1 Review concomitant medications to assess for drug interactions.1

Administration

Doravirine is administered orally once daily without regard to food.1

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

Single-entity doravirine (Pifeltro^®) is commercially available as tablets.1

Doravirine also is commercially available in fixed-combination tablets containing doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF; Delstrigo^®).254

Store doravirine tablets in the original bottle at 20-25°C (excursions permitted to 15-30°C); protect from moisture and do not remove the desiccant.1

Dosage

Pediatric Dosage

Treatment of HIV-1 Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric patients weighing at least 35 kg, the recommended dosage of doravirine is 100 mg once daily.1

In patients receiving concomitant therapy with rifabutin, increase the dosage of doravirine to 100 mg twice daily (approximately 12 hours apart).1

Adult Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in adults, the recommended dosage of doravirine is 100 mg once daily.1

In patients receiving concomitant therapy with rifabutin, increase the dosage of doravirine to 100 mg twice daily (approximately 12 hours apart).1

Special Populations

Hepatic Impairment

Dosage adjustments of doravirine are not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustments of doravirine are not necessary in patients with mild, moderate, or severe renal impairment.1 The drug has not been adequately studied in patients with end-stage renal disease and has not been studied in patients receiving dialysis.1

Geriatric Patients

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.1

Contraindications

• 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.1 Concomitant use with such drugs may result in substantially decreased doravirine plasma concentrations and may decrease the effectiveness of doravirine.1

Warnings/Precautions

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

Concomitant use of doravirine and certain other 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.1

Consider the potential for drug interactions prior to and during doravirine therapy; review concomitant drugs during doravirine therapy and monitor the patient for adverse effects.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in human immunodeficiency virus (HIV)-infected patients receiving multiple-drug antiretroviral therapy.1 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 , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]);1 such responses may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].1

Human data are not adequate to establish whether or not doravirine poses a risk to pregnancy outcomes.1

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.1 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 20.1

Lactation

It is not known whether doravirine is distributed into human milk, affects human milk production, or affects the breast-fed infant.1

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).1

Because of the risk of adverse effects in the infant, the risk of HIV transmission, and the risk of developing viral resistance in HIV-positive infants, HIV-infected women should not breast-feed infants.1

Pediatric Use

Safety and efficacy of doravirine have been established in pediatric patients weighing ≥35 kg.1

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.1 The safety, efficacy, and pharmacokinetics of doravirine in this patient population were similar to that in adults.1

The safety and efficacy of doravirine have not been established in pediatric patients weighing <35 kg.1

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;1 however, these differences are not considered clinically important.1

Geriatric Use

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently to doravirine than younger adults.1

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.1

The pharmacokinetics of doravirine in adults are not substantially affected by age in those 18-78 years of age.1

Hepatic Impairment

There are no clinically important differences in the pharmacokinetics of doravirine in individuals with moderate hepatic impairment (Child-Pugh class B) compared with those without hepatic impairment.1,27 Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Dosage adjustments of doravirine are not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

Renal Impairment

Following a single dose of doravirine, exposures of the drug were 43% higher in individuals with severe renal impairment compared with those without renal impairment.1 Based on population pharmacokinetic analysis, renal function does not have a clinically important effect on doravirine pharmacokinetics.1

Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in patients receiving dialysis.1

Dosage adjustments of doravirine are not necessary in patients with mild, moderate, or severe renal impairment.1

Common Adverse Effects

The most common adverse effects of doravirine (≥5%; all grades) include nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams.1

Doravirine is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro, doravirine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and is not likely to induce CYP1A2, 2B6, or 3A4.1 In vitro, doravirine does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1 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.1

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Concomitant use of doravirine and CYP3A inducers may result in decreased doravirine plasma concentrations and may reduce the efficacy of doravirine.1 Concomitant use of doravirine and CYP3A inhibitors may result in increased plasma concentrations of doravirine.1

Doravirine is not likely to have a clinically important effect on the exposures of drugs metabolized by CYP isoenzymes.1

Antacids

No clinically important pharmacokinetic interactions were observed when doravirine was used concomitantly with an antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone.1

Anticonvulsants

Carbamazepine, Oxcarbazepine, Phenobarbital, and Phenytoin

Pharmacokinetic interactions with doravirine and certain anticonvulsants that are CYP3A inducers (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin) are expected (decreased doravirine concentrations and possible decreased efficacy).1

