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].
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].
FACEBOOK TWITTER EMAIL PRINT
DRUG DESCRIPTION
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-[(2S)-1-HYDROXY-3-METHYLBUTAN-2-YL]-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID.
IT HAS A MOLECULAR FORMULA OF C23H23CLFNO5 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.
COBICISTAT
THE CHEMICAL NAME FOR COBICISTAT IS 1,3-THIAZOL-5-YLMETHYL [(2R,5R)-5-{[(2S)-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 C40H53N7O5S2 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.
EMTRICITABINE
THE CHEMICAL NAME OF EMTRICITABINE IS 5-FLUORO-1-[(2R,5S)-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 C8H10FN3O3S 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.
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 C19H30N5O10P o C4H4O4 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.
INDICATIONS
STRIBILD® IS INDICATED AS A COMPLETE REGIMEN FOR THE TREATMENT OF HIV-1 INFECTION IN ADULT PATIENTS WHO HAVE NO ANTIRETROVIRAL TREATMENT HISTORY OR TO REPLACE THE CURRENT ANTIRETROVIRAL REGIMEN IN THOSE WHO ARE VIROLOGICALLY-SUPPRESSED (HIV-1 RNA < 50 COPIES/ML) ON A STABLE ANTIRETROVIRAL REGIMEN FOR AT LEAST 6 MONTHS WITH NO HISTORY OF TREATMENT FAILURE AND NO KNOWN SUBSTITUTIONS ASSOCIATED WITH RESISTANCE TO THE INDIVIDUAL COMPONENTS OF STRIBILD [SEE CLINICAL STUDIES].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
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 ( 1 ) ON THE OTHER SIDE OF THE TABLET.
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 [1] ON THE OTHER SIDE. EACH BOTTLE CONTAINