Introduction

Antiretroviral; fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF). Doravirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), lamivudine is an HIV nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir DF is an HIV nucleotide reverse transcriptase inhibitor classified as an NRTI.

Uses for Doravirine, Lamivudine, and Tenofovir Disoproxil

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults.

Fixed combination of doravirine/lamivudine/tenofovir DF used alone as a complete regimen for treatment of HIV-1 infection; use with other antiretrovirals not recommended.

For initial treatment in antiretroviral-naive adults, experts state that doravirine/lamivudine/tenofovir DF is a recommended NNRTI-based regimen in certain clinical situations.

For antiretroviral-experienced adults, manufacturer states that doravirine/lamivudine/tenofovir DF can be used to replace the current antiretroviral regimen in those with plasma HIV-1 RNA levels <50 copies/mL on a stable antiretroviral regimen who have no history of treatment failure and are infected with HIV-1 with no known substitutions associated with resistance to doravirine, lamivudine, or tenofovir DF.

Most appropriate antiretroviral regimen cannot be defined for every clinical scenario; select regimen based on information regarding antiretroviral potency, potential rate of resistance development, known toxicities, potential for pharmacokinetic interactions, and patient's virologic, immunologic, and clinical characteristics. Guidelines for the management of HIV infection, including specific recommendations for initial treatment in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, are available at [Web].

Doravirine, Lamivudine, and Tenofovir Disoproxil Dosage and Administration

General

• Determine S_cr, estimated Cl_cr, urine glucose, and urine protein prior to initiation of doravirine/lamivudine/tenofovir DF and routinely monitor during treatment in all patients as clinically appropriate. Also determine serum phosphorus in patients with chronic kidney disease. (See Renal Impairment under Cautions.)

• Test for HBV infection prior to initiation. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.

Doravirine/lamivudine/tenofovir DF is used alone as a complete antiretroviral regimen.

Dosage

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

Adults

Treatment of HIV Infection

Antiretroviral-naive or Antiretroviral-experienced Adults

1 tablet of doravirine/lamivudine/tenofovir DF (doravirine 100 mg, lamivudine 300 mg, tenofovir DF 300 mg) once daily.

Antiretroviral-naive or Antiretroviral-experienced Adults Receiving Rifabutin

1 tablet of doravirine/lamivudine/tenofovir DF (doravirine 100 mg, lamivudine 300 mg, tenofovir DF 300 mg) once daily and one 100-mg tablet of single-entity doravirine once daily given approximately 12 hours after the fixed-combination tablet. (See Specific Drugs under Interactions.)

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. (See Hepatic Impairment under Cautions.)

Renal Impairment

Estimated Cl_cr <50 mL/minute: Not recommended. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations; use with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. (See Geriatric Use under Cautions.)

Contraindications

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

• History of hypersensitivity reaction to lamivudine.

Warnings/Precautions

Warnings

HIV-infected Individuals Coinfected with HBV

Test all HIV-infected patients for presence of HBV before initiating antiretroviral therapy.

In HIV-infected patients with HBV coinfection, severe acute exacerbations of HBV, including liver decompensation and liver failure, reported following discontinuance of lamivudine or tenofovir DF (components of doravirine/lamivudine/tenofovir DF). Such reactions could occur following discontinuance of doravirine/lamivudine/tenofovir DF.

Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after doravirine/lamivudine/tenofovir DF is discontinued in patients coinfected with HIV and HBV. If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.

Other Warnings and Precautions

Renal Toxicity

Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with hypophosphatemia), reported with tenofovir DF (a component of doravirine/lamivudine/tenofovir DF).

Determine S_cr, estimated Cl_cr, urine glucose, and urine protein prior to initiation of doravirine/lamivudine/tenofovir DF and routinely monitor as clinically appropriate during treatment in all patients. Also determine serum phosphorus in those with chronic kidney disease. (See Renal Impairment under Cautions.)

Discontinue doravirine/lamivudine/tenofovir DF if clinically important decreases in renal function or evidence of Fanconi syndrome occurs or if estimated Cl_cr decreases to <50 mL/minute.

Because persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy, promptly evaluate renal function in patients at risk for renal dysfunction who present with such symptoms. (See Bone Effects under Cautions.)

Avoid doravirine/lamivudine/tenofovir DF in patients who are receiving or have recently received a nephrotoxic drug (e.g., high-dose or multiple NSAIAs). Acute renal failure reported after initiation of high-dose or multiple NSAIAs in HIV-infected patients at risk for renal dysfunction who appeared stable while receiving tenofovir DF; hospitalization and renal replacement therapy required in some patients. Consider alternatives to NSAIAs in patients at risk for renal dysfunction.

Bone Effects

Decreases in bone mineral density (BMD) from baseline at lumbar spine and hip, increases in several biochemical markers of bone metabolism, and increased serum parathyroid hormone and 1,25 vitamin D levels reported in patients receiving tenofovir DF (a component of doravirine/lamivudine/tenofovir DF). Effects of tenofovir-associated changes in BMD on long-term bone health and future fracture risk unknown.

Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, reported in patients receiving tenofovir DF. Arthralgia and muscle pain or weakness also reported in cases of proximal renal tubulopathy. Consider hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving preparations containing tenofovir DF.

Consider BMD monitoring in adults with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Effect of calcium and vitamin D supplementation not studied, but may be beneficial for all patients. If bone abnormalities suspected, obtain appropriate consultation.

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 the antiretrovirals and possible development of resistance or may increase plasma concentrations of the antiretroviral agents and/or concomitant drugs leading to clinically important adverse reactions.

