doravirine/lamivudine/tenofovir DF (Rx)

Brand and Other Names:Delstrigo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

doravirine/lamivudine/tenofovir DF

tablet

  • 100mg/300mg/300mg

HIV Infection

Indicated as a complete regimen for treatment of HIV-1 infection in adults without prior antiretroviral therapy (ART) treatment history

1 tablet PO qDay with or without food

Dosage Modifications

Renal impairment

  • Estimated CrCl <50 mL/min: Use not recommended (unable to adjust fixed-dose combination)

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Not studied

Coadministration with rifabutin

  • If coadministered with rifabutin, 1 tablet (ie, 100 mg) of doravirine (Pifeltro) should be taken ~12 hr after Delstrigo dose

Dosing Considerations

Monitoring

  • Obtain baseline test for hepatitis B virus (HBV) infection (see Black Box Warnings)
  • Patients with chronic kidney disease: Obtain baseline serum phosphorus and periodically assess during treatment
  • Obtain the following tests at baseline and periodically assess during treatment for all patients
    • Serum creatinine
    • Estimated CrCl
    • Urine glucose
    • Urine protein

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and doravirine/lamivudine/tenofovir DF

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            Adverse Effects

            >10%

            Sleep disorders and disturbances (12%)

            1-10%

            Dizziness (9%)

            Nausea (7%)

            Headache (6%)

            Fatigue (6%)

            Diarrhea (5%)

            Abdominal pain (5%)

            Total bilirubin 1.1 to <1.6x ULN (5%)

            Altered sensorium (4%)

            AST 2.5 to <5x ULN (4%)

            Lipase 1.5 to <3x ULN (4%)

            Creatinine >1.3 to 1.8x ULN (3%)

            ALT 2.5 to <5x ULN (3%)

            Lipase ≥3x ULN (3%)

            Creatine kinase ≥10x ULN (3%)

            Rash (2%)

            Total bilirubin 1.6 to <2.6x ULN (2%)

            Creatinine >1.8x ULN (2%)

            Creatine kinase 6 to <10x ULN (2%)

            Abnormal dreams (1%)

            Insomnia (1%)

            ALT ≥5x ULN (1%)

            <1%

            AST ≥5x ULN

            Alkaline phosphatase 2.5 to <5x ULN

            LDL cholesterol, fasted ≥190 mg/dL

            Triglycerides, fasted >500 mg/dL

            Postmarketing Reports

            Lamivudine

            • Body as a whole: Redistribution/accumulation of body fat
            • Endocrine and metabolic: Hyperglycemia
            • General: Weakness
            • Hemic and lymphatic: Anemia (eg, pure red cell aplasia and severe anemias progressing on therapy)
            • Hepatic and pancreatic: Lactic acidosis and hepatic steatosis, posttreatment exacerbations of hepatitis B
            • Hypersensitivity: Anaphylaxis, urticaria
            • Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis
            • Skin: Alopecia, pruritus

            Tenofovir DF

            • Immune system disorders: Allergic reaction, including angioedema
            • Metabolism and nutrition disorders: Lactic acidosis, hypokalemia, hypophosphatemia
            • Respiratory, thoracic, and mediastinal disorders: Dyspnea
            • Gastrointestinal disorders: Pancreatitis, increased amylase, abdominal pain
            • Hepatobiliary disorders: Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
            • Skin and SC tissue disorders: Rash
            • Musculoskeletal and connective tissue disorders: Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
            • Renal and urinary disorders: Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
            • General disorders and administration site conditions: Asthenia
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            Warnings

            Black Box Warnings

            Test all patients for HBV before initiating ARTs

            Severe acute hepatitis B exacerbations reported in patients coinfected with HIV-1 and HBV who have discontinued lamivudine or tenofovir DF

            Monitor both clinical and laboratory values for several months after discontinuing Delstrigo in patients who are coinfected with HIV-1 and HBV

            If appropriate, initiate antihepatitis B therapy

            Contraindications

            Hypersensitivity to lamivudine

            Strong CYP3A inducers

            • Doravirine is contraindicated with strong CYP3A inducers, which may decrease effectiveness
            • Strong CYP3A inducer examples
              • Anticonvulsants (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
              • Antimycobacterials (eg, rifampin, rifapentine)
              • Enzalutamide
              • Mitotane
              • St. John’s wort (Hypericum perforatum)

            Cautions

            Severe acute exacerbations of hepatitis B (eg, liver decompensated, liver failure) reported in patients coinfected with HIV-1 and HBV and who have discontinued products containing lamivudine and/or tenofovir DF

            Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), reported with tenofovir DF; avoid with concurrent or recent use of nephrotoxic agents (eg, high-dose or multiple NSAIDs)

            Discontinue if CrCl declines below 50 mL/min

            Tenofovir DF associated with decreased bone mineral density (BMD) and increased biochemical markers of bone metabolism; consider assessing BMD in patients at risk

            Immune reconstitution syndrome reported with combination ART

            Autoimmune disorders (eg, Grave disease, polymyositis, Guillain-Barré syndrome) reported to occur in the setting of immune reconstitution; however, time to onset varies and can occur many months after initiation of treatment

            Drug interaction overview

            • Coadministration of doravirine with strong CYP3A inducers may decrease systemic exposure and lead to loss of therapeutic effect and possible HIV resistance
            • Since Delstrigo is a complete regimen for HIV-1 infection, coadministration with other antiretroviral medications for HIV-1 infection not recommended; information regarding potential drug-drug interactions with other antiretroviral medications is not provided
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            Pregnancy

            Pregnancy

            Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263; pregnancy exposure registry monitors pregnancy outcomes in individuals exposed during pregnancy

            Data are not available to establish drug-associated risks to pregnancy outcomes

            Doravirine has not been evaluated in pregnancy; however, lamivudine and tenofovir DF use during pregnancy has been evaluated in a limited number of individuals reported to the APR; available data from the APR show no difference in the overall risk of major birth defects for lamivudine and TDF compared with the background rate for major birth defects of 2.7% in the US reference population

            Lactation

            The Centers for Disease Control and Prevention do not recommend HIV-infected women breastfeed their infants, owing to potential risk for postnatal transmission of HIV

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Doravirine: Non-nucleoside reverse transcriptase inhibitor (NNRTI); inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase

            Lamivudine: Nucleoside reverse transcriptase inhibitor (NRTI); following phosphorylation to active metabolite, inhibits HIV reverse transcriptase via DNA chain termination after incorporation

            Tenofovir DF: NRTI; following hydrolysis and subsequent phosphorylation, inhibits HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5′-triphosphate (ATP) and, after incorporation into DNA, by DNA chain termination

            Absorption

            Bioavailability

            • Doravirine: 64%
            • Lamivudine: 86%
            • Tenofovir AF: 25%

            Peak plasma time

            • Doravirine: 2 hr
            • Tenofovir AF: 1 hr

            Peak plasma concentration

            • Doravirine: 0.962 mcg/mL
            • Lamivudine: 2.04 mcg/mL
            • Tenofovir AF: 0.3 mcg/mL

            AUC

            • Doravirine: 16.1 mcg·h/mL
            • Lamivudine: 8.87 mcg·h/mL
            • Tenofovir AF: 2.29 mcg·h/mL

            Distribution

            Protein bound

            • Doravirine: 76%
            • Lamivudine: <36%
            • Tenofovir AF: <0.7%

            Vd

            • Doravirine: 60.5 L
            • Lamivudine: 1.3 L/kg
            • Tenofovir AF: 1.3 L/kg

            Metabolism

            Doravirine: CYP3A (primary)

            Lamivudine: CYP3A (minor)

            Tenofovir AF: No CYP metabolism

            Elimination

            Half-life

            • Doravirine: 15 hr
            • Lamivudine: 5-7 hr
            • Tenofovir AF: 17 hr

            Renal clearance

            • Doravirine: 9.3 mL/min
            • Lamivudine: 199.7 mL/min
            • Tenofovir AF: 243.5 mL/min

            Total clearance

            • Doravirine: 106 mL/min
            • Lamivudine: 398.5 mL/min
            • Tenofovir AF: 1043.7 mL/min

            Excretion

            • Major elimination route
              • Doravirine: Metabolism
              • Lamivudine and tenofovir AF: Glomerular filtration and active tubular secretion
            • Urine (unchanged)
              • Doravirine: 6%
              • Lamivudine: 71%
              • Tenofovir AF: 70-80%
            • Biliary/fecal (unchanged)
              • Doravirine: Minor
              • Lamivudine and tenofovir AF: Not applicable
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            Administration

            Oral Administration

            Complete regimen for HIV in adults without prior ART treatment history; do not prescribe with other ARTs

            Instruct patient to take at a regularly scheduled time of the day

            May take with or without food

            Missed dose

            • If patient forgets dose, instruct them to take the missed dose right away, unless it is almost time for the next dose
            • If time nearer to next dose, advise not to take 2 doses at once and to take the next dose at the regularly scheduled time

            Storage

            Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Store in original bottle

            Keep bottle tightly closed to protect from moisture; do not remove desiccants

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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