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Stribild ™ - Elvitegravir/cobicistat/emtricitabine/tenofovir

Stribild ™ - Elvitegravir/cobicistat/emtricitabine/tenofovir. Manufacturer: Gilead Sciences FDA Approval Date: August 2012. Stribild ™ - Elvitegravir/cobicistat/emtricitabine/tenofovir Clinical Application. Indications:

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Stribild ™ - Elvitegravir/cobicistat/emtricitabine/tenofovir

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  1. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovir Manufacturer: Gilead Sciences FDA Approval Date: August 2012

  2. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirClinical Application • Indications: • Complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve • Place in therapy: • First line therapy - option

  3. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirClinical Application • Contraindications: • Coadministration with drugs highly dependent on CYP3A for clearance & for which elevated concentrations may lead to serious or life threatening events (e.g. alfuzosin, rifampin, ergotamines, cisapride, St. John’s wort, lovastatin, simvastatin, pimozie, sildenafil (Revatio), triazolam, PO midazolam)

  4. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirClinical Application • Black Box warnings • Lactic acidosis/severe hepatomegaly • Reports, including fatalities, have been reported for the use of nuceloside analogs in combination with other antiretrovirals • Hepatitis B coinfection • Safety and efficacy not studied. Reports of severe, acute exacerbations of hepatitis B have been reported in coinfected patients who discontinued emtricitabine or tenofovir. Monitor renal function for several months in coinfected patients who discontinue this drug. Consider initiating anti-hepatitis B treatment.

  5. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirClinical Application • Warnings and Precautions • New onset or worsening renal impairment • Use with other antiretroviral products – Stribild™ is a complete regimen • Decreases in bone mineral density • Fat redistribution • Immune reconstitution syndrome

  6. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirClinical Application • Pregnancy: • Category B • Lactation: • CDC recommends for HIV infected mothers not to breastfeed their infants to avoid postnatal transmission of HIV

  7. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirDrug Facts • Pharmacology • Emtricitabine – nucleoside reverse transcriptase inhibitor • nucleoside analog of cytidine; once phosphorylated to emtricitabine-5’TP, it competes with the natural substrate and inhibits the activity of HIV-1 reverse transcriptase resulting in chain termination • Tenofovir disoproxil fumarate - nucleoside analog HIV-1 reverse transcriptase • acyclic nucleoside analog of AMP; after hydrolysis and phosphorylation to form tenofovir diphosphate, it can now inhibit the HIV-1 reverse transcriptase by competing with the natural substrate to be incorporated into the DNA

  8. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirDrug Facts • Pharmacology • Elvitegravir - an integrase strand transfer inhibitor • works on HIV-1 integrase to inhibit its strand transferring activity and as a result, preventing the HIV-1 DNA from integrating into the host DNA • Cobicistat - selective inhibitor of CYP450 3A family • works to increase the systemic exposure of CYP3A substrate, elvitegravir

  9. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirDrug Facts • Pharmacokinetics • A – light meal (20% fat)  elvitegravir (34%) & tenofovir (24%); high fat meal (50% fat)  elvitegravir (87%) & tenofovir (23%) • D – protein binding: elvitegravir 98-99%; cobicistat 97-98%; emtricitabine <4%; tenofovir <0.7% • M – elvitegravir (CYP3A, glucoronidation); cobicistat (CYP3A, CYP2D6); emtricitabine and tenofovir not significantly metabolized • E – elvitegravir t1/2 9h (urine, feces); cobicistat t1/2 3.5 h (urine, feces); emtricitabine & tenefovir (urine)

  10. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirDrug Interactions • Drug Interactions – Object Drugs • Antiarrhythmics, digoxin (serum concentration) • Clarithromycin, telithromycin (serum concentration) • Clonazepam, ethosuximide (serum concentration) • SSRIs, TCAs, trazodone (serum concentration) • Ketoconazole, itraconazole, voriconazole (serum concentration) • Colchicine  (do not coadminister in pts with renal/hepatic impairment) • Beta blockers, calcium channel blockers (serum concentration) • Salmeterol, fluticasone (serum concentration) • Bosentan (serum concentration) • Atorvastatin (serum concentration) • Norgestimate ; ethinyl estradiol  (use alternative contraceptive) • Cyclosporine, sirolimus, tacrolimus (serum concentration) • Perphenazine, risperidone, thioridazine (serum concentration) • PDE5 inhibitors (hypotension, syncope, visual disturbances, priapism) • BZDs (serum concentration)

