Dosing and uses of Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir DF)
Adult dosage forms and strengths
elvitegravir/cobicistat/emtricitabine/tenofovir DF (ie, tenofovir disoproxil fumarate)
tablet
- 150mg/150mg/200mg/300mg
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir DF) adverse (side) 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
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)
Should not be coadministered with antiretroviral agents containing any of the same active components; with products containing lamivudine; with adefovir dipivoxil; or with products containing ritonavir
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
Pregnancy and 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.
Pharmacology of Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir DF)
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