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Introduction ⬇

AHFS Class:

Generic Name(s):

Doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF) is a fixed-combination antiretroviral agent containing doravirine (human immunodeficiency virus [HIV] nonnucleoside reverse transcriptase inhibitor [NNRTI]), lamivudine (HIV nucleoside reverse transcriptase inhibitor [NRTI]), and tenofovir DF (HIV nucleotide reverse transcriptase inhibitor classified as an NRTI).1

Uses ⬆ ⬇

[Section Outline]

Treatment of HIV Infection !!navigator!!

The fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF) is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing ≥35 kg who are antiretroviral-naive or to replace a current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known resistance to any of the individual components of the fixed combination.1

Doravirine/lamivudine/tenofovir DF is used as a single-tablet antiretroviral regimen; 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

Clinical Experience

Antiretroviral-naïve Adults

Efficacy and safety of doravirine/lamivudine/tenofovir DF in antiretroviral-naïve HIV-1-infected adults was evaluated in a phase 3 randomized study (DRIVE-AHEAD).1,2,3,351 Results indicated that doravirine/lamivudine/tenofovir DF was noninferior to a regimen of efavirenz in conjunction with 2 NRTIs for initial treatment in antiretroviral-naïve adults.1,2 3,351

In DRIVE-AHEAD, 728 patients (median age 31 years, median baseline HIV-1 RNA level of 4.4 log10 copies/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

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, 77.5% of patients in the doravirine/lamivudine/tenofovir DF group and 73.6% 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-naïve adults.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 doravirine/lamivudine/tenofovir DF was evaluated in a phase 3, open-label, active-controlled, noninferiority trial (DRIVE-SHIFT).1,30 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 (PI; atazanavir, darunavir, lopinavir), cobicistat-boosted elvitegravir, or a nonnucleoside reverse transcriptase inhibitor (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).1,30 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 At week 144, virologic suppression (HIV-1 RNA levels <50 copies/mL) was maintained in 80.1 or 83.7% of patients in the immediate- and delayed-switch groups, respectively.501

Antiretroviral-experienced or -naïve Pediatric Patients

The combination of doravirine/lamivudine/tenofovir DF was evaluated in a phase 1/2 open-label trial (IMPAACT 2014) enrolling pediatric patients (12 to <18 years of age weighing ≥35 kg).1,352 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 of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy 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 antiretroviral therapy 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 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 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), an NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 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), antiretroviral regimen selection should also consider the potential for activity against other present infections, drug-drug interactions, and timing of initiation relative to other anti-infective regimens.200

Doravirine/lamivudine/tenofovir DF is used as a single-tablet antiretroviral regimen; the tablet contains an NNRTI (doravirine) plus 2 NRTIs (lamivudine and tenofovir DF).200 The regimen of doravirine/lamivudine/tenofovir DF is listed among recommended initial regimens in certain clinical situations (e.g., in situations where a one-pill, once-daily regimen is desired).200

In the 2024 HHS pediatric HIV treatment guideline, doravirine/lamivudine/tenofovir DF is included as an alternative NNRTI-based regimen for initial treatment of HIV in children and adolescents weighing ≥35 kg.201

In the 2024 HHS perinatal HIV treatment guideline, doravirine/lamuvidine/tenofovir DF is described as having insufficient data for use as an initial regimen before or during pregnancy, primarily due to a lack of data on the doravirine component.202 For patients already receiving doravirine/lamivudine/tenofovir DF who have acheived viral suppression and who become pregnant, the regimen may be continued, with frequent monitoring of viral load.202 Alternatively, it may be appropriate to consider switching to a different regimen due to insufficient data on the use of doravirine during pregnancy.202

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Other General Considerations

Administration !!navigator!!

The fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF) is administered orally once daily without regard to food.1

Doravirine/lamivudine/tenofovir DF is used alone as a complete antiretroviral regimen for the treatment of HIV-1 infection.1

If a dose is missed, the missed dose should be taken as soon as possible, unless it is almost time for the next dose; the patient should not take 2 doses at one time.1

Store doravirine/lamivudine/tenofovir DF at 20-25°C (excursions permitted between 15-30°C).1

Store in original bottle.1 Protect from moisture; do not remove desiccant and keep bottle tightly closed.1

Dosage !!navigator!!