  11. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirDrug Interactions • Drug Interactions – Precipitant Drugs • Antacids elvitegravir (separate by at least 2h) • Clarithromycin, telithromycin cobicistat • Carbamazepine, oxcarbazepine, phenobarbital, phenytoin  cobicistat, elvitegravir (use alternative anticonvulsant) • Rifabutin, rifapentine elvitegravir, cobicistat (avoid coadministration) • Dexamethasone  elvitegravir, cobicistat

  12. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirAdverse Effects

  13. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirAdverse Effects

  14. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirMonitoring Parameters • Efficacy Monitoring • HIV RNA, CD4 count • Toxicity Monitoring • Renal function • Liver function tests • HBV coinfection

  15. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirPrescription Information • Dosing – Initial and Maintenance • 1 tablet PO daily with food • Dosing – Max • Unknown • Cost – accessed 01/02/2013 • $2451 (www.goodrx.com)

  16. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks Sax PE, et al. Lancet. 2012;379:2439-2448.

  17. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Sax PE, et al. Lancet. 2012;379:2439-2448.

  18. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: • Inclusion Criteria: • Infected with HIV-1 • >18 years old • HIV-1 RNA > 5000 copies/mL • No previous use of antiretroviral drugs • GFR >70 mL/min • Susceptible to efavirenz, emtricitabine, tenofovir • AST/ALT<5x ULN, Tbili <25.65 umol/L, ANC>1000 cells/uL, plts>50,000/uL; Hgb>85 g/L; negative pregnancy test Sax PE, et al. Lancet. 2012;379:2439-2448.

  19. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: • Exclusion Criteria: • Patients with new AIDS-defining disorders or serious infections within 30 days of screening were excluded Sax PE, et al. Lancet. 2012;379:2439-2448.

  20. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: • Intervention (1:1) • Elvitegravir 150 mg/cobicistat 150 mg/ emtricitabine 200 mg/tenofovir 300 mg once daily with food • Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QHS on empty stomach Sax PE, et al. Lancet. 2012;379:2439-2448.

  21. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: • Primary endpoint: • Proportion of patients in the intention-to-treat population with viral suppression (HIV RNA <50 copies/mL) at week 48 Sax PE, et al. Lancet. 2012;379:2439-2448.

  22. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: • Other endpoints: • Treatment differences by subgroup • Achievement and maintenance of HIV RNA <50 copies/mL • Proportion of patients with HIV RNA <50 copies/mL when classing missing as failure and missing as excluded • Change in HIV RNA concentration and CD4 count from baseline Sax PE, et al. Lancet. 2012;379:2439-2448.

  23. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Results • Primary endpoint: • EVG/COBI/FTC/TDF 87.6% versus EFV/FTC/TDF 84.1% • Difference 3.6%, 95% CI (-1.6 to 8.8%) • Non-inferior Sax PE, et al. Lancet. 2012;379:2439-2448.

  24. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Results Sax PE, et al. Lancet. 2012;379:2439-2448.

  25. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Results Sax PE, et al. Lancet. 2012;379:2439-2448.

  26. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Results Sax PE, et al. Lancet. 2012;379:2439-2448.

  27. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: AE Sax PE, et al. Lancet. 2012;379:2439-2448.

  28. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: AE Sax PE, et al. Lancet. 2012;379:2439-2448.

  29. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirLiterature Review: Conclusion • EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF (standard of care) for HIV-1 infection in treatment naïve patients. • Nausea and increased serum creatinine were more common in EVG/COBI/FTC/TDF group, but dizziness, abnormal dreams, insomnia, and rash were less common when compared to EFV/FTC/TDF. • EVG/COBI/FTC/TDF is the first single-tablet, once-daily, integrase-inhibitor based regimen for HIV infection in treatment naïve patients. Sax PE, et al. Lancet. 2012;379:2439-2448.

  30. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirSummary • Stribild™ is a complete, fixed-combination, once daily, integrase-inhibitor based regimen for HIV-1 infected patients who are naïve to treatment. • Stribild™ is composed of 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 300 mg tenofovir. • Precautions include declining renal function or bone mineral density, fat redistribution, immune reconstitution syndrome, HBV coinfections, and lactic acidosis/severe hepatomegaly. • Elvitegravir and cobicistat, the novel components of Stribild™, work as an integrase inhibitor and as a pharmacokinetic enhancer, respectively.

  31. Stribild™ - Elvitegravir/cobicistat/emtricitabine/tenofovirReferences • http://www.Stribild.com • Stribild package insert. Foster City, CA. Gilead Sciences. January 2013. • Sax PE, et al. Co-formulated elvitegarivr, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379:2439-48.

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