elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

General

Pronunciation:
el-vi-teg-ra-vir/koe-bik-i-stat/em-trye-sye-ta-been/ten-of-oh-vir al-a-fen-a-mide

Trade Name(s)

  • Genvoya

Ther. Class.
antiretrovirals

Pharm. Class.
integrase strand transfer inhibitors
enzyme inhibitors
nucleoside reverse transcriptase inhibitors

Indications

  • Management of HIV infection in treatment-naïve adults.
  • Management of HIV infection in patients with HIV-1 RNA <50 copies/mL (to replace their current antiretroviral regimen) who are on a stable antiretroviral regimen for ≥6 mo, have no history of treatment failure, and have no known substitutions associated with resistance to the individual medications in the combination product.

Action

  • Elvitegravir–An integrase strand transfer inhibitor that inhibits an enzyme necessary for viral replication.
  • Cobicistat–A pharmacokinetic enhancer (inhibits CYP3A and CYP2D6) that increases systemic exposure to elvitegravir.
  • Emtricitabine–Phosphorylated intracellularly where it inhibits HIV reverse transcriptase, resulting in viral DNA chain termination.
  • Tenofovir alafenamide–Phosphorylated intracellularly where it inhibits HIV reverse transcriptase resulting in disruption of DNA synthesis. When compared to tenofovir disoproxil fumarate, tenofovir alafenamide is associated with fewer episodes of renal impairment and reductions in bone mineral density.

Therapeutic Effect(s):

Slowed progression of HIV infection and decreased occurrence of sequelae.

Pharmacokinetics

elvitegravir

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 98–99%.

Metabolism and Excretion: Metabolized by CYP3A; 94.5% eliminated in feces, 6.7% in urine.

Half-life: 12.9 hr.

cobicistat

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 97–98%.

Metabolism and Excretion: Metabolized by CYP3A and to a small extent by CYP2D6; 86.2% eliminated in feces, 8.2% in urine.

Half-life: 3.5 hr.

emtricitabine

Absorption: Rapidly and extensively absorbed; 93% bioavailable.

Distribution: Unknown.

Metabolism and Excretion: Some metabolism; 86% eliminated in urine, 14% in feces.

Half-life: 10 hr.

tenofovir alafenamide

Absorption: Tenofovir alafenamide is a prodrug, which is hydrolyzed into tenofovir, the active component; absorption enhanced by high-fat meals.

Distribution: Unknown.

Metabolism and Excretion: Tenofovir is phosphorylated to tenofovir diphosphate (active metabolite); 32% excreted in feces, <1% in urine.

Half-life: 0.51 hr.

TIME/ACTION PROFILE (blood levels)

ROUTEONSETPEAKDURATION
elvitegravir POunknown4 hr24 hr
cobicistat POunknown3 hr24 hr
emtricitabine POrapid1–2 hr 24 hr
tenofovir alafenamide POunknown0.5 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment;
  • Concurrent use of drugs that depend mainly on CYP3A for metabolism and whose blood levels, when ↑, are associated with serious/life-threatening adverse reactions;
  • Concurrent use of drugs that induce the CYP3A enzyme system which may ↓ blood levels/effectiveness and promote development of viral resistance;
  • Should not be used concurrently with other antiretrovirals that contain cobicistat, elvitegravir, emtricitabine, tenofovir disoproxil fumarate, lamivudine, adefovir, or ritonavir;
  • Severe renal impairment (CCr <30 mL/min);
  • Severe hepatic impairment;
  • Lactation: HIV-infected women should not breast feed due to risk of viral transmission.

Use Cautiously in:

  • Female patients or obese patients (may be at ↑ risk for lactic acidosis/hepatic steatosis);
  • Chronic hepatitis B virus infection (may exacerbate following discontinuation);
  • Concurrent use of nephrotoxic drugs (↑ risk of renal impairment);
  • Geri: Elderly may be more sensitive to drug effects; consider age-related ↓ in renal, hepatic, and cardiovascular function; concurrent disease states and medications;
  • OB: Use during pregnancy only if potential benefits justify fetal risks;
  • Pedi: Children <25 kg (safety and effectiveness not established).

Exercise Extreme Caution in:

Hepatitis B (may cause severe acute exacerbation).

Adverse Reactions/Side Effects

CNS: headache

F and E: hypophosphatemia

GI: LACTIC ACIDOSIS/HEPATOMEGALY WITH STEATOSIS, POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B, nausea, diarrhea

GU: proteinuria, renal impairment

Metabolic: ↑ lipids

Misc: fatigue, immune reconstitution syndrome.