Consider potential for drug interactions prior to and during doravirine/lamivudine/tenofovir DF therapy; review concomitant drugs during doravirine/lamivudine/tenofovir DF therapy and monitor for adverse effects. (See Interactions.)

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.

Use of Fixed Combinations

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

Doravirine/lamivudine/tenofovir DF is used alone as a complete regimen; use in conjunction with other antiretrovirals not recommended.

Specific Populations

Pregnancy

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

Doravirine/lamivudine/tenofovir DF: Insufficient data in pregnant women to assess the risk of birth defects and miscarriage.

Doravirine: Human data not available to establish whether or not doravirine poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects observed in rabbits or rats at exposures 8 or 9 times higher, respectively, than human exposures at recommended human dosage. In pregnant 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.

Lamivudine: Available human data show no difference in the overall risk of major birth defects. In pregnant rabbits, oral administration during organogenesis resulted in embryolethality at systemic exposures similar to the recommended clinical dose; no adverse development effects observed in rats and rabbits with oral administration during organogenesis at peak plasma concentrations approximately 35 times higher than human exposure at the recommended clinical dose.

Tenofovir DF: Available human data show no difference in the overall risk of major birth defects. No adverse developmental effects observed in pregnant rats and rabbits at doses up to 14 and 19 times higher, respectively, than recommended human dosage.

Lactation

Doravirine: Not known whether distributed into human milk. Distributed into milk of lactating rats (milk concentrations approximately 1.5 times higher than maternal plasma concentrations at 2 hours after a dose on lactation day 14).

Lamivudine and tenofovir DF: Distributed into human milk.

Doravirine/lamivudine/tenofovir DF: Not known whether the fixed combination or individual drug components affect human milk production or affect the breast-fed infant.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

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

Doravirine: No clinically important differences in doravirine pharmacokinetics in patients with moderate hepatic impairment (Child-Pugh class B). Not studied in those with severe hepatic impairment (Child-Pugh class C).

Lamivudine: Pharmacokinetics not substantially affected by diminishing hepatic function. Safety and efficacy not established in patients with decompensated liver disease.

Tenofovir: Pharmacokinetics not substantially affected by any degree of hepatic impairment.

Renal Impairment

Not recommended in patients with estimated Cl_cr <50 mL/minute because dosage of lamivudine and tenofovir DF (components of doravirine/lamivudine/tenofovir DF) cannot be adjusted for renal impairment.

Common Adverse Effects

Dizziness, nausea, abnormal dreams.

General

• Determine S_cr, estimated Cl_cr, urine glucose, and urine protein prior to initiation of doravirine/lamivudine/tenofovir DF and routinely monitor during treatment in all patients as clinically appropriate. Also determine serum phosphorus in patients with chronic kidney disease. (See Renal Impairment under Cautions.)

• Test for HBV infection prior to initiation. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.

Doravirine/lamivudine/tenofovir DF is used alone as a complete antiretroviral regimen.

Dosage

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

Adults

Treatment of HIV Infection

Antiretroviral-naive or Antiretroviral-experienced Adults

1 tablet of doravirine/lamivudine/tenofovir DF (doravirine 100 mg, lamivudine 300 mg, tenofovir DF 300 mg) once daily.

Antiretroviral-naive or Antiretroviral-experienced Adults Receiving Rifabutin

1 tablet of doravirine/lamivudine/tenofovir DF (doravirine 100 mg, lamivudine 300 mg, tenofovir DF 300 mg) once daily and one 100-mg tablet of single-entity doravirine once daily given approximately 12 hours after the fixed-combination tablet. (See Specific Drugs under Interactions.)

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. (See Hepatic Impairment under Cautions.)

Renal Impairment

Estimated Cl_cr <50 mL/minute: Not recommended. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations; use with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. (See Geriatric Use under Cautions.)

The following drug interactions are based on studies using the individual components of doravirine/lamivudine/tenofovir DF. Consider interactions associated with each drug in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Doravirine: Primarily metabolized by CYP3A. In vitro, does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; not likely to induce CYP1A2, 2B6, or 3A4. Concomitant use of doravirine and CYP3A inducers may decrease doravirine plasma concentrations and may reduce efficacy of doravirine. Concomitant use of doravirine/lamivudine/tenofovir DF with CYP3A inhibitors may increase doravirine plasma concentrations. Not likely to have a clinically important effect on the exposure of drugs metabolized by CYP isoenzymes.

Lamivudine: Not substantially metabolized by CYP isoenzymes; does not inhibit or induce CYP isoenzymes. Clinically important CYP-mediated drug interactions unlikely.

Tenofovir DF: Not a substrate of CYP isoenzymes. In vitro, does not inhibit CYP isoenzymes 3A4, 2D6, 2C9, or 2E1; may have a slight inhibitory effect on CYP1A. Pharmacokinetic interactions with inhibitors or substrates of CYP isoenzymes unlikely.

Drugs Affecting or Metabolized by UGT

Doravirine: In vitro, does not inhibit UGT1A1.

Drugs Affecting or Affected by Other Transporters

Doravirine: Based on in vitro studies, not likely to inhibit 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. Not a substrate of breast cancer resistance protein (BCRP); unlikely to be a substrate of OATP1B1 or 1B3.

Lamivudine: Primarily eliminated in urine by active organic cationic secretion. Potential pharmacokinetic interactions with drugs that are primarily eliminated by active renal secretion via organic cationic transport.

Drugs Affecting Renal Function

Drugs that reduce renal function or compete for active tubular secretion: Potential increased concentrations of lamivudine, tenofovir, and/or concomitant drug.

Specific Drugs