Elvitegravir, Cobicistat, Emtricitabine, and tenofovir Disoproxil Fumarate

Absorption

Bioavailability

Following an oral dose of EVG/c/FTC/TDF with food, peak plasma concentrations of elvitegravir and cobicistat occur at 4 and 3 hours, respectively, and peak plasma concentrations of emtricitabine and tenofovir occur at 3 and 2 hours, respectively.1

Cobicistat component of EVG/c/FTC/TDF increases plasma concentrations of elvitegravir;1 8 200 cobicistat does not have clinically important effect on pharmacokinetics of emtricitabine or tenofovir DF.8

Food

Relative to fasting, administration of EVG/c/FTC/TDF with high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of elvitegravir and tenofovir by 87 and 23%, respectively, and decreases mean systemic exposures of cobicistat and emtricitabine by 17 and 4%, respectively.1 9

Distribution

Extent

Elvitegravir and cobicistat: Distributed into milk in rats;1 not known whether distributed into human milk.1

Emtricitabine and tenofovir: Distributed into human milk.1

Plasma Protein Binding

Elvitegravir: Approximately 99%.1

Cobicistat: Approximately 98%.1

Emtricitabine: <4%.1

Tenofovir: <0.7%.1

Elimination

Metabolism

Elvitegravir: Metabolized principally by CYP3A to produce inactive M1 metabolite, also undergoes glucuronidation via UGT1A1/3 to produce inactive M4 metabolite.1 9 Cobicistat, a CYP3A inhibitor, is included in fixed combination of EVG/c/FTC/TDF to inhibit metabolism of and increase plasma concentrations of elvitegravir.1 8 200

Cobicistat: Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6.1 Does not undergo glucuronidation.1

Emtricitabine: Undergoes oxidation and conjugation with glucuronic acid.1 Phosphorylated intracellularly and converted by cellular enzymes to the active emtricitabine 5′-triphosphate.1

Tenofovir DF: Prodrug of tenofovir;1 undergoes initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate.1

Elimination Route

Elvitegravir: 94.8% in feces, 6.7% in urine.1 Unlikely to be removed by hemodialysis or peritoneal dialysis.1

Cobicistat: 86.2% in feces, 8.2% in urine.1 Unlikely to be removed by hemodialysis or peritoneal dialysis.1

Emtricitabine: 70% in urine (glomerular filtration and active tubular secretion), 13.7% in feces.1 Removed by hemodialysis;1 not known whether removed by peritoneal dialysis.1

Tenofovir: 70–80% in urine (glomerular filtration and active tubular secretion).1 Removed by hemodialysis.1

Half-life

Elvitegravir: 12.9 hours.1

Cobicistat: 3.5 hours.1

Emtricitabine: 10 hours.1

Tenofovir: 12–18 hours.1

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): No clinically important effect on pharmacokinetics of elvitegravir or cobicistat.1 Pharmacokinetics of emtricitabine and tenofovir unlikely to be affected.1

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics of EVG/c/FTC/TDF not studied.1

Renal impairment: No clinically important effects on pharmacokinetics of elvitegravir or cobicistat.1 Pharmacokinetics of emtricitabine and tenofovir altered (decreased clearance resulting in increased plasma concentrations and AUC).1 218 221

Storage

Oral

25°C (may be exposed to 15–30°C).1

Store in original container; keep tightly closed.1

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

• Antiretroviral therapy is not a cure for HIV infection;1 opportunistic infections and other complications associated with HIV disease may still occur.1

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.1

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

• Importance of reading patient information provided by the manufacturer.1

• Advise patients that the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF) is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1

• Importance of taking EVG/c/FTC/TDF with food.1

• If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1

• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred with emtricitabine and tenofovir DF (components of EVG/c/FTC/TDF).1 Importance of contacting clinician if symptoms suggestive of lactic acidosis or hepatotoxicity (e.g., nausea, vomiting, unusual/unexpected stomach discomfort, weakness) occur.1

• Inform patients that testing for HBV infection recommended before antiretroviral therapy initiated.1 Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV.1

• Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred.1 Importance of not using EVG/c/FTC/TDF concomitantly with or shortly after nephrotoxic agents (e.g., high-dose or multiple NSAIAs).1

• Advise patients that decreased bone mineral density (BMD) has occurred and that assessment of BMD should be considered in those with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1

• Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy;1 cause and long-term health effects unknown.1

• Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with advanced HIV infection (AIDS).1 These symptoms may be due to an improvement in immune response, enabling the body to fight infections that may have been present with no obvious symptoms.1 Importance of immediately informing a healthcare provider if any symptoms of infection occur.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John's wort), as well as any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

• Importance of advising patients of other important precautionary information.1 (See Cautions.)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of too much lactic acid in the blood (lactic acidosis) like fast breathing, fast heartbeat, a heartbeat that does not feel normal, very bad upset stomach or throwing up, feeling very sleepy, shortness of breath, feeling very tired or weak, very bad dizziness, feeling cold, or muscle pain or cramps.
• Bone pain.
• Muscle pain or weakness.
• Pain in arms or legs.
• This medicine may help the immune system work. If you have an infection that you did not know you had, it may show up when you take elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. Tell your doctor right away if you notice any signs of infection like fever, sore throat, weakness, cough, or shortness of breath after you start this medicine.

Coadministration with alfuzosin, carbamazepine, cisapride, ergot derivatives (eg, dihydroergotamine, ergotamine, methylergonovine), lovastatin, lurasidone, midazolam (oral), phenobarbital, phenytoin, pimozide, rifampin, sildenafil (for the treatment of pulmonary arterial hypertension), simvastatin, St John's wort, or triazolam

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to any component of the formulation; coadministration with ergonovine, salmeterol, astemizole, or terfenadine

Note: Prior to initiation, patients should be tested for hepatitis B infection, and baseline serum creatinine, estimated creatinine clearance, serum phosphorous, urine glucose, and urine protein should be assessed in all patients.

HIV-1: Oral: One tablet once daily. Note: This combination is a recommended initial regimen for antiretroviral-naive patients with CrCl >70 mL/minute (HHS [adult] 2016).

Adults:

CrCl ≥70 mL/minute: No dosage adjustment necessary.

CrCl <70 mL/minute at initiation of therapy: Initial use is not recommended.

CrCl <50 mL/minute during therapy: Continued use is not recommended.

Children and Adolescents ≥12 years and weighing ≥35 kg: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Administer with food.

In general, women who become pregnant on a stable combination antiretroviral therapy (cART) regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. The Health and Human Services (HHS) Perinatal HIV Guidelines note there are insufficient data to recommend use of this combination product as an initial regimen in antiretroviral-naive pregnant women (HHS [perinatal] 2016). Refer to individual monographs.