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;
Concurrent or recent use of nephrotoxic medications;
CCr <50 mL/min;
Lactation: Breastfeeding not recommended in women with HIV.

Use Cautiously in:

Coinfection with hepatitis B virus (HBV) (hepatitis may recur after discontinuation of lamivudine and ↑ risk of lamivudine-resistant HBV);
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

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, ↑creatine kinase, 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; 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.

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 mo after stopping therapy.
- Monitor liver function tests before and periodically during therapy, especially in patients with underlying liver disease or marked ↑ transaminases. May cause ↑ serum creatinine, AST, ALT, total bilirubin, total cholesterol, LDL, and triglycerides. May cause lactic acidosis and severe hepatomegaly with steatosis. These events are more likely to occur if patients are female, obese, or receiving nucleoside analogue medications for extended periods of time. Monitor patient for signs (increased serum lactate levels, elevated liver enzymes, liver enlargement on palpation). Therapy should be suspended if clinical or laboratory signs occur.
- Assess serum creatinine, CCr, urine glucose, and urine protein before starting and periodically during therapy. Also assess serum phosphorous in patients with chronic kidney disease. Patients taking nephrotoxic agents, including NSAIDs, are at increased risk for renal impairment.

Implementation ⬆ ⬇

Administer once daily without regard to meals.

Patient/Family Teaching ⬆ ⬇

Instruct patient on the importance of taking medication as directed, even if feeling better. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Discontinuing therapy may lead to severe exacerbations. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes. Caution patient not to share or trade Delstrigo™ with others.
Inform patient of importance of hepatitis B testing before starting antiretroviral therapy.
Inform patient that Delstrigo™ does not cure HIV and may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and avoid sharing needles or donating blood to prevent spreading HIV to others.
Advise patient to notify health care professional if bone pain (bone pain that does not go away or worsening bone pain; pain in arms, legs, hands or feet; broken bones, muscle pain or weakness). May be symptoms of a bone or kidney problem.
Advise patient to notify health care professional if signs and symptoms of immune reconstitution syndrome (signs and symptoms of an infection) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
Rep: Advise patient to notify health care professional if pregnancy is planned or suspected. Encourage pregnant women to enroll in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. Advise female patient that pregnancy is not recommended and to avoid breastfeeding during therapy.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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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 ⬆