Concomitant use of doravirine and carbamazepine, oxcarbazepine, phenobarbital, or phenytoin is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after these anticonvulsants are discontinued.1

Antimycobacterial Agents

Rifabutin

When doravirine (single 100-mg dose) was used with rifabutin (300 mg once daily), AUC of doravirine decreased by 50%, but peak plasma concentrations were not affected.1

If doravirine is used concomitantly with rifabutin, dosage of doravirine should be increased to 100 mg twice daily, which provides similar AUC and peak plasma exposures as doravirine 100 mg once daily when given without rifabutin.1

Rifampin

When doravirine (single 100-mg dose) was used with rifampin (600 mg once daily), doravirine AUC and peak plasma concentrations were decreased by 88 and 57%, respectively;1 decreased doravirine exposures may decrease efficacy of the drug.1

Concomitant use of doravirine and rifampin is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after rifampin is discontinued.1

Rifapentine

Pharmacokinetic interactions with rifapentine and doravirine are expected (decreased doravirine concentrations and possible decreased efficacy).1

Concomitant use of doravirine and rifapentine is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after rifapentine is discontinued.1

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and enfuvirtide or maraviroc.1

HIV Integrase Inhibitors (INSTIs)

Raltegravir

There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and raltegravir.1

Dolutegravir

No clinically important effect on the pharmacokinetics of either drug has been observed when doravirine is used concomitantly with dolutegravir.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine.1

Efavirenz

When doravirine (100 mg once daily) was initiated on the first day following discontinuance of efavirenz (600 mg once daily), doravirine exposures were decreased by 62% and peak plasma concentrations were decreased by 35%;1 by 14 days after discontinuance of efavirenz, doravirine exposures were decreased by 32% and peak plasma concentrations were decreased by 14%.1

Concomitant use of doravirine and efavirenz is not recommended.1

Etravirine

Pharmacokinetic interactions with etravirine and doravirine are expected (decreased doravirine concentrations).1

Concomitant use of doravirine and etravirine is not recommended.1

Nevirapine

Pharmacokinetic interactions with nevirapine and doravirine are expected (decreased doravirine concentrations).1

Concomitant use of doravirine and nevirapine is not recommended.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and abacavir, didanosine, emtricitabine, lamivudine, tenofovir disoproxil fumarate (tenofovir DF), or zidovudine.1

Lamivudine

No clinically important effect on the pharmacokinetics of either drug has been observed when doravirine is used concomitantly with lamivudine.1

Tenofovir DF

No clinically important effect on the pharmacokinetics of either drug has been observed when doravirine is used concomitantly with tenofovir DF.1

HIV Protease Inhibitors (PIs)

There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and darunavir or indinavir.1

Ritonavir

When doravirine (single 50-mg dose) was used with ritonavir (100 mg twice daily), doravirine exposures increased by approximately 3.5-fold and peak plasma concentrations increased by 31%.1 However, these changes are not considered to be clinically important.1

Atorvastatin

Concomitant use of atorvastatin and doravirine did not result in clinically important pharmacokinetic interactions.1

Elbasvir and Grazopevir

No clinically important pharmacokinetic interactions have been observed when doravirine was used concomitantly with elbasvir and grazoprevir.1

Enzalutamide

Pharmacokinetic interactions with enzalutamide and doravirine are expected (decreased doravirine concentrations and possible decreased efficacy).1

Concomitant use of doravirine and enzalutamide is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after enzalutamide is discontinued.1

Ethinyl Estradiol and Levonorgestrel

No clinically important pharmacokinetic interactions are expected when doravirine is administered concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel.1

Ketoconazole

When doravirine (single 100-mg dose) was used with ketoconazole (400 mg once daily), doravirine exposures increased by approximately threefold and peak plasma concentrations increased by 25%.1 However, these changes are not considered clinically important.1

Ledipasvir and Sofosbuvir

No clinically important pharmacokinetic interactions have been observed when doravirine was used concomitantly with ledipasvir and sofosbuvir.1

Metformin

No clinically important pharmacokinetic interactions have been obsserved when doravirine was used concomitantly with metformin.1

Methadone

No clinically important pharmacokinetic interactions have been observed when doravarine was used concomitantly with methadone.1

