Indications
Management of HIV infection in treatment-naı¨ve 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 Effects: 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)
ROUTE ONSET PEAK DURATION
elvitegravir
PO
unknown 4 hr 24 hr
cobicistat PO unknown 3 hr 24 hr
emtricitabine
PO
rapid 1–2 hr 24 hr
tenofovir alafenamide
PO
unknown 0.5 hr 24 hr
Contraindications/Precautions
Contraindicated in: Severe hepatic impairment;
Concurrent use of drugs that depend mainly on CYP3A
for metabolism and whose blood levels, whenq, are associated
with serious/life-threatening adverse reactions;
Concurrent use of drugs that induce the CYP3A enzyme
system which maypblood 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 atqrisk for lactic acidosis/hepatic steatosis);
Chronic hepatitis B virus infection (may exacerbate
following discontinuation); Moderate renal
impairment (CCr30–50 mL/min); Concurrent use
of nephrotoxic drugs (qrisk of renal impairment);
Geri: Elderly may be more sensitive to drug effects; consider
age-relatedpin 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: headache. F and E: hypophosphatemia. GI:
LACTIC ACIDOSIS/HEPATOMEGALY WITH STEATOSIS, POSTTREATMENT
ACUTE EXACERBATION OF HEPATITIS B, nausea,
diarrhea. GU: proteinuria, renal impairment.Metab:
qlipids. Misc: fatigue, immune reconstitution syndrome.
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. Mayqlevels 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
significantlyplevels/effectiveness of cobicistat, elvitegravir,
and tenofovir alafenamide andqrisk of resistance;
concurrent use contraindicated. Nephrotoxic
agents, including NSAIDs and aminoglycosides may
qrisk of nephrotoxicity; avoid concurrent use. Drugs
that induce CYP3A willplevels/effectiveness of elvitegravir,
cobicistat, and tenofovir alafenamide. Drugs that
inhibit CYP3A willqlevels/toxicity of cobicistat. Acyclovir,
cidofovir, ganciclovir, valacyclovir, and valganciclovir
mayprenal elimination andqlevels/toxicity
of emtricitabine and tenofovir alafenamide.
Antacids, including aluminum hydroxide and magnesium
hydroxide, mayplevels/effectiveness of elvitegravir;
separate administration by 2 hr. Mayqlevels/
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
mayqlevels/toxicity of clarithromycin and/or cobicistat
(for patients with CCr 50–60 mL/min,pdose of clarithromycin
by 50%). Mayqlevels/toxicity of ethosuximide;
clinical monitoring recommended. Oxcarbamazepine
mayplevels/effectiveness of cobicistat,
elvitegravir, and tenofovir alafenamide; consider using
alternative anticonvulsant. Mayqlevels/toxicity of
SSRIs (except sertraline), tricyclic antidepressants,
and trazodone; careful titration and monitoring recommended.
Concurrent use with itraconazole, ketoconazole,
orvoriconazole mayqlevels/toxicity of
itraconazole, ketoconazole, voriconazole, elvitegravir,
and cobicistat; (max dose of ketoconazole or itraconazole
300 mg/day; assess risk vs. benefit before using
voriconazole). Mayqlevels/toxicity of colchicine; concurrent
use contraindicated in renal or hepatic impairment;
Dosing adjustment for gout flares—0.6 mg,
then 0.3 mg 1 hr later, do not repeat for 3 days; Dosing
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 daily; Dosing 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 mayplevels/effectiveness of cobicistat, elvitegravir,
and tenofovir alafenamide and may foster resistance;
concurrent use not recommended. Mayqlevels/
toxicity of beta blockers; careful monitoring
recommended;pdose of beta blocker if necessary.
Mayqlevels/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, mayplevels/effectiveness
andqrisk 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
mayqrisk of Cushing’s disease and adrenal
suppression (consider use of other corticosteroids,
such as beclomethasone or prednisolone). Mayqlevels/
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. Mayqlevels/toxicity of atorvastatin;
initiate atorvastatin at lowest dose and titrate cautiously.
Mayqlevels/toxicity of norgestimate andplevels of
ethinyl estradiol; due to unpredictable effects, nonhormonal
contraceptive methods should be considered.
Mayqlevels/toxicity of immunosuppressants,
including cyclosporine, sirolimus, and tacrolimus;
careful monitoring recommended. Cyclosporine may
qlevels/toxicity of cobicistat and elvitegravir; careful
monitoring recommended. Mayqlevels/toxicity of buprenorphine
andplevels of naloxone; carefully
monitor for sedation and altered cognitive effects. May
qlevels of and risk of adverse cardiovascular effects
with salmeterol, concurrent use not recommended.
qlevels/toxicity of neuroleptics, including perphenazine,
risperidone, and thioridazine; may need to
pdose of neuroleptic. Mayqlevels of quetiapine; if
taking quetiapine when initiating therapy, consider alternative
antiretroviral therapy orpquetiapine dose to
1⁄6 of the original dose and monitor for adverse effects.
Mayqlevels/toxicity of PDE5 inhibitors, including
sildenafil, tadalafil, and vardenafil; Dosing 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 daily; Dosing 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.qlevels/toxicity of sedative/hypnotics, including
midazolam (parenteral), diazepam, buspirone,
and zolpidem; consider dosepof parenteral midazolam;
clinical monitoring and dosep, if necessary, is
recommended for other sedative/hypnotics.
Drug-Natural Products: St. John’s wort may significantlyplevels/
effectiveness of cobicistat and elvitegravir
andqrisk of resistance; concurrent use contraindicated.
Route/Dosage
PO (Adults and Children 12 yr and 35 kg): 1
tablet once daily.
Availability
Tablets: elvitegravir 150 mg/cobicistat 150 mg/emtricitabine
200 mg/tenofovir alafenamide 10 mg.
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