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • May alter blood levels and effects of other drugs metabolized by the CYP3A or CYP2D6 enzyme systems. Other drugs that induce the CYP3A system can alter blood levels and effects.
  • May ↑ levels and potentially cause serious/life-threatening adverse reactions of drugs that depend mainly on CYP3A for metabolism including alfuzosin, dihydroergotamine, ergotamine, lovastatin, methylergonovine, lurasidone, pimozide, sildenafil (when used for pulmonary hypertension), simvastatin, and triazolam; concurrent use contraindicated.
  • Carbamazepine, phenobarbital, phenytoin, or rifampin may significantly ↓ levels/effectiveness of cobicistat, elvitegravir, and tenofovir alafenamide and ↑ risk of resistance; concurrent use contraindicated.
  • Nephrotoxic agents, including NSAIDs and aminoglycosides may ↑ risk of nephrotoxicity; avoid concurrent use.
  • Drugs that induce CYP3A will ↓ levels/effectiveness of elvitegravir, cobicistat, and tenofovir alafenamide.
  • Drugs that inhibit CYP3A will ↑ levels/toxicity of cobicistat.
  • Acyclovir, cidofovir, ganciclovir, valacyclovir, and valganciclovir may ↓ renal elimination and ↑ levels/toxicity of emtricitabine and tenofovir alafenamide.
  • Antacids, including aluminum hydroxide and magnesium hydroxide, may ↓ levels/effectiveness of elvitegravir; separate administration by ≥2 hr.
  • May ↑ levels/toxicity of amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, propafenone and quinidine; careful monitoring recommended.
  • May alter effects of warfarin; careful monitoring of INR recommended.
  • Concurrent use with clarithromycin may ↑ levels/toxicity of clarithromycin and/or cobicistat (for patients with CCr 50–60 mL/min, ↓ dose of clarithromycin by 50%).
  • May ↑ levels/toxicity of ethosuximide; clinical monitoring recommended.
  • Oxcarbamazepine may ↓ levels/effectiveness of cobicistat, elvitegravir, and tenofovir alafenamide; consider using alternative anticonvulsant.
  • May ↑ levels/toxicity of SSRIs (except sertraline), tricyclic antidepressants, and trazodone; careful titration and monitoring recommended.
  • Concurrent use with itraconazole, ketoconazole, orvoriconazole may ↑ levels/toxicity of itraconazole, ketoconazole, voriconazole, elvitegravir, and cobicistat; (max dose of ketoconazole or itraconazole = 300 mg/day; assess risk vs. benefit before using voriconazole).
  • May ↑ levels/toxicity of colchicine; concurrent use contraindicated in renal or hepatic impairmentDosing adjustment for gout flares–0.6 mg, then 0.3 mg 1 hr later, do not repeat for ≥3 daysDosing adjustment for gout flare prophylaxis–0.3 mg once daily if original regimen was 0.6 mg twice daily, 0.3 mg every other day if original regimen was 0.6 mg once dailyDosing adjustment for treatment of familial Mediterranean fever–not to exceed 0.6 mg daily, may be given as 0.3 mg twice daily.
  • Rifabutin or rifapentine may ↓ levels/effectiveness of cobicistat, elvitegravir, and tenofovir alafenamide and may foster resistance; concurrent use not recommended.
  • May ↑ levels/toxicity of beta blockers; careful monitoring recommended; ↓ dose of beta blocker if necessary.
  • May ↑ levels/toxicity of calcium channel blockers including amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and verapamil; careful monitoring recommended.
  • Concurrent use of corticosteroids that induce CYP3A, including budesonide, dexamethasone, methylprednisolone, prednisone, or inhaled betamethasone, ciclesonide, fluticasone, mometasone, and triamcinolone, may ↓ levels/effectiveness and ↑ risk of resistance to elvitegravir (consider use of other corticosteroids, such as beclomethasone or prednisolone).
  • Concurrent use of corticosteroids that are metabolized by CYP3A including budesonide, dexamethasone, methylprednisolone, prednisone, or inhaled betamethasone, ciclesonide, fluticasone, mometasone, and triamcinolone may ↑ risk of Cushing's disease and adrenal suppression (consider use of other corticosteroids, such as beclomethasone or prednisolone).
  • May ↑ levels/toxicity of bosentan; initiate bosentan at 62.5 mg once daily or every other day if already receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for ≥10 days; if already receiving bosentan, discontinue bosentan ≥36 hr prior to starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; after 10 days, bosentan may be restarted at 62.5 mg once daily or every other day.
  • May ↑ levels/toxicity of atorvastatin; initiate atorvastatin at lowest dose and titrate cautiously.
  • May ↑ levels/toxicity of norgestimate and ↓ levels of ethinyl estradiol; due to unpredictable effects, non-hormonal contraceptive methods should be considered.
  • May ↑ levels/toxicity of immunosuppressants, including cyclosporine, sirolimus, and tacrolimus; careful monitoring recommended.
  • Cyclosporine may ↑ levels/toxicity of cobicistat and elvitegravir; careful monitoring recommended.
  • May ↑ levels/toxicity of buprenorphine and ↓ levels of naloxone; carefully monitor for sedation and altered cognitive effects.
  • May ↑ levels of and risk of adverse cardiovascular effects with salmeterol, concurrent use not recommended.
  • ↑ levels/toxicity of neuroleptics, including perphenazine, risperidone, and thioridazine; may need to ↓ dose of neuroleptic.
  • May ↑ levels of quetiapine; if taking quetiapine when initiating therapy, consider alternative antiretroviral therapy or ↓ quetiapine dose to ⅙ of the original dose and monitor for adverse effects
  • May ↑ levels/toxicity of PDE5 inhibitors, including sildenafil, tadalafil, and vardenafilDosing adjustment for pulmonary hypertension–sildenafil is contraindicated; in patients who have received elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for ≥7 days, start tadalafil at 20 mg once daily and carefully titrate if tolerating to 40 mg once daily; in patients already receiving tadalafil, discontinue tadalafil for ≥24 hr before initiating elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; after ≥1 wk, resume tadalafil at 20 mg once daily and titrate if tolerating to 40 mg once dailyDosing adjustment for erectile dysfunction–sildenafil dose should not exceed 25 mg in 48 hr, vardenafil dose should not exceed 2.5 mg in 72 hr, and tadalafil dose should not exceed 10 mg in 72 hr.
  • ↑ levels/toxicity of sedative/hypnotics, including midazolam (parenteral), diazepam, buspirone, and zolpidem; consider dose ↓ of parenteral midazolam; clinical monitoring and dose ↓, if necessary, is recommended for other sedative/hypnotics.
  • ↑ risk of hyperkalemia with drospirenone/ethinyl estradiol; closely monitor serum potassium concentrations.