Each fixed-combination tablet of doravirine/lamivudine/tenofovir DF contains doravirine 100 mg, lamivudine 300 mg, and tenofovir DF 300 mg.1

Adults

Treatment of HIV Infection

For the treatment of HIV-1 infection in adults, the recommended dosage of doravirine/lamivudine/tenofovir DF is 1 tablet (100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir DF) once daily.1

Pediatric Patients

Treatment of HIV Infection

For the treatment of HIV-1 infection in pediatric patients weighing ≥35 kg, the recommended dosage of doravirine/lamivudine/tenofovir DF is 1 tablet (100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir DF) once daily.1

Dosage Modification for Concomitant Use with Rifabutin

If doravirine/lamivudine/tenofovir DF is used for the treatment of HIV-1 infection in pediatric or adult patients receiving concomitant therapy with rifabutin, patients should receive 1 tablet of the fixed combination (100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir DF) once daily and a 100-mg tablet of single-entity doravirine once daily given approximately 12 hours after the fixed-combination tablet.1

Special Populations !!navigator!!

Hepatic Impairment

Dosage adjustments are not necessary if doravirine/lamivudine/tenofovir DF is used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

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

Renal Impairment

Doravirine/lamivudine/tenofovir DF is not recommended in patients with an estimated creatinine clearance <50 mL/minute.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for doravirine/lamivudine/tenofovir DF 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

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Post-treatment Acute Exacerbations of Hepatitis B

A boxed warning is included in the prescribing information for doravirine/lamivudine/tenofovir DF regarding the risk of severe post-treatment acute exacerbations of hepatitis B virus (HBV) infection in human immunodeficiency virus type 1 (HIV-1) patients coinfected with HBV who discontinue products containing lamivudine and/or tenofovir DF.1

In HIV-infected patients with HBV coinfection, severe acute exacerbations of HBV infection, including liver decompensation and liver failure, have occurred following discontinuance of preparations containing lamivudine and/or tenofovir DF (components of doravirine/lamivudine/tenofovir DF).1

All patients with HIV infection should be tested for HBV before antiretroviral therapy is initiated.1 Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after doravirine/lamivudine/tenofovir DF is discontinued in patients coinfected with HIV and HBV.1 If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.1

Other Warnings and Precautions

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in patients receiving tenofovir DF (a component of doravirine/lamivudine/tenofovir DF).1

Serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiation of doravirine/lamivudine/tenofovir DF and routinely monitored during treatment with the drug in all patients as clinically appropriate.1 In patients with chronic kidney disease, serum phosphorus also should be monitored.1

Doravirine/lamivudine/tenofovir DF should be discontinued if clinically important decreases in renal function or evidence of Fanconi syndrome occur.1 The fixed combination also should be discontinued if estimated creatinine clearance decreases to <50 mL/minute.1

Because persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy, renal function should be promptly evaluated in patients at risk for renal dysfunction who present with such symptoms.1

Doravirine/lamivudine/tenofovir DF should be avoided in patients who are receiving or have recently received a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1 Acute renal failure has been reported after initiation of high-dose or multiple NSAIA therapy in HIV-infected patients at risk for renal dysfunction who appeared stable while receiving tenofovir DF; hospitalization and renal replacement therapy were required in some patients.1 Alternatives to NSAIAs should be considered if such therapy is needed in patients at risk for renal dysfunction.1

Bone Loss and Mineralization Defects

Decreases in bone mineral density (BMD) from baseline, increases in several biochemical markers of bone metabolism, and increased serum parathyroid hormone levels and 1,25 vitamin D levels have been reported during adult clinical trials of tenofovir DF (a component of doravirine/lamivudine/tenofovir DF).1 The effects of tenofovir-associated changes in BMD on long-term bone health and future fracture risk are unknown.1

