Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Delstrigo: Doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg

Pharmacology

Mechanism of Action

Doravirine: Pyridinone non-nucleoside reverse transcriptase inhibitor that inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase.

Lamivudine: Cytosine analog that is phosphorylated intracellularly to its active 5'-triphosphate metabolite. The principal mode of action is inhibition of HIV reverse transcription via viral DNA chain termination; inhibits RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase.

Tenofovir disoproxil fumarate: Nucleotide reverse transcriptase inhibitor; analog of adenosine 5' monophosphate that interferes with the HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication. TDF is first converted intracellularly by hydrolysis to tenofovir and subsequently phosphorylated to the active tenofovir diphosphate.

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine, lamivudine, or tenofovir disoproxil fumarate.

Contraindications

Hypersensitivity to lamivudine or any component of the formulation; concurrent administration of strong CYP3A inducers, including, but not limited to: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, enzalutamide, rifampin, rifapentine, mitotane, St John's wort

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: One tablet (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) once daily

Dosage adjustment for rifabutin coadministration: One tablet (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) once daily followed by 1 tablet of doravirine 100 mg (~12 hours later), for the duration of rifabutin coadministration

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with or without food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original bottle; protect from moisture. Do not remove desiccants.

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Atazanavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Must use boosted atazanavir in adults; give combo (atazanavir/ritonavir or atazanavir/cobicistat with tenofovir) as a single daily dose with food. Pediatric patients, pregnant patients, and users of H2-blockers require other dose changes. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Doravirine. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Doravirine. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Darunavir. Darunavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Didanosine: Tenofovir Disoproxil Fumarate may diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine. Management: Avoid concomitant treatment with tenofovir disoproxil fumarate and didanosine. Consider altering even existing, stable treatment to avoid this combination. Avoid combination

Efavirenz: May decrease the serum concentration of Doravirine. Avoid combination

Emtricitabine: LamiVUDine may enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: May decrease the serum concentration of Doravirine. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ledipasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoidance of this combination is recommended under some circumstances. Refer to full monograph for details. Consider therapy modification

Levomethadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Levomethadone. Management: Levomethadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Lopinavir: May enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Nevirapine: May decrease the serum concentration of Doravirine. Avoid combination

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Doravirine. Avoid combination

Rifabutin: May decrease the serum concentration of Doravirine. Management: Increase doravirine dose to 1 tablet (100 mg) twice daily when combined with rifabutin. If taking the combination product doravirine/lamivudine/tenofovir, an additional tablet of doravirine (100 mg) should be given 12 hours after the combination product. Consider therapy modification

Rifapentine: May decrease the serum concentration of Doravirine. Avoid combination

Rilpivirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Sorbitol: May decrease the serum concentration of LamiVUDine. Management: When possible, avoid chronic coadministration of sorbitol-containing solutions with lamivudine, but if this combination cannot be avoided, monitor patients more closely for possible therapeutic failure associated with decreased lamivudine exposure. Consider therapy modification

St John's Wort: May decrease the serum concentration of Doravirine. Avoid combination

Tipranavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Trimethoprim: May increase the serum concentration of LamiVUDine. Monitor therapy

Velpatasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Voriconazole: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Management: Consider avoiding when possible. Use efavirenz with voriconazole only if voriconazole is dosed at 400 mg every 12 hours and efavirenz is dosed at 300 mg daily (adult doses) throughout therapy. Avoid Atripla (efavirenz/emtricitabine/tenofovir). Consider therapy modification

Voxilaprevir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Voxilaprevir. Voxilaprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Adverse Reactions

Also see individual agents.

