elvitegravir 150 MG / cobicistat 150 MG / emtricitabine 200 MG / tenofovir disoproxil fumarate 300 MG Oral Tablet
DRUG INTERACTIONS
7 See also Contraindications (4) and Clinical Pharmacology (12.3) .
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.
( 5.4 , 7.1 ) STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6.
Drugs that induce CYP3A can alter the concentrations of one or more components of STRIBILD.
Consult the full prescribing information prior to and during treatment for potential drug-drug interactions.
( 4 , 7.2 , 7.3 , 12.3 ) 7.1 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.
7.2 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.
7.3 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 ).
7.4 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 (5.3) ] .
7.5 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 (12.3) ] .
The table includes potentially significant interactions but is not all inclusive.
Table 6 Established and Other Potentially Significant This 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 Indicates that a drug-drug interaction trial was conducted.
(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.
7.6 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, H 2 receptor antagonists, methadone, proton pump inhibitors and ribavirin.
OVERDOSAGE
10 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.
DESCRIPTION
11 STRIBILD is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF for oral administration.
Elvitegravir is an HIV-1 integrase strand transfer inhibitor.
Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
Emtricitabine is a synthetic nucleoside analog of cytidine.
EMTRIVA is the brand name for emtricitabine.
Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
VIREAD is the brand name for tenofovir DF.
Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil).
The tablets include the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate.
The tablets are film-coated with a coating material containing indigo carmine (FD&C Blue #2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
Elvitegravir: The chemical name of elvitegravir is 6-(3-Chloro-2-fluorobenzyl)-1-[(2 S )-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
It has a molecular formula of C 23 H 23 ClFNO 5 and a molecular weight of 447.9.
It has the following structural formula: Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Chemical Structure Cobicistat: The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate.
It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0.
It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide.
Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.
Chemical Structure Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-[(2 R ,5 S )-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.25.
It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Chemical Structure Tenofovir Disoproxil Fumarate: Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir.
The chemical name of tenofovir DF is 9-[( R )-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).
It has a molecular formula of C 19 H 30 N 5 O 10 P ∙ C 4 H 4 O 4 and a molecular weight of 635.51.
It has the following structural formula: Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in water at 25 °C.
All dosages are expressed in terms of tenofovir DF except where otherwise noted.
Chemical Structure
CLINICAL STUDIES
14 The efficacy of STRIBILD is based on the analyses of 96-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103, in treatment-naïve, HIV-1 infected subjects (N=1408, randomized and dosed) with baseline estimated creatinine clearance above 70 mL per min.
In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily.
The mean age was 38 years (range 18–67), 89% were male, 63% were White, 28% were Black, and 2% were Asian.
Twenty-four percent of subjects identified as Hispanic/Latino.
The mean baseline plasma HIV-1 RNA was 4.8 log 10 copies per mL (range 2.6–6.5).
The mean baseline CD4+ cell count was 386 cells per mm 3 (range 3–1348) and 13% had CD4+ cell counts less than 200 cells per mm 3 .
Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.
In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg + RTV 100 mg + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) (N=355) once daily.
The mean age was 38 years (range 19–72), 90% were male, 74% were White, 17% were Black, and 5% were Asian.
Sixteen percent of subjects identified as Hispanic/Latino.
The mean baseline plasma HIV-1 RNA was 4.8 log 10 copies per mL (range 1.7–6.6).
The mean baseline CD4+ cell count was 370 cells per mm 3 (range 5–1132) and 13% had CD4+ cell count less than 200 cells per mm 3 .
Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.
In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).
Treatment outcomes of Study 102 and Study 103 through 96 weeks are presented in Table 10.
Table 10 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 96 Week 96 window is between Day 631 and 714 (inclusive).
Study 102 Study 103 STRIBILD (N=348) ATRIPLA (N=352) STRIBILD (N=353) ATV + RTV + TRUVADA (N=355) Virologic Success HIV-1 RNA < 50 copies/mL 84% 82% 83% 82% Treatment Difference 2.7% (95% CI = -2.9%, 8.3%) 1.1% (95% CI = -4.5%, 6.7%) Virologic Failure Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
6% 8% 7% 7% No Virologic Data at Week 96 Window Discontinued Study Drug Due to AE or Death Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
5% 6% 4% 6% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mL Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.