Clinical studies of tenofovir DF in pediatric patients 2 to <18 years of age found similar bone effects with tenofovir DF to those observed in adults, suggesting increased bone turnover.1 Typically, BMD undergoes rapid increases in pediatric patients; however, total body increases in BMD were shown to be reduced in HIV-1 infected pediatric patients receiving tenofovir DF compared to controls.1 Similar trends have been observed in pediatric patients 2 to <18 years of age with chronic HBV infection.1 Across pediatric clinical studies, normal skeletal growth (height) was observed for the duration of the studies.1

Osteomalacia associated with proximal renal tubulopathy, which manifested as bone pain or pain in extremities and may contribute to fractures, has been reported in patients receiving tenofovir DF.1 Arthralgia and muscle pain or weakness also have been reported in patients with proximal renal tubulopathy.1 Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk for renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving preparations containing tenofovir DF.1

Bone mineral density monitoring should be considered in HIV-1-infected adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1 Although the effect of calcium and vitamin D supplementation was not studied, such supplementation may be beneficial for all patients.1 If bone abnormalities are suspected, appropriate consultation should be obtained.1

Interactions

Concomitant use of doravirine/lamivudine/tenofovir DF with certain drugs may result in clinically important interactions, including decreased plasma concentrations of the antiretroviral agents leading to loss of therapeutic effect and possible development of resistance; other interactions may increase plasma concentrations of the antiretroviral agents and/or concomitant drugs leading to clinically important adverse reactions.1

The potential for drug interactions should be considered prior to and during doravirine/lamivudine/tenofovir DF therapy; concomitant drugs should be reviewed during doravirine/lamivudine/tenofovir DF therapy and the patient should be monitored for adverse effects.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in 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 , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ], tuberculosis); 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

Use of Fixed Combinations

The usual cautions, precautions, contraindications, and interactions associated with each component of doravirine/lamivudine/tenofovir DF should be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.1

Specific Populations

Pregnancy

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

There are insufficient prospective data in pregnant women to assess the risk of birth defects and miscarriage in those receiving doravirine/lamivudine/tenofovir DF.1 Human data are not available 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 Available data from the antiretroviral pregnancy registry show no differences in the overall risk of major birth defects for lamivudine and tenofovir DF.1

Lactation

It is not known whether doravirine is distributed into human milk.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 Lamivudine and tenofovir DF are distributed into milk in humans.1 It is not known whether doravirine/lamivudine/tenofovir DF or the individual drug components affect human milk production or the breast-fed infant.1

The HHS perinatal HIV transmission guideline provides updated recommmendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision-making about infant feeding.202 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.202 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 eliminate the risk.202 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.202

Pediatric Use

Safety and efficacy of doravirine/lamivudine/tenofovir DF have been established in pediatric patients weighing at least 35 kg.1

Use of doravirine/lamivudine/tenofovir DF in this population is supported by data from randomized studies in adults, with additional pharmacokinetic, safety, and efficacy data from a 24-week, open-label study conducted in 54 antiretroviral naïve or antiretroviral experienced pediatric patients 12 to <18 years of age.1 Doravirine/lamivudine/tenofovir DF demonstrated similar safety and efficacy in this population compared to adult patients, with no clinically important differences detected in exposures for the individual components of doravirine/lamivudine/tenofovir DF.1

Safety and efficacy of doravirine/lamivudine/tenofovir DF have not been established in pediatric patients weighing <35 kg.1

Geriatric Use

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently to doravirine, lamivudine, or tenofovir DF than younger patients.1

Doravirine/lamivudine/tenofovir DF 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

Hepatic Impairment

Doravirine pharmacokinetics are not substantially affected in individuals with moderate hepatic impairment (Child-Pugh class B) compared with those without hepatic impairment.1 Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Lamivudine pharmacokinetics are not substantially affected by diminishing hepatic function.1 Safety and efficacy of lamivudine have not been established in patients with decompensated liver disease.1

Tenofovir pharmacokinetics are not substantially affected by any degree of hepatic impairment.1

No dosage adjustment of doravirine/lamivudine/tenofovir DF is required in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment; no studies have been conducted in patients with severe (Child-Pugh class C) hepatic impairment.1

Renal Impairment

Because doravirine/lamivudine/tenofovir DF is a fixed-combination tablet and the dosage of lamivudine and tenofovir DF (components of doravirine/lamivudine/tenofovir DF) cannot be adjusted, doravirine/lamivudine/tenofovir DF is not recommended in patients with estimated creatinine clearance <50 mL/minute.1

