elvitegravir/cobicistat/emtricitabine/tenofovir DF (Rx)

Brand and Other Names:Stribild
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

elvitegravir/cobicistat/emtricitabine/tenofovir DF (ie, tenofovir disoproxil fumarate)

tablet

  • 150mg/150mg/200mg/300mg
more...

HIV Infection

Combination integrase inhibitor, CYP3A4 inhibitor (boosted therapy), and 2 NRTIs as a complete regimen for treatment of HIV infection in treatment-naive adults

Also indicated as replacement of the current antiretroviral regimen in patients who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Stribild

1 tablet PO qDay with food

Dosage Modifications

Renal impairment

  • CrCl <70 mL/min: Do not initiate
  • CrCL that has declined below 50 mL/min: Discontinue

Hepatic impairment

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

Dosing Considerations

Patients must have a CrCl ≥70 mL/min to initiate Stribild

Testing prior to initiating therapy

  • Patients should be tested for hepatitis B virus infection
  • It is recommended that serum creatinine, serum phosphorous, eCrCl, urine glucose, and urine protein should be assessed before initiating and during therapy in all patients as clinically appropriate

Dosage Forms & Strengths

elvitegravir/cobicistat/emtricitabine/tenofovir DF (ie, tenofovir disoproxil fumarate)

tablet

  • 150mg/150mg/200mg/300mg
more...

HIV Infection

Combination integrase inhibitor, CYP3A4 inhibitor (boosted therapy), and 2 NRTIs as a complete regimen for treatment of HIV infection in treatment-naive pediatric patients aged ≥12 yr

Also indicated as replacement of the current antiretroviral regimen in patients who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Stribild

<12 years: Safety and efficacy not established

≥12 years who weigh at least 35 kg: 1 tablet PO qDay with food

Dosage Modifications

Renal impairment: No data are available to make dose recommendations for pediatric patients with renal impairment

Hepatic impairment

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

Dosing Considerations

Patients must have a CrCl ≥70 mL/min to initiate Stribild

Testing prior to initiating therapy

  • Patients should be tested for hepatitis B virus infection
  • It is recommended that serum creatinine, serum phosphorous, eCrCl, urine glucose, and urine protein should be assessed before initiating and during therapy in all patients as clinically appropriate
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Interactions

Interaction Checker

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            Adverse Effects

            >10%

            Proteinuria (39%)

            Nausea (16%)

            Diarrhea (12%)

            1-10%

            Abnormal dreams (9%)

            Headache (7%)

            Serum creatinine increased (7%)

            Fatigue (5%)

            Creatine kinase increased ≥10 x ULN (5%)

            Serum lipids increased (4%); ie, additional patients started on lipid lowering agents while on Stribild

            Rash (3%)

            Dizziness (3%)

            Insomnia (3%)

            Hematuria (3%) Flatulence (2%)

            AST increased >5 x ULN (2%)

            Amylase increased >2 x ULN (2%)

            Somnolence (1%)

            Emtricitabine & tenofovir

            • In addition to the adverse drug reactions observed with Stribild, the following adverse drug reactions occurred in at least 5% of patients receiving emtricitabine or tenofovir with other ARTs:
            • Depression, anxiety
            • Abdominal pain, dyspepsia, vomiting, fever
            • Nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, increased cough, rhinitis
            • Arthralgia, pain, back pain, myalgia
            • Paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy
            • Skin discoloration: Higher frequency among emtricitabine-treated patients including hyperpigmentation on the palms and/or soles

            <1%

            Ocular icterus

            Postmarketing Reports

            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 subcutaneous 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

            Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Stribild, in combination with other antiretrovirals

            Not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy have not been established in patients coinfected with HBV and HIV-1; severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir, which are components of Stribild

            Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Stribild; if appropriate, initiation of anti-hepatitis B therapy may be warranted

            Contraindications

            Hypersensitivity

            Drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; cobicistat is a CYP3A4 inhibitor and will increase serum levels of CYP3A4 substrates

            Strong CYP3A inducers (may lead to a loss of virologic response and possible resistance)

            Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, lurasidone, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, carbamazepine, phenobarbital, phenytoin, and St. John’s wort

            Cautions

            Lactic acidosis and severehepatomegaly with steatosis reported (see Black Box Warnings)

            Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy (ART); not approved for the treatment of chronic HBV infection (see Black Box Warnings)

            Concomitant use with other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effects and possible development of resistance

            Decreases in bone mineral density (BMD) and cases of osteomalacia reported with tenofovir; consider monitoring BMD with a history of pathologic fracture or risk factors for bone loss exist

            Fat redistribution and accumulation observed with antiretroviral therapy

            Immune reconstitution syndrome reported, including the occurrence of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barre syndrome) with variable time to onset

            New onset or worsening renal impairment

            • Estimate CrCl in all patients before initiating and avoid concurrent or recent use of nephrotoxic drugs
            • Cases of acute renal failure and Fanconi syndrome reported with the use of tenofovir and Stribild; monitor estimated CrCl, urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment
            • Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety
            • Do not initiate with CrCl <70 mL/min
            • Discontinue if CrCl declines below 50 mL/min

            Bone effects of tenofovir

            • Bone mineral density may decrease
            • Osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported
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            Pregnancy & Lactation

            Pregnancy Category: B; an ART pregnancy registry has been established

            Lactation: Emtricitabine and tenofovir have been detected in human milk; because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed

            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

            Elvitegravir: Integrase inhibitor; inhibits catalytic activity (ie, strand transfer) of HIV-1 integrase, an HIV encoded enzyme required for viral replication; CYP3A4 substrate

            Cobicistat: CYP3A4 inhibitor; mechanism-based pharmaco-enhancer, 1st product to be developed and submitted solely as pharmacokinetic booster for elvitegravir; enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism

            Emtricitabine: Synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate (active); inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination

            Tenofovir: An acyclic nucleoside phosphonate diester analog of adenosine monophosphate; tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate; tenofovir diphosphate inhibits HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination

            Absorption

            Food increases mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively

            A high fat meal (~800 kcal, 50% fat) increases mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively

            Elvitegravir

            • Peak Plasma Time: 4 hr
            • Peak Plasma Concentration: 1.7 mcg/mL
            • Trough Plasma Concentration: 0.45 mcg/mL
            • AUC: 23 mcg•hr/mL

            Cobicistat

            • Peak Plasma Time: 3 hr
            • Peak Plasma Concentration: 1.1 mcg/mL
            • Trough Plasma Concentration: 0.05 mcg/mL
            • AUC: 8.3 mcg•hr/mL

            Emtricitabine

            • Peak Plasma Time: 3 hr
            • Peak Plasma Concentration: 1.9 mcg/mL
            • Trough Plasma Concentration: 0.14 mcg/mL
            • AUC: 12.7 mcg•hr/mL

            Tenofovir

            • Peak Plasma Time: 1 hr (fasting); 2 hr (with food)
            • Peak Plasma Concentration: 0.45 mcg/mL
            • Trough Plasma Concentration: 0.1 mcg/mL
            • AUC: 4.4 mcg•hr/mL

            Distribution

            Elvitegravir

            • Protein Bound: 98-99%

            Cobicistat

            • Protein Bound: 97-98%

            Emtricitabine

            • Protein Bound: <4%

            Tenofovir

            • Protein Bound: <0.7
            • Vd: 1.2-1.3 L/kg

            Metabolism

            Elvitegravir

            • Metabolized by CY3A4
            • Also undergoes glucuronidation via UGT1A1/3 enzymes

            Cobicistat

            • Metabolized by CYP3A4 and CYP2D6 (minor)
            • CYP3A4 inhibitor

            Emtricitabine

            • Not significantly metabolized
            • Metabolized by oxidation

            Tenofovir

            • Not significantly metabolized
            • Converted intracellularly by hydrolysis to tenofovir, then phosphorylated to active tenofovir diphosphate

            Elimination

            Elvitegravir

            • Half-life: 12.9 hr
            • Excretion: 94.8% feces; 6.7% urine

            Cobicistat

            • Half-life: 3.5 hr
            • Excretion: 86.2% feces; 8.2% urine

            Emtricitabine

            • Half-life: 10 hr
            • Dialyzable: 30% removed by hemodialysis
            • Excretion: 86% urine; 14% feces

            Tenofovir

            • Excretion: 70-80% in urine via filtration and active secretion, primarily as unchanged tenofovir
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            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.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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