doravirine/lamivudine/tenofovir disoproxil fumarate

REMS

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

Action ⬆ ⬇

Doravirine: Binds to the enzyme reverse transcriptase, which results in disrupted viral DNA synthesis. Lamivudine: After intracellular conversion to its active form (lamivudine-5-triphosphate), inhibits viral DNA synthesis by inhibiting the enzyme HIV reverse transcriptase. Tenofovir disoproxil fumarate: Phosphorylated intracellularly, where it inhibits HIV reverse transcriptase, resulting in disruption of DNA synthesis.

Therapeutic effects:

Evidence of decreased viral replication and reduced viral load with slowed progression of HIV and its sequelae.

Pharmacokinetics ⬆ ⬇

Doravirine

Absorption: 64% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Primarily metabolized in the liver by CYP3A enzymes. Primarily excreted in feces (as metabolites); 6% unchanged in urine.

Half-Life: 15 hr.

Lamivudine

Absorption: 86% absorbed after oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: 71% excreted unchanged in urine by glomerular filtration and active tubular secretion.

Half-Life: 5–7 hr.

Tenofovir Disoproxil Fumarate

Absorption: 25% absorbed after oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: 70–80% excreted unchanged in urine by glomerular filtration and active tubular secretion.

Half-Life: 17 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Doravirine (PO)	unknown	2 hr	24 hr
Lamivudine (PO)	unknown	unknown	24 hr
Tenofovir (PO)	unknown	1 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Previous hypersensitivity reaction to lamivudine;
Concurrent use of carbamazepine, enzalutamide, mitotane, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St. John's wort;
CCr <50 mL/min;
Lactation: Breastfeeding not recommended in women with HIV.

Use Cautiously in:

Coinfected with hepatitis B virus (HBV) (severe acute exacerbations of HBV may recur after discontinuation of lamivudine or tenofovir disoproxil fumarate)
;
Severe hepatic impairment;
OB: Safety of doravirine not established in pregnancy;
Pedi: Children <35 kg (safety and effectiveness not established);
Geri: Consider age-related ↓ in organ function and body mass, concurrent disease states and medications in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

Derm: rash, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

Endo: Graves' disease

GI: ↑lipase, ↑liver enzymes, autoimmune hepatitis, diarrhea, HEPATOTOXICITY ( WITH HBV OR HEPATITIS C), ↑ with HBV or hepatitis C), hyperbilirubinemia, nausea

GU: ↑serum creatinine, ACUTE RENAL FAILURE/FANCONI SYNDROME

MS: ↓bone mineral density, ↑CK, arthralgia, muscle weakness, myalgia, osteomalacia, polymyositis

Neuro: abnormal dreams, dizziness, Guillan-Barré syndrome, insomnia, sedation

Misc: immune reconstitution syndrome

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A inducers, including carbamazepine, enzalutamide, mitotane, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine, may significantly ↓ levels and effectiveness of doravirine; concurrent use contraindicated; should discontinue these medications for ≥4 wk before initiating doravirine/lamivudine/tenofovir disoproxil fumarate therapy.
Rifabutin may ↓ levels and effectiveness of doravirine; take one doravirine 100-mg tablet 12 hr after doravirine/lamivudine/tenofovir disoproxil fumarate dose.
Nephrotoxic drugs, including acyclovir, aminoglycosides, cidofovir, ganciclovir, NSAIDs, valacyclovir, or valganciclovir, may ↑ risk of nephrotoxicity; avoid recent or concurrent use.
Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir may ↑ tenofovir levels and risk of toxicity; closely monitor.
Medications containing sorbitol may ↓ lamivudine levels and effectiveness; avoid concurrent use.

Drug-Natural Products:

St. John's wort may significantly ↓ levels and effectiveness of doravirine; concurrent use contraindicated; should discontinue this medication for ≥4 wk before initiating doravirine therapy.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥35 kg): One tablet (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) once daily.

Availability ⬆ ⬇

Tablets: doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg

Assessment ⬆ ⬇

Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Assess bone mineral density in patients with HIV who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Consider supplementation with calcium and vitamin D.
Monitor for severe skin reactions including signs of SJS and TEN. If a painful rash with mucosal involvement or a progress rash occurs, discontinue therapy immediately and monitor closely.

Lab Test Considerations:

Monitor viral load and CD4 cell count regularly during therapy.
- Assess for HBV. Not approved for administration in patients with HIV and HBV. If therapy is discontinued, may cause severe exacerbation of hepatitis B. Monitor liver function in coinfected patients for several months after stopping therapy.
- Monitor liver function periodically. May ↑ levels of AST, ALT, and alkaline phosphatase, which usually resolve after interruption of therapy. Patients with concurrent hepatitis B or C should be followed for at least several months after stopping therapy. Lactic acidosis may occur with hepatic toxicity, causing hepatic steatosis; may be fatal, especially in women.
- May ↑ LDL cholesterol, total cholesterol, and triglyceride concentrations.
- Assess serum creatinine, CCr, urine glucose, and urine protein before starting and periodically during therapy. Assess serum phosphorous in patients with chronic kidney disease, especially if taking nephrotoxic agents including NSAIDs.

Implementation ⬆ ⬇

Do not confuse lamivudine with lamotrigine. Do not confuse tenofovir disoproxil fumarate with tenofovir alafenamide.
Administer once daily without regard to meals.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy. Instruct patient on the importance of taking medication as directed, even if feeling better. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Caution patient not to share or trade medication with others.
Advise patient that discontinuing therapy may lead to severe exacerbations of HBV.
Inform patient of importance of HBV testing before starting antiretroviral therapy.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.
Inform patient that medication does not cure HIV and may ↓ risk of transmission of HIV to others. Caution patient to use condoms and avoid sharing needles or donating blood.
Advise patient to notify health care provider if bone pain that does not go away or worsens, pain in extremities, broken bones, or muscle pain or weakness occurs.
Advise patient to notify health care provider if signs and symptoms of immune reconstitution syndrome (inflammation from prior infection, symptoms of infection) occur.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort.
Rep: Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Encourage pregnant patients to enroll in the Antiretroviral Pregnancy Registry: 1-800-258-4263.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