The pharmacokinetics of doravirine were not significantly impacted in patients with mild to severe renal impairment (creatinine clearance >15 mL/minute).1 Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.1

Lamivudine exposures, peak plasma concentrations, and half-life are increased and clearance of the drug is decreased to a clinically important extent by diminishing renal function (creatinine clearances 111 to <10 mL/minute).1

Tenofovir exposures and peak plasma concentrations are substantially increased in individuals with creatinine clearances <50 mL/minute or with end-stage renal disease requiring dialysis.1

Common Adverse Effects !!navigator!!

Adverse effects reported in ≥5% of patients receiving doravirine/lamivudine/tenofovir DF include dizziness, nausea, and abnormal dreams.1

Drug Interactions ⬆ ⬇

[Section Outline]

The following drug interactions are based on studies using the individual components of the fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF).1

When doravirine/lamivudine/tenofovir DF is used, interactions associated with each drug in the fixed combination should be considered.1

Drugs Affecting or Metabolized by Microsomal Enzymes !!navigator!!

Doravirine is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A.1 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 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 Doravirine is not likely to have a clinically important effect on the exposure of drugs metabolized by CYP isoenzymes.1

Lamivudine is not substantially metabolized by CYP isoenzymes and does not inhibit or induce CYP isoenzymes.1 It is unlikely that clinically important CYP-mediated drug interactions with lamivudine will occur.1

Pharmacokinetic interactions between tenofovir and drugs that are inhibitors or substrates of CYP isoenzymes are unlikely.1

Drugs Affecting or Metabolized by Uridine Diphosphate-gluuronosyltransferases !!navigator!!

In vitro, doravirine does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1

Drugs Affecting or Affected by Other Transporters !!navigator!!

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 Renal Function !!navigator!!

There is potential for pharmacokinetic interactions with drugs that reduce renal function or that may compete with lamivudine or tenofovir for active renal tubular secretion (e.g., acyclovir, aminoglycosides [e.g., gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]); increased plasma concentrations of lamivudine, tenofovir, and/or the concomitantly administered drug may occur.1

Drugs Affecting Gastric Acidity !!navigator!!

Antacids

No clinically important effect on doravirine concentrations when doravirine was used concomitantly with an antacid containing aluminum hydroxide, magnesium hydroxide and simethicone.1

Proton pump Inhibitors

No clinically important effect on doravirine concentrations were observed when the drug was used concomitantly with pantoprazole.1

Anticonvulsants !!navigator!!

Carbamazepine, Oxcarbazepine, Phenobarbital, and Phenytoin

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

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

Antimycobacterial Agents !!navigator!!

Rifabutin

When doravirine (single 100-mg dose) was used with rifabutin (300 mg once daily), doravirine area under the plasma concentration-time curve (AUC) and trough plasma concentrations were decreased by 50 and 68%, respectively, but peak plasma concentrations were not affected.1 When doravirine (100 mg twice daily) was used with rifabutin (300 mg once daily), doravirine AUC, peak plasma concentrations, and trough plasma concentrations were not affected, and were similar to concentrations observed without concomitant rifabutin.1

If doravirine/lamivudine/tenofovir DF is used concomitantly with rifabutin, the patient should receive 1 tablet of the fixed combination (100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir DF) and 100 mg of single-entity doravirine once daily (the single-entity tablet should be given approximately 12 hours after the fixed-combination tablet).1

Rifampin

When doravirine (single 100-mg dose) was used with rifampin (600 mg once daily), doravirine AUC, peak plasma concentrations, and trough plasma concentrations were decreased by 88, 57, and 97%, respectively;1, decreased doravirine exposures may decrease efficacy of the drug.1

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

Rifapentine

Pharmacokinetic interactions with rifapentine expected (decreased doravirine concentrations; possible decreased efficacy of doravirine).1

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

Antiretroviral Agents !!navigator!!

