Elvitegravir + Cobicistat + Emtricitabine + Tenofovir

Oral
HIV-1 infection

CrCl (mL/min)	Dosage
<30	As tenofovir alafenamide: Initial use is not recommended.
<50	As tenofovir disoproxil fumarate: Continued use is not recommended.
<70	As tenofovir disoproxil fumarate: Initial use is not recommended.

Severe (Child-Pugh Class C): Not recommended.

Hypersensitivity to any of the substances. Lactation. Co-administration with drugs that are highly dependent on CYP3A for clearance and strong CYP3A inducers.

Patient with hepatitis B or C infection. Severe hepatic impairment (Child-Pugh Class C). Do not initiate if CrCl is <30 mL/min (tenofovir alafenamide) or CrCl <70 mL/min (tenofovir disoproxil fumarate); discontinue if CrCl <50 mL/min (tenofovir disoproxil fumarate). Pregnancy.

Significant: Immune reconstitution inflammatory syndrome, acute renal injury and/or Fanconi syndrome, opportunistic infections, decreased BMD, osteomalacia; severe acute exacerbation of hepatitis B in patients coinfected with HIV-1 and HBV.
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, abdominal pain, flatulence.
General disorders and administration site conditions: Fatigue.
Investigations: LDL cholesterol increased, blood creatine phosphokinase increased, blood cholesterol increased, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, amylase increased.
Nervous system disorders: Dizziness, headache, abnormal dreams.
Renal and urinary disorders: Haematuria.
Skin and subcutaneous tissue disorders: Rash.
Potentially Fatal: Lactic acidosis and severe hepatomegaly with steatosis.

PO: B

This drug may cause dizziness, if affected, do not drive or operate machinery.

Perform test for hepatitis B infection prior to initiation of treatment. Monitor CBC with differential, reticulocyte count, creatine kinase, CD4 count, HIV RNA plasma levels, serum phosphorous, renal and hepatic functions, urine glucose, urine protein prior to initiation and periodically during therapy.

May increase plasma levels of ketoconazole, itraconazole, fluconazole, posaconazole. Loss of therapeutic effect and development of resistance when administered with rifabutin. May alter plasma levels of macrolide antibiotics (e.g. clarithromycin, telithromycin). May increase plasma levels of corticosteroids (e.g. betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone), oral contraceptives, antiarrhythmics, β-blockers, calcium channel blockers, metformin, salmeterol, colchicine, antidepressants (e.g. TCAs, SSRIs), immunosuppressants. Decreased plasma levels of elvitegravir when taken with Al- or Mg-containing antacids. Increased risk of nephrotoxicity with NSAIDs.
Potentially Fatal: Co-administration with drugs that are highly dependent on CYP3A for clearance (e.g. alfuzosin, cisapride, ergot derivatives, lovastatin, simvastatin, lurasidone, oral midazolam, sildenafil (for pulmonary arterial hypertension), triazolam) may result in serious adverse events. Significantly decreased plasma concentration, leading to loss of therapeutic effect when given with strong CYP3A inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin).

Food increases absorption of elvitegravir. Significantly reduced plasma concentration with St John’s wort, avoid use.

Description:
Mechanism of Action: Elvitegravir inhibits HIV-1 integrase activity, thereby preventing viral replication by stopping insertion of viral DNA into the host DNA.
Cobicistat inhibits CYP3A and acts as a pharmacokinetic enhancer when used concomitantly with elvitegravir.
Emtricitabine and tenofovir inhibit viral replication by interfering with the activity of HIV viral RNA dependent DNA polymerase.
Pharmacokinetics:
Absorption: Elvitegravir: Increased bioavailability with food. Time to peak plasma concentration: Elvitegravir: 4 hours; Cobicistat: 3 hours; Emtricitabine: 3 hours; Tenofovir: 1 hour (as alafenamide); 2 hours (as disoproxil fumarate).
Distribution: Plasma protein binding: Elvitegravir: Approx 99%; Cobicistat: Approx 98%; Emtricitabine: <4%; Tenofovir: Approx 80% (as alafenamide); <0.7% (as disoproxil fumarate).
Metabolism: Elvitegravir: Undergoes primary oxidative metabolism by CYP3A, and secondary glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1/3 enzymes.
Cobicistat: Undergoes primary oxidative metabolism by CYP3A, and to a minor extent by CYP2D6.
Tenofovir alafenamide: Metabolised to tenofovir (major metabolite) by cathepsin A in peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 in hepatocytes.
Excretion: Elvitegravir: Via faeces (94.8%), urine (6.7%). Elimination half-life: 12.9 hours.
Cobicistat: Via faeces (86.2%), urine (8.2%). Elimination half-life: 3.5 hours.
Emtricitabine: Via faeces (13.7%), urine (70%). Elimination half-life: 10 hours.
Tenofovir: As alafenamide: Via faeces (31.7%), urine (<1%). Elimination half-life: 0.51 hours. As disoproxil fumarate: Via urine (70-80%). Elimination half-life: 12-18 hours.

Source: National Center for Biotechnology Information. PubChem Database. Elvitegravir, CID=5277135, https://pubchem.ncbi.nlm.nih.gov/compound/Elvitegravir (accessed on Jan. 22, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Cobicistat, CID=25151504, https://pubchem.ncbi.nlm.nih.gov/compound/Cobicistat (accessed on Jan. 22, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Emtricitabine, CID=60877, https://pubchem.ncbi.nlm.nih.gov/compound/Emtricitabine (accessed on Jan. 22, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Tenofovir, CID=464205, https://pubchem.ncbi.nlm.nih.gov/compound/Tenofovir (accessed on Jan. 22, 2020)

Store below 30°C.

Antivirals

J05AR18 - emtricitabine, tenofovir alafenamide, elvitegravir and cobicistat ; Belongs to the class of antivirals for treatment of HIV infections, combinations.
J05AR09 - emtricitabine, tenofovir disoproxil, elvitegravir and cobicistat ; Belongs to the class of antivirals for treatment of HIV infections, combinations.

Anon. Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 13/03/2018.

Anon. Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 19/03/2018.

Genvoya Tablet (Gilead Sciences, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/03/2018.

Joint Formulary Committee. Elvitegravir with Cobicistat, Emtricitabine and Tenofovir Disoproxil. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 13/03/2018.

McEvoy GK, Snow EK, Miller J et al (eds). Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Fumarate. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 13/03/2018.

Stribild Tablet, Film Coated (Gilead Sciences, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/03/2018.