Drug-Natural Products:

St. John's wort may significantly ↓ levels/effectiveness of cobicistat and elvitegravir and ↑ risk of resistance; concurrent use contraindicated.

Route/Dosage

PO: (Adults and Children) ≥25 kg): 1 tablet once daily.

Availability

Tablets: elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg

Assessment

  • Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.

Lab Test Considerations: Monitor viral load and CD4 count before and routinely during therapy to determine response.

  • Monitor liver function tests and hepatitis B virus levels throughout and following therapy. If therapy is discontinued, may cause severe exacerbation of hepatitis B. May cause ↑ LDL cholesterol, total cholesterol, and triglyceride concentrations. Lactic acidosis may occur with hepatic toxicity causing hepatic steatosis; may be fatal, especially in women. Discontinue therapy if symptoms occur.
  • Calculate serum creatinine, CCr, urine glucose, and urine protein prior to and periodically during therapy and when clinically indicated. In patients with chronic kidney disease, assess creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to and periodically during therapy. May cause hypophosphatemia in patients with renal impairment.
  • May cause hyperglycemia and glycosuria.

Potential Diagnoses

Implementation

  • Test patient for hepatitis B prior to starting therapy. Genvoya™ may cause exacerbations of hepatitis B with liver decompensation and liver failure. Monitor hepatic function closely for at least several mo in patients infected with both HIV and HBV who discontinue this medication.
  • PO: Administer once daily with food.
    • Administer antacids at least 2 hr before or after medication.

Patient/Family Teaching

  • Instruct patient on the importance of taking medication as directed, even if feeling better. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Discontinuing therapy may lead to severe exacerbations. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes. Caution patient not to share or trade Genvoya™ with others.
  • Inform patient of importance of hepatitis B testing before starting antiretroviral therapy.
  • Advise patients if antacids containing aluminum, magnesium hydroxide, or calcium carbonate, take at least 2 hrs before or after Genvoya™.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
  • Advise patient to notify health care professional immediately if symptoms of lactic acidosis (nausea, vomiting, unusual or unexpected stomach discomfort, unusual muscle pain, difficulty breathing, feeling cold, especially in arms and legs, dizziness, fast or irregular heartbeat, and weakness or tiredness) liver problems (yellow skin or whites of eyes, dark urine, light colored stools, loss of appetite, nausea, stomach pain) or signs of Immune Reconstitution Syndrome (signs and symptoms of an infection or inflammation) occur.
  • Inform patient that Genvoya™ does not cure AIDS and does not reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and avoid sharing needles or donating blood to prevent spreading HIV to others.
  • Rep: Advise patient to notify health care professional if pregnancy is planned or suspected. Encourage pregnant women to enroll in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. Advise female patient to avoid breast feeding during therapy.

Evaluation/Desired Outcomes

Slowed progression of HIV infection and decreased occurrence of sequelae.

elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide is the Word of the Day!

elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide is a topic covered in the Davis's Drug Guide.

To view the entire topic, please or purchase a subscription.

Medicine Central™ is a quick-consult mobile and web resource that includes diagnosis, treatment, medications, and follow-up information on over 700 diseases and disorders, providing fast answers—anytime, anywhere. Explore these free sample topics:

Medicine Central