Doravirine/lamivudine/tenofovir DF is a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naïve adults, and concomitant use with other antiretroviral agents is not recommended.1

No clinically important pharmacokinetic interactions have been reported between the components of the fixed combination (i.e., doravirine, lamivudine, tenofovir DF).1 There is no in vitro evidence of antagonistic antiretroviral effects between doravirine and lamivudine or tenofovir DF.1

Atorvastatin !!navigator!!

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

Co-trimoxazole !!navigator!!

Concomitant use of co-trimoxazole and lamivudine resulted in a 43% increase in lamivudine AUC and a 30% decrease in lamivudine renal clearance, but did not affect the pharmacokinetics of trimethoprim or sulfamethoxazole.1

Entecavir !!navigator!!

No clinically important pharmacokinetic interactions between entecavir and tenofovir DF.1

Enzalutamide !!navigator!!

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

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

Estrogens and Progestins !!navigator!!

No clinically important effects on the pharmacokinetics of ethinyl estradiol or levonorgestrel when doravirine was used concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel.1 No clinically important pharmacokinetic interactions between tenofovir DF and oral contraceptives containing ethinyl estradiol and norgestimate.1

HCV Antivirals !!navigator!!

HCV Polymerase Inhibitors

Sofosbuvir

No clinically important pharmacokinetic interactions between sofosbuvir and tenofovir DF.1

Sofosbuvir and Velpatasvir

Possible pharmacokinetic interactions with the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) (increased tenofovir concentrations and AUC).1

If doravirine/lamivudine/tenofovir DF is used concomitantly with sofosbuvir/velpatasvir, the patient should be monitored for tenofovir-associated adverse effects.1

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

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

Ledipasvir and Sofosbuvir

No clinically important pharmacokinetic interactions when doravirine was used concomitantly with the fixed combination of ledipasvir and sofosbuvir.1 Concomitant use of ledipasvir/sofosbuvir and tenofovir DF results in increased tenofovir exposures.1

If doravirine/lamivudine/tenofovir DF is used concomitantly with ledipasvir/sofosbuvir, the patient should be monitored for tenofovir-associated adverse effects.1

Ketoconazole !!navigator!!

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

Metformin !!navigator!!

No clinically important interactions observed when metformin was used concomitantly with doravirine.1

Methadone !!navigator!!

No clinically important effects on the pharmacokinetics of either drug when doravirine was used concomitantly with methadone.1 No clinically important pharmacokinetic interactions between methadone and tenofovir DF.1

Midazolam !!navigator!!

Concomitant use of midazolam and do1 ravirine did not result in clinically important pharmacokinetic interactions.1

Mitotane !!navigator!!

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

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

St. John's Wort !!navigator!!

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

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

Sorbitol !!navigator!!

Concomitant use of a single dose of lamivudine with a single 3.2-, 10.2-, or 13.4-g dose of sorbitol results in a 14, 32, or 36% decrease in lamivudine AUC, respectively, and a 28, 52, or 55% decrease in lamivudine peak plasma concentrations, respectively.1

Concomitant use of sorbitol-containing drugs and lamivudine-containing drugs, including doravirine/lamivudine/tenofovir DF, should be avoided.

Tacrolimus !!navigator!!

No clinically important pharmacokinetic interactions between tacrolimus and tenofovir DF.1

Other Information ⬆ ⬇

Description

The fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF) contains a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral (doravirine), an HIV nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral (lamivudine), and a nucleotide reverse transcriptase inhibitor antiretroviral classified as an HIV NRTI (tenofovir disoproxil fumarate; tenofovir DF).1

Doravirine is a pyridinone NNRTI and inhibits replication of HIV type 1 (HIV-1) by interfering with viral polymerase activities of reverse transcriptase.1,17,18,19 Doravirine is active against 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

Lamivudine is a synthetic nucleoside analog that is phosphorylated intracellularly to the active 5'-triphosphate metabolite (lamivudine triphosphate).1 After conversion to the pharmacologically active metabolite, the drug acts as a reverse transcriptase inhibitor via DNA chain termination after incorporation of the nucleotide analogue.1 Lamivudine is active against HIV-1.1

Tenofovir DF is a tenofovir prodrug and is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite (tenofovir diphosphate).1 Tenofovir is active against HIV-1.1

HIV-1 strains resistant to doravirine, lamivudine, or tenofovir have been produced in vitro and have emerged during doravirine/lamivudine/tenofovir DF therapy.1 In the clinical trial evaluating doravirine/lamivudine/tenofovir DF in antiretroviral-naive patients, one or more primary mutations associated with resistance to doravirine were identified in HIV-1 isolates from 10 of 24 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); genotypic resistance against lamivudine and tenofovir DF developed in 7 patients.1 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; however, the treatment-emergent doravirine resistance-associated substitution Y318F does not appear to confer reduced susceptibility to efavirenz, etravirine, or rilpivirine.1 Cross-resistance also occurs among the HIV NRTIs.1

A fixed-combination tablet containing doravirine 100 mg, lamivudine 300 mg, and tenofovir DF 300 mg is bioequivalent to a 100-mg tablet of doravirine, 300-mg tablet of lamivudine, and 300-mg tablet of tenofovir DF given simultaneously.1 The absolute oral bioavailability of doravirine, lamivudine, and tenofovir DF is 64, 86, and 25%, respectively; peak plasma concentrations of doravirine and tenofovir occur 2 hours and 1 hour, respectively, after administration.1 Administration of doravirine, lamivudine, and tenofovir DF with a high-fat meal increases the area under the plasma concentration-time curve (AUC) of doravirine and tenofovir by 10 and 27%, respectively, and decreases the AUC of lamivudine by 7% compared with administration in the fasted state; this effect of food is not considered clinically important.1 Doravirine is primarily metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; lamivudine is metabolized by CYP isoenzymes only to a minor extent and tenofovir does not undergo hepatic metabolism.1 Approximately 6% of an oral dose of doravirine is eliminated in urine as unchanged drug;1,24 unchanged doravirine also is eliminated to a minor extent by biliary and/or fecal routes.1 Lamivudine and tenofovir are eliminated by glomerular filtration and active tubular secretion.1 The elimination half-life of doravirine, lamivudine, and tenofovir is 15, 5-7, and 17 hours, respectively.1 Doravirine, lamivudine, and tenofovir are 76, <35, and <0.7% bound to plasma proteins, respectively.1

There are no clinically relevant differences in pharmacokinetics based on age in adults (doravirine), race (doravirine, lamivudine), body mass index (BMI) (doravirine), or sex (doravirine, lamivudine, tenofovir DF).1 Doravirine, lamivudine, and tenofovir DF exposures in pediatric patients 12 to <18 years of age weighing ≥35 kg are similar to those in adults following administration.1

Advice to Patients

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.

Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Doravirine 100 mg, Lamivudine 300 mg, and Tenofovir Disoproxil Fumarate 300 mg

Delstrigo®

Merck

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

References ⬆

1. Merck & Co. Delstrigo® (doravirine, lamivudine, and tenofovir disoproxil fumarate) tablets prescribing information. Whitehouse Station, NJ; 2023 Nov.

2. Orkin C, Molina JM, Lombaard J et al. Once-Daily Doravirine in HIV-1-Infected, Antiretroviral-Naive Adults: An Integrated Efficacy Analysis. Clin Infect Dis . 2019; [PubMed 31121015]

3. Orkin C, Squires KE, Molina JM et al. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clin Infect Dis . 2019; 68:535-544. [PubMed 30184165]

7. Khalilieh S, Yee KL, Sanchez RI et al. Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study. Antimicrob Agents Chemother . 2017; 61 [PubMed 27872071]

8. Yee KL, Khalilieh SG, Sanchez RI et al. The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects. Clin Drug Investig . 2017; 37:659-667. [PubMed 28353169]

9. Sanchez RI, Yee KL, Fan L et al. Evaluation of the Pharmacokinetics of Metformin Following Coadministration With Doravirine in Healthy Volunteers. Clin Pharmacol Drug Dev . 2019; [PubMed 30973682]

10. Kreutzwiser D, Tseng A. Drug interactions between antiretrovirals and drugs used to treat benign prostatic hyperplasia/lower urinary tract symptoms. Expert Opin Drug Metab Toxicol . 2016; 12:1211-24. [PubMed 27376653]