>10%: Central nervous system: Sleep disorder (≤12%), sleep disturbance (≤12%)

1% to 10%:

Cardiovascular: Increased serum creatine kinase (3% to 4%)

Central nervous system: Dizziness (7% to 9%), abnormal dreams (5%), headache (4%), impaired consciousness (4%), insomnia (4%), depression (≤4%), suicidal tendencies (≤4%), drowsiness (3%)

Dermatologic: Skin rash (2%)

Endocrine & metabolic: Increased serum cholesterol (1%), increased serum triglycerides (1%)

Gastrointestinal: Increased serum lipase (2% to 6%), nausea (5%), diarrhea (4%)

Hepatic: Increased serum bilirubin (1% to 5%), increased serum alanine aminotransferase (1% to 4%), increased serum aspartate aminotransferase (1% to 3%)

Renal: Increased serum creatinine (3%)

<1%: Increased LDL cholesterol, increased serum alkaline phosphatase

Warnings/Precautions

Concerns related to adverse effects:

• Decreased bone mineral density: In clinical trials, tenofovir disoproxil fumarate has been associated with decreases in bone mineral density in HIV-1 infected adults and increases in bone metabolism markers. Serum parathyroid hormone and 1,25 vitamin D levels were also higher. Consider monitoring of bone density in adults with a history of pathologic fractures or with other risk factors for bone loss or osteoporosis. Consider calcium and vitamin D supplementation for all patients; effect of supplementation has not been studied, but may be beneficial. Long-term bone health and fracture risk are unknown. If abnormalities are suspected, expert assessment is recommended.
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) later in therapy; further evaluation and treatment may be required.
• Osteomalacia and renal dysfunction: May cause osteomalacia with proximal renal tubulopathy. Bone pain, extremity pain, fractures, arthralgias, weakness, and muscle pain have been reported. In patients at risk for renal dysfunction, persistent or worsening bone or muscle symptoms should be evaluated for hypophosphatemia and osteomalacia.
• Renal toxicity: Tenofovir disoproxil fumarate may cause renal toxicity (acute renal failure and/or Fanconi syndrome); avoid use with concurrent or recent nephrotoxic therapy (including high dose or multiple NSAID use). Acute renal failure has occurred in HIV-infected patients with risk factors for renal impairment who were on a stable tenofovir disoproxil fumarate regimen to which a high dose or multiple NSAID therapy was added. Consider alternatives to NSAIDS in patients taking tenofovir disoproxil fumarate and at risk for renal impairment. Assess serum creatinine, estimated CrCl, urine glucose, and urine protein in all patients prior to initiation of therapy and as clinically appropriate during therapy. In patients with chronic kidney disease, also assess serum phosphorus. IDSA guidelines recommend discontinuing tenofovir disoproxil fumarate (and substituting with alternative antiretroviral therapy) in HIV-infected patients who develop a decline in GFR (a >25% decrease in GFR from baseline and to a level of <60 mL/minute/1.73 m²) during use, particularly in presence of proximal tubular dysfunction (eg, euglycemic glycosuria, increased urinary phosphorus excretion and hypophosphatemia, proteinuria [new onset or worsening]) (IDSA [Lucas 2014]).

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Severe acute exacerbations of hepatitis B have been reported in patients coinfected with hepatitis B virus (HBV) and HIV-1, following discontinuation of antiretroviral therapy. Closely monitor hepatic function in these patients; if appropriate, antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis. All patients with HIV should be tested for HBV prior to initiation of treatment.
• Renal impairment: Do not use in patients with CrCl <50 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CD4 count, viral load; liver function tests, serum creatinine, urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); serum phosphorous (in patients with chronic kidney disease); bone density (patients with a history of bone fracture or have risk factors for bone loss); testing for HBV is recommended prior to the initiation of antiretroviral therapy. Patients with HIV and HBV coinfection should hepatic function monitored for several months following therapy discontinuation.

Pregnancy

Pregnancy Considerations

The Health and Human Services (HHS) perinatal HIV guidelines consider information related to this fixed-dose combination insufficient to make recommendations for use in pregnant females living with HIV who are antiretroviral-naive, who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), who are not yet pregnant but are trying to conceive, or who become pregnant while taking the regimen (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, dizziness, nightmares, trouble sleeping, diarrhea, abdominal pain, headache, or loss of strength and energy. Have patient report immediately to prescriber signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), bone pain, muscle pain, muscle weakness, painful extremities, change in body fat, depression, or signs of infection (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.