5% 4% 5% 5% Missing Data During Window but on Study Drug 0% 1% 1% 0 % In Study 102, the mean increase from baseline in CD4+ cell count at Week 96 was 278 cells per mm 3 in the STRIBILD-treated subjects and 247 cells per mm 3 in the ATRIPLA -treated subjects.
In Study 103, the mean increase from baseline in CD4+ cell count at Week 96 was 242 cells per mm 3 in the STRIBILD-treated subjects and 240 cells per mm 3 in the ATV + RTV + TRUVADA-treated subjects.
HOW SUPPLIED
16 /STORAGE AND HANDLING STRIBILD tablets are green, capsule-shaped, film-coated, debossed with “GSI” on one side and the number “1” surrounded by a square box ( ) on the other side.
They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod.
Code 53808-0887-1 150 MG / 150 MG / 200 MG / 300 MG 30 Tablets in a Blister Pack GREEN 61958-1201 Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).
RECENT MAJOR CHANGES
Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) 10/2013 Warnings and Precautions New Onset or Worsening Renal Impairment ( 5.3 ) 10/2013 Bone Effects of Tenofovir DF ( 5.5 ) 10/2013
GERIATRIC USE
8.5 Geriatric Use Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, caution should be exercised in the administration of STRIBILD in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] .
DOSAGE FORMS AND STRENGTHS
3 Each STRIBILD tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, equivalent to 245 mg of tenofovir disoproxil).
The tablets are green, capsule-shaped, film-coated, debossed with “GSI” on one side and the number “1” surrounded by a square box ( ) on the other side of the tablet.
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate.
( 3 ) figure
MECHANISM OF ACTION
12.1 Mechanism of Action STRIBILD is a fixed-dose combination of antiviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF [see Microbiology (12.4) ] .
INDICATIONS AND USAGE
1 STRIBILD ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve.
STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir DF, both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of STRIBILD in pediatric patients less than 18 years of age have not been established [see Clinical Pharmacology (12.3) ] .
PREGNANCY
8.1 Pregnancy
NUSRING MOTHERS
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk.
It is not known whether elvitegravir or cobicistat is excreted in human milk.
In humans, samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk.
Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine.
Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk.
Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD.
BOXED WARNING
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of STRIBILD, in combination with other antiretrovirals [see Warnings and Precautions (5.1) ] .
STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1.
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD.
Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD.
If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2) ] .
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), a component of STRIBILD.
( 5.1 ) STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection.
Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD.
Hepatic function should be monitored closely in these patients.
If appropriate, initiation of anti-hepatitis B therapy may be warranted.
( 5.2 )
WARNING AND CAUTIONS
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.
Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD.
Monitor CLcr, urine glucose, and urine protein in all patients.
Monitor serum phosphorus in patients at risk for renal impairment.
Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs.
( 5.3 ) Avoid coadministration with other anti-retroviral products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine; or with drugs or regimens containing ritonavir.
Do not administer in combination with HEPSERA.
( 5.4 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss.
( 5.5 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.
( 5.6 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment.
( 5.7 ) 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals.
A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.2 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy.
STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1.
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD.
In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure.
Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD.
If appropriate, initiation of anti-hepatitis B therapy may be warranted.
5.3 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF, a component of STRIBILD, and with the use of STRIBILD [see Adverse Reactions (6.2) ] .
In the clinical trials of STRIBILD over 96 weeks, 10 (1.4%) subjects in the STRIBILD group (N=701) and 2 (0.3%) subjects in the combined comparator groups (N = 707) discontinued study drug due to a renal adverse reaction.
Of these discontinuations, 8 in the STRIBILD group and 1 in the combined comparator groups occurred during the first 48 week.
Four (0.6%) of the subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups.
Two of these four subjects had renal impairment (i.e.
estimated creatinine clearance less than 70 mL per minute) at baseline.