11. Khalilieh SG, Yee KL, Sanchez RI et al. A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid-Reducing Agents. J Clin Pharmacol . 2019; [PubMed 30817001]

12. Khalilieh S, Yee KL, Sanchez RI et al. Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone. Clin Pharmacol Drug Dev . 2019; [PubMed 31120195]

13. Khalilieh SG, Yee KL, Sanchez RI et al. Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects. J Clin Pharmacol . 2018; [PubMed 29723418]

14. Ankrom W, Sanchez RI, Yee KL et al. Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir. Antimicrob Agents Chemother . 2019; 63 [PubMed 30782982]

15. Khalilieh SG, Yee KL, Sanchez RI et al. Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions. Antimicrob Agents Chemother . 2019; 63 [PubMed 30783000]

16. Bleasby K, Fillgrove KL, Houle R et al. In Vitro Evaluation of the Drug Interaction Potential of Doravirine. Antimicrob Agents Chemother . 2019; 63 [PubMed 30745395]

17. Lai MT, Feng M, Falgueyret JP et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother . 2014; 58:1652-63. [PubMed 24379202]

18. Côté B, Burch JD, Asante-Appiah E et al. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses. Bioorg Med Chem Lett . 2014; 24:917-22. [PubMed 24412110]

19. Namasivayam V, Vanangamudi M, Kramer VG et al. The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic. J Med Chem . 2019; 62:4851-4883. [PubMed 30516990]

21. Feng M, Wang D, Grobler JA et al. In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother . 2015; 59:590-8. [PubMed 25385110]

22. Feng M, Sachs NA, Xu M et al. Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations. Antimicrob Agents Chemother . 2016; 60:2241-7. [PubMed 26833152]

23. Sterrantino G, Borghi V, Callegaro AP et al. Prevalence of predicted resistance to doravirine in HIV-1-positive patients after exposure to non-nucleoside reverse transcriptase inhibitors. Int J Antimicrob Agents . 2019; 53:515-519. [PubMed 30769200]

24. Anderson MS, Gilmartin J, Cilissen C et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther . 2015; 20:397-405. [PubMed 25470746]

25. Yee KL, Ouerdani A, Claussen A et al. Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1. Antimicrob Agents Chemother . 2019; 63 [PubMed 30745394]

26. Behm MO, Yee KL, Liu R et al. The Effect of Food on Doravirine Bioavailability: Results from Two Pharmacokinetic Studies in Healthy Subjects. Clin Drug Investig . 2017; 37:571-579. [PubMed 28349328]

27. Khalilieh S, Yee KL, Liu R et al. Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics. J Clin Pharmacol . 2017; 57:777-783. [PubMed 28026013]

28. Ankrom W, Yee KL, Sanchez RI et al. Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics. Antimicrob Agents Chemother . 2018; 62 [PubMed 29891610]

29. Behm MO, Yee KL, Fan L et al. Effect of gender and age on the relative bioavailability of doravirine: results of a Phase I trial in healthy subjects. Antivir Ther . 2017; 22:337-344. [PubMed 28206979]

30. Johnson M, Kumar P, Molina JM et al. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr . 2019; 81:463-472. [PubMed 30985556]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (February 27, 2024). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2024). Updates may be available at HIV.gov website. [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2024). Updates may be available at HIV.gov website. [Web]

351. Orkin C, Squires K, Molina J, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate (TDF) versus efavirenz/emtricitabine/TDF in treatment-naïve adults with human immunodeficiency virus type 1 infection: week 96 results of the randomized, double-blind, phase 3 DRIVE-AHEAD noninferiority trial. Clin Infect Dis . 2021;73(1):33-42.

352. Melvin A, Yee K, Gray K, et al. Pharmacokinetics, tolerability, and safety of doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in adolescents living with HIV: week 24 results from IMPAACT 2014. J Acquir Immune Defic Syndr . 2023;92(2):153-162.

501. Kumar P, Johnson M, Molina J, et al. Switching to DOR/3TC/TDF maintains HIV-1 virologic suppression through week 144 in the DRIVE-SHIFT trial. J Acquir Immune Defic Syndr . 2021;87:801-805.