Midazolam

Concomitant use of midazolam and doravirine did not result in clinically important pharmacokinetic interactions.1

Mitotane

Pharmacokinetic interactions with mitotane and doravirine are expected (decreased doravirine concentrations and possible decreased efficacy).1

Concomitant use of doravirine and mitotane is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after mitotane is discontinued.1

Pantoprazole

No clinically important pharmacokinetic interactions have been observed when doravirine was used concomitantly with pantoprazole.1

St. John's Wort

Pharmacokinetic interactions with St. John's wort ( Hypericum perforatum ) and doravirine are expected (decreased doravirine concentrations and possible decreased efficacy).1

Concomitant use of doravirine and St. John's wort is contraindicated.1 Doravirine should not be initiated until at least 4 weeks after St. John's wort is discontinued.1

Description

Doravirine, a pyridinone human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of HIV type 1 (HIV-1) by interfering with viral polymerase activities of reverse transcriptase.1,17,18,19 Doravirine is a noncompetitive, non-active site inhibitor that binds to a hydrophobic pocket in the p66 subunit of the p66/p51 heterodimer of the reverse transcriptase enzyme.17,19 This causes conformational changes within active site residues resulting in an inactive conformation, which inhibits the chemical step of a polymerization reaction.17,19 Doravirine does not inhibit human cellular α- and β-DNA polymerases and does not inhibit mitochondrial γ-DNA polymerase.1,17

Doravirine is active against wild-type HIV-1, including certain strains resistant to some other NNRTIs (i.e., those with K103N and/or Y181C substitutions).1,17,18,19,21,22,23 However, doravirine-resistant strains have been selected in cell culture and have emerged during clinical use.1 In vitro, the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L resulted in more than 100-fold reduced susceptibility to doravirine.1,20,21,23 In clinical trials evaluating doravirine in antiretroviral-naive patients, treatment-emergent doravirine resistance-associated substitutions were observed in HIV-1 strains from 13 of 36 patients in the resistance analysis subset (i.e., those with plasma HIV-1 RNA levels exceeding 400 copies/mL at virologic failure or early study discontinuation with resistance data).1 These HIV-1 strains exhibited one or more of the following substitutions: A98G, V106I, V106A, V106M/T, V108I, E138G/K, Y188L, H221Y, P225H/L, P225P/S, F227C, F227C/R, Y318Y/F, and Y318Y/S.1,2,3 Cross-resistance occurs among HIV NNRTIs (e.g., efavirenz, etravirine, nevirapine, rilpivirine).1 Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to other NNRTIs;1 however, the treatment-emergent doravirine resistance-associated substitution Y318F does not appear to confer reduced susceptibility to efavirenz, etravirine, or rilpivirine.1

Following oral administration, the absolute bioavailability of doravirine is 64%;1 peak plasma concentrations occur 2 hours after administration.1 Steady state is achieved after 2 days.1 Administration of doravirine with a high-fat meal increases AUC, peak plasma concentrations, and trough plasma concentrations by 16, 3, and 36%, respectively, compared with administration in the fasted state;1,24,26 this effect of food is not considered clinically important.1 Doravirine is primarily metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A.1 Approximately 6% of an oral dose is eliminated in urine as unchanged doravirine;1 unchanged drug also is eliminated to a minor extent by biliary and/or fecal routes.1 The elimination half-life of doravirine is 15 hours.1 Doravirine is 76% bound to plasma proteins.1 There are no clinically relevant differences in the pharmacokinetics of doravirine based on age (in adults), race, body mass index (BMI), or sex.1,25,29

Advice to Patients

• Advise patients to take doravirine once every day at a regularly scheduled time with or without food.1
• Advise patients not to miss or skip doses since this can result in development of resistance.1 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.1 Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time.1
• Advise patients that doravirine may interact with certain other drugs.1 For patients receiving rifabutin, importance of taking one 100-mg tablet of doravirine twice daily (approximately 12 hours apart).1
• Inform patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with advanced HIV infection (AIDS).1 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.1 Advise patients to immediately inform a clinician if any symptoms of infection occur.1
• 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.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to doravirine.1 Advise HIV-infected women not to breast-feed because HIV-1 can be passed to the baby in breast milk.1
• Inform patients of other important precautionary information.1

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.

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