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Stribild (Elvitegravir / Cobicistat / Emtricitabine / Tenofovir Disoproxil Fumarate) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

See also Contraindications (4) and Clinical Pharmacology.

Other Antiretroviral Medications

STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

Potential for STRIBILD to Affect Other Drugs

Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.

Potential for Other Drugs to Affect One or More Components of STRIBILD

Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.

Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (see Table 6).

Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 6).

Drugs Affecting Renal Function

Because emtricitabine and tenofovir, components of STRIBILD are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g. gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions].

Established and Other Potentially Significant Interactions

Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD, (elvitegravir, cobicistat, emtricitabine, and tenofovir DF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction, see Clinical Pharmacology ]. The table includes potentially significant interactions but is not all inclusive.

Table 6 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease, ⇔ = No Effect Clinical Comment
Acid Reducing Agents:
Antacids 1 (for example aluminum and magnesium hydroxide)
↓ elvitegravir Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Antiarrhythmics:
e.g.
amiodarone
bepridil
digoxin
disopyramide
flecainide
systemic lidocaine mexiletine
propafenone
quinidine
↑ antiarrhythmics
↑ digoxin
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials:
clarithromycin
telithromycin
↑ clarithromycin
↑ telithromycin
↑ cobicistat
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD.
Patients with CLcr greater than or equal to 60 mL/min:
No dose adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/min and 60 mL/min:
The dose of clarithromycin should be reduced by 50%.
Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants:
warfarin
Effect on warfarin unknown Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants:
carbamazepine
oxcarbazepine phenobarbital
phenytoin
↑ carbamazepine
↓ elvitegravir
↓ cobicistat
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam
ethosuximide
↑ clonazepam
↑ ethosuximide
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g.
paroxetine

Tricyclic
Antidepressants (TCAs)
e.g.
amitriptyline
desipramine
imipramine
nortriptyline
buproprion
trazodone
↑ SSRIs
↑ TCAs
↑ trazodone
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.
Antifungals:
itraconazole ketoconazole
voriconazole
↑ elvitegravir
↑ cobicistat
↑ itraconazole
↑ ketoconazole
↑voriconazole
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout:
colchicine
↑ colchicine STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin
rifapentine
↓ elvitegravir
↓ cobicistat
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers:
e.g.
metoprolol
timolol
↑ beta-blockers Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers:
e.g. amlodipine
diltiazem
felodipine
nicardipine
nifedipine
verapamil
↑ calcium channel blockers Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid:
Systemic:

dexamethasone
↓ elvitegravir
↓ cobicistat
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid:
Inhaled/Nasal:

fluticasone
↑ fluticasone Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on STRIBILD:
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of STRIBILD in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
↑ atorvastatin Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives:
norgestimate/ethinyl estradiol
↑ norgestimate
↓ ethinyl estradiol
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events.
Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants:
e.g.
cyclosporine
sirolimus
tacrolimus
↑ immuno-suppressants Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Narcotic Analgesics:
buprenorphine/
naloxone

↑ buprenorphine
↑ norbuprenorphine
↓ naloxone
Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist:
salmeterol
↑ salmeterol Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics:
e.g.
perphenazine
risperidone
thioridazine
↑ neuroleptics A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors:
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
  • Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).
  • The following dose adjustments are recommended for the use of tadalafil with STRIBILD:
    Coadministration of tadalafil in patients on STRIBILD:
       In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
    Coadministration of STRIBILD in patients on tadalafil:
  •  Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.
Sedative/hypnotics:
Benzodiazepines:
e.g.
Parenterally administered midazolam
clorazepate
diazepam
estazolam
flurazepam
buspirone
zolpidem
↑ sedatives/hypnotics Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated.
With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.

1 Indicates that a drug-drug interaction trial was conducted.

Drugs without Clinically Significant Interactions with STRIBILD

Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors and ribavirin.

OVERDOSAGE

No data are available on overdose of STRIBILD in patients. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with STRIBILD consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Elvitegravir: Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. In one study, boosted elvitegravir equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Cobicistat: Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, a single dose of cobicistat 400 mg (2.7 times the dose in STRIBILD) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in STRIBILD) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir DF: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF (2 times the dosage in STRIBILD) was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

CONTRAINDICATIONS

Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed in Table 1 [see Drug Interactions, Clinical Pharmacology].

Table 1 Drugs that are Contraindicated with STRIBILD
Drug Class Drugs within class that are contraindicated with STRIBILD Clinical Comment
Alpha 1-Adrenoreceptor Antagonist Alfuzosin Potential for increased alfuzosin concentrations, which can result in hypotension.
Antimycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir and cobicistat. This may result in loss of therapeutic effect to STRIBILD.
Ergot Derivatives Dihydroergotamine
Ergotamine
Methylergonovine
Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent Cisapride Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Herbal Products St. John's wort (Hypericum perforatum) Coadministration of products containing St. John's wort and STRIBILD may result in reduced plasma concentrations of elvitegravir and cobicistat. This may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors Lovastatin
Simvastatin
Potential for serious reactions such as myopathy, including rhabdomyolysis.
Neuroleptic Pimozide Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Phosphodiesterase-5 (PDE5) Inhibitor SildenafilSee Drug Interactions (7), Table 6 for sildenafil when dosed as VIAGRA for erectile dysfunction. when dosed as REVATIO for the treatment of pulmonary arterial hypertension There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Sedative/hypnotics Triazolam
Orally administered midazolamSee Drug Interactions (7), Table 6 for parenterally administered midazolam.
Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

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