The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of STRIBILD.
Renal replacement therapy was not required for these subjects.
Estimated creatinine clearance, urine glucose and urine protein should be documented in all patients prior to initiating therapy.
Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.
STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.4) ] .
Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF.
Some patients required hospitalization and renal replacement therapy.
Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.
Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients.
Additionally, serum phosphorus should be measured in patients at risk for renal impairment.
Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [see Adverse Reactions (6.1) ] , patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
The emtricitabine and tenofovir DF components of STRIBILD are primarily excreted by the kidney.
STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet.
5.4 Avoid Use with Other Antiretroviral Products STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended.
STRIBILD is not recommended for coadministration with the following: emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD); products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR) or adefovir dipivoxil (HEPSERA); ritonavir (NORVIR, KALETRA).
5.5 Bone Effects of Tenofovir DF Bone Mineral Density: In clinical trials in HIV-1 infected adults, tenofovir DF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators.
Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving tenofovir DF.
For additional information, see Adverse Reactions (6.1) and consult the VIREAD prescribing information.
The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Assessment of BMD should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients.
If bone abnormalities are suspected, then appropriate consultation should be obtained.
Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [see Adverse Reactions (6.2) ] .
Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.
Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [see Warnings and Precautions (5.3) ] .
5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD.
During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with STRIBILD.
Patients should be advised that: STRIBILD may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St.
John’s wort.
Patients should remain under the care of a healthcare provider when using STRIBILD.
Patients should be informed that STRIBILD is not a cure for HIV-1 infection.
Patients should stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should avoid doing things that can spread HIV-1 infection to others.
Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection.
Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed.
At least two of the drugs contained in STRIBILD can be passed to the baby in breast milk.
It is not known whether this could harm the baby.
Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.
It is important to take STRIBILD on a regular dosing schedule with food and to avoid missing doses.
Do not miss a dose of STRIBILD.
If a patient misses a dose of STRIBILD, the patient should take the missed dose as soon as they remember.
If it is almost time for the next dose of STRIBILD, the patient should not take the missed dose, but resume the usual dosing schedule.
Inform the patient that he or she should not take more or less than the prescribed dose of STRIBILD at any one time.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.
Advise patients that treatment with STRIBILD should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1) ] .
Instruct the patient that hepatitis B testing is recommended prior to initiating antiretroviral therapy.
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD [see Warnings and Precautions (5.2) ] .
STRIBILD should not be discontinued without first informing their healthcare provider.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of STRIBILD.
STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high dose or multiple NSAIDs) [see Warnings and Precautions (5.3) ] .
STRIBILD should not be coadministered with other antiretroviral products because it provides a complete treatment regimen and because of potential drug interactions [see Warnings and Precautions (5.4) and Drug Interactions (7) ] .
STRIBILD should not be administered in combination with ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine, including COMBIVIR, EPIVIR or EPIVIR-HBV, EPZICOM, or TRIZIVIR; with drugs containing RTV or regimens containing RTV; or with HEPSERA [see Warnings and Precautions (5.4) ] .
Decreases in bone mineral density have been observed with the use of STRIBILD.
Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.5) ] .
Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.6) ] .
In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.
It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms.
Patients should be advised to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.7) ].
DOSAGE AND ADMINISTRATION
Recommended dosage: One tablet taken once daily with food.
( 2.1 ) Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.
Discontinue in patients with estimated creatinine clearance below 50 mL per minute.
( 2.2 ) 2.1 Dosage Information The recommended dosage of STRIBILD is one tablet taken orally once daily with food [see Clinical Pharmacology (12.3) ] .
2.2 Dosage Adjustment in Patients with Renal Impairment Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.
Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with STRIBILD as dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ].
2.3 Dosage in Patients with Hepatic Impairment No dosage adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C).
Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].
2.4 Testing Prior to Initiation of STRIBILD Prior to initiation of STRIBILD, patients should be tested for hepatitis B infection [see Warnings and Precautions (5.2) ] and estimated creatinine clearance, urine glucose and urine protein should be documented in all patients [see Warnings and Precautions (5.3) ] .