integrase strand transfer inhibitors
nucleoside reverse transcriptase inhibitors
Management of HIV infection, a complete regimen for treatment-naïve adults
- Elvitegravir– Antegrase 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
Slowed progression of HIV infection and decreased occurrence of sequelae
Absorption: Absorption follows oral administration
Protein Binding: 98–99%
Metabolism and Excretion: Metabolized by CYP3A, 94.5% eliminated in feces, 6.7% in urine.
Half-life: 12.9 hr
Absorption: Absorption follows oral administration
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
Absorption: Rapidly and extensively absorbed; 93% bioavailable
Metabolism and Excretion: Some metabolism, 86% renally excreted, 14% fecal excretion
Half-life: 10 hr
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
|elivtegravir PO||unknown||4 hr||24 hr|
|cobicistat PO||unknown||3 hr||24 hr|
|emtricitabine PO||rapid||1–2 hr||24 hr|
|tenofovir PO||unknown||2 hr||24 hr|
- 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 CYP3A enzyme system which may ↓ blood levels/effectiveness and promote development of viral resistance;
- Should not be used concurrently with other antiretrovirals that contain common ingredients (emtricitabine, tenofovir) or antiretrovirals that contain lamivudine or ritonavir due to altered drug effects;
- Renal impairment (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: 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, proteinuria
GI: LACTIC ACIDOSIS/HEPATIC STEATOSIS, POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B, diarrhea, nausea
Derm: rash, hyperpigmentation
F and E: hypophosphatemia
Metabolic: ↑ lipids, redistribution of body fat
MS: ↓ bone mineral density
Misc: immune reconstitution syndrome.
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- 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, dihyroergotamine, ergotamine, lovastatin, oral midazolam, methylergonovine, rifampin, sildenafil (when used for pulmonary hypertension), simvastatin, and triazolam.
- Concurrent/recent use of nephrotoxic agents (↑ risk of nephrotoxicity)
- 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 adminstration by at least 2 hr).
- ↑ blood levels and risk of toxicity from amiodarone, bepridil, digoxin, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone or quinidine; careful monitoring recommended.
- May alter effects of warfarin.
- Concurrent use with clarithromycin or telithromycin can result in altered levels of clarithromycin and/or cobicistat (for patients with CCr 50–60 mL/min ↓ dose of clarithromycin by 50%), levels of telithromycin and/or cobicistat may be ↑.
- Concurrent use of carbamazepine, oxcarbazepine, phenobarbital, or phentoin may significantly ↓ levels/effectiveness of cobicistat and elvitegravir and ↑ risk of resistance (alternative anticonvulsants should be considered).
- May ↑ levels of clonazepam and ethosuximide (clinical monitoring recommended).
- ↑ levels and risk of adverse effects with SSRIs, 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, 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 three daysprophylaxis 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 dailytreatment 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.
- ↓ blood levels/effectiveness and ↑ risk of resistance with concurrent systemic dexamethasone, consider other corticosteroids.
- ↑ systemic levels from long term use of nasal or inhaled fluticasone, consider other corticosteroids.
- ↑ 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 titrate cautiously).
- ↑ levels of norgestimate and ↓ levels of ethinyl estradiol (due to unpredictable effects, non-hormonal contraception should be considered).
- ↑ 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 ↓.
- ↑ 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 titirate as necessary to 40 mg/dayfor 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 reduction of parenteral midazolam should be considered, clinical monitoring and dose reduction if necessary is recommended for others.
Blood levels and effectiveness are ↓ by St. John's wort , concurrent use is contraindicated.
PO: (Adults) One tablet once daily.
Tablets: elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir 300 mg
- 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.
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.
- 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 CCr, urine glucose, and urine protein prior to therapy. CCr should be >70 mL/min before starting therapy. Monitor CCr, urine glucose, and urine protein periodically during therapy and serum phosphorous in patients at risk for renal impairment.
- PO: Administer once daily with a meal.
- 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.
- Inform patient that changes in body fat (increased fat in upper back and neck, breast, and around back, chest, and stomach area, loss of fats from legs, arms, and face) may occur.
- 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.
- 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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