elvitegravir/cobicistat/emtricitabine/tenofovir

General

Pronunciation:
el-vi-teg-ra vir/koe-bik-i-stat/em-tri-sye-ti-been/te-noe-fo-veer


Trade Name(s)

  • Stribild

Ther. Class.
antiretrovirals

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

Indications

Management of HIV infection, a complete regimen for treatment-naïve adults or in adults who are virologically suppressed (HIV–1 RNA <50 copies/mL) on a stable regimen for ≥6 mo with no history of treatment failure and no known substitutions associated with resistance to the individual components of this medication

Action

  •  Elvitegravir– An integrase strand transfer inhibitor that inhibits an enzyme necessary for viral replication.
  •  Cobicistat– A pharmacokinetic enhancer (inhibits CYP3A and CYP2D6) enhancing systemic exposure to elvitegravir.
  •  Emtricitabine– Phosphorylated intracellularly where it inhibits HIV reverse transcriptase, resulting in viral DNA chain termination
  •  Tenofovir– Phosphorylated intracellularly where it inhibits HIV reverse transcriptase resulting in disruption of DNA synthesis

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% renally excreted, 14% fecal excretion

Half-life: 10 hr

tenofovir

Absorption: Tenofovir disoproxil fumarate is a prodrug, which is split into tenofovir, the active component

Distribution: Absorption is enhanced by food

Metabolism and Excretion: 70–80% excreted unchanged in urine by glomerular filtration and active tubular secretion

Half-life: Unknown

TIME/ACTION PROFILE

ROUTEONSETPEAKDURATION
elvitegravir POunknown4 hr24 hr
cobicistat POunknown3 hr24 hr
emtricitabine POrapid1–2 hr 24 hr
tenofovir POunknown2 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment
  • Concurrent administration of other drugs that depend mainly on CYP3A for metabolism and whose blood levels, when ↑, are associated with serious/life-threatening adverse reactions;
  • Concurrent administration of other 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, lamivudine, adefovir, or ritonavir;
  • Renal impairment (do not initiate if CCr <70 mL/min, discontinue if CCr <50 mL/min)
  • 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);
  • 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 <12 yr (safety and effectiveness not established).

Exercise Extreme Caution in:

Hepatitis B (may cause severe acute exacerbation)

Adverse Reactions/Side Effects

CNS: abnormal dreams, dizziness, headache, insomnia, drowsiness

GU: ACUTE RENAL FAILURE/FANCONI SYNDROME, ↑ serum creatinine, proteinuria

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

Derm: rash, hyperpigmentation

F and E: hypophosphatemia

Metabolic: ↑ lipids

MS: bone pain, ↓ bone mineral density, muscle pain, osteomalacia

Misc: 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.
  • Concurrent administration of other drugs that depend mainly on CYP3A for metabolism and whose blood levels, when ↑, are associated with serious/life-threatening adverse reactions including alfuzosin, dihydroergotamine, ergotamine, lovastatin, oral midazolam, 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 and elvitegravir and ↑ risk of resistance; concurrent use contraindicated.
  • Nephrotoxic agents, including  NSAIDs  ↑ risk of nephrotoxicity; avoid concurrent use
  • Drugs that induce CYP3A will ↓ levels/effectiveness of elvitegravir and cobicistat
  • Drugs that inhibit CYP3A will also ↑ levels/effectiveness of cobicistat
  • Acyclovir, cidofovir, ganciclovir, valacyclovir, and  valganciclovir  may ↓ renal elimination of emtricitabine and tenofovir, ↑ levels and effects.
  • Antacids, including aluminum and magnesium hydroxide , may ↓ levels and effectiveness of elvitegravir; separate administration by at least 2 hr.
  • ↑ blood levels and risk of toxicity from amiodarone, digoxin, disopyramide, flecainide, systemic lidocaine, mexiletine,  propafenone  or  quinidine ; careful monitoring recommended.
  • May alter effects of  warfarin .
  • Concurrent use with  clarithromycin  can result in altered levels of clarithromycin and/or cobicistat; ↓ dose of clarithromycin by 50% in patients with CCr 50–60 mL/min.
  •  Oxcarbamazepine  may ↓ levels/effectiveness of cobicistat and elvitegravir; consider using alternative anticonvulsant
  • May ↑ levels of  clonazepam  and  ethosuximide ; clinical monitoring recommended.
  • ↑ levels and risk of adverse effects with  SSRIs  (except for sertraline), tricyclic antidepressants, and  trazodone ; careful titration and monitoring recommended.
  • ↑ levels of itraconazole, ketoconazole, and  voriconazole ; maximum daily dose of ketoconazole or itraconazole should not exceed 300 mg, use voriconazole with extreme caution. These  azole antifungals  may also ↑ levels of cobicistat and elvitegravir.
  • ↑ levels and risk of toxicity from  colchicine  (concurrent use is contraindicated in patients with renal or hepatic impairment) gout flares– 0.6 mg followed by 0.3 mg 1 hr later, do not repeat for at least 3 days prophylaxis of gout flares– 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 daily treatment of familial Mediterranean fever– not to exceed 0.6 mg daily, may be given as 0.3 mg twice daily.
  • Concurrent use with  rifabutin  or  rifapentine  may significantly ↓ levels/effectiveness of cobicistat and elvitegravir and may foster resistance, concurrent use is not recommended.
  • May ↑ levels and effects of  beta blockers  including  metoprolol  and  timolol;  careful monitoring is recommended, ↓ dose of beta blocker if necessary.
  • May ↑ levels and effects of  calcium channel blockers  including amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and  verapamil;  careful monitoring is 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.
  • ↑ levels and effects of  bosentan ; initiate bosentan at 62.5 mg daily or every other day if already receiving elvitegravir/cobicistat/emtricitabine/tenofovir for at least 10 days, if already receiving bosentan discontinue at least 36 hr prior to starting elvitegravir/cobicistat/emtricitabine/tenofovir; after 10 days, bosentan may be restarted at 62.5 mg daily or every other day.
  • ↑ levels and risk of adverse effect with  atorvastatin ; initiate atorvastatin at lowest dose and do not exceed dose of 20 mg/day; titrate cautiously.
  • ↑ levels of  norgestimate  and ↓ levels of  ethinyl estradiol ; consider using non-hormonal contraception.
  • ↑ risk of hyperkalemia with  drospirenone/ethinyl estradiol ; closely monitor serum potassium concentrations.
  • ↑ levels and effects of  immunosuppressants  including cyclosporine, sirolimus, and  tacrolimus ; careful monitoring recommended.
  • ↑ levels and risk of adverse cardiovascular reactions with  salmeterol ; concurrent use is not recommended.
  • ↑ blood levels and effects of  neuroleptics  including perphenazine, risperidone, and  thioridazine ; neuroleptic dose may need to ↓.
  • 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
  • ↑ levels and risk of serious cardiovascular adverse effects from  PDE5 inhibitors  including sildenafil, tadalafil, and  vardenafil  for pulmonary hypertension– sildenafil is contraindicated; in patients who have received elvitegravir/cobicistat/emtricitabine/tenofovir for at least 7 days, tadalafil may be started at 20 mg/day and carefully titrated if necessary to 40 mg/day; in patients already receiving tadalafil, discontinue for at least 24 hr before initiating elvitegravir/cobicistat/emtricitabine/tenofovir; after 7 days, resume at 20 mg/day and titrate as necessary to 40 mg/day 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 and risk of sedation with  sedative/hypnotics  including midazolam, clorazepate, diazepam, estazolam, flurazepam, buspirone, and  zolpidem ; concurrent use with oral midazolam is contraindicated, dose ↓ of parenteral midazolam should be considered, clinical monitoring and dose reduction if necessary is recommended for others.
  •  Ledipasvir/sofosbuvir  may ↑ tenofovir levels

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)  ≥12 yr and ≥35 kg) One tablet once daily.

Availability

Tablets: elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir 300 mg

Assessment

  • Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
  • Monitor bone mineral density in patients who have a history of pathologic bone fracture or are at risk for osteoporosis or bone loss. Consider calcium and vitamin D supplementation.

Lab Test Considerations: Monitor viral load and CD4 cell count regularly during therapy.

  • Assess for hepatitis B virus (HBV).  Stribild  is not approved for administration in patients with HIV and HBV.
  • Determine serum phosphorous before initiating and periodically during therapy.
  • Monitor liver function tests before and periodically during therapy, especially in patients with underlying liver disease or marked ↑ transaminase. May cause ↑ serum creatinine, AST, ALT, total bilirubin, total cholesterol, LDL, amylase, and triglycerides. Lactic acidosis may occur with hepatic toxicity causing hepatic steatosis; may be fatal, especially in women.
  • Calculate serum creatinine, creatinine clearance (CCr), urine glucose, and urine protein prior to and periodically during therapy. CCr should be >70 mL/min before starting therapy. Monitor CCr, urine glucose, and urine protein in all patients periodically during therapy and serum phosphorous in patients at risk for renal impairment. Assess patients with persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness for proximal renal tubulopathy; evaluate renal function promptly.

Potential Diagnoses

Implementation

  • PO  Administer once daily with food.

Patient/Family Teaching

  • Emphasize the importance of taking  Stribild  as directed, at the same time each day. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Take missed doses with a meal if 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.
  • Advise patient to take antacids 2 hr before or 4 hr after and H2  antagonists 12 hr before or 4 hr after  Stribild.
  • Instruct patient that  Stribild  should not be shared with others.
  • Inform patient that  Stribild  does not cure AIDS or prevent associated or opportunistic infections. Rilpivirine does not reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and to avoid sharing needles or donating blood to prevent spreading the AIDS virus to others. Advise patient that the long-term effects of  Stribild  are unknown at this time.
  • Advise patient to notify health care professional immediately if symptoms of lactic acidosis (nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) occur.
  • Immune reconstitution syndrome may trigger opportunistic infections or autoimmune disorders. Notify health care professional if symptoms occur.
  • May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
  • Rep:  Advise patients to notify health care professional if pregnancy is planned or suspected. Advise patient to avoid breast feeding during  Stribild  therapy. Encourage women who become pregnant during  Stribild  therapy to enroll in Antiviral Pregnancy Registry by calling 1-800-258-4263.
  • Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

  • Delayed progression of AIDS and decreased opportunistic infections in patients with HIV.
  • Decrease in viral load and increase in CD4 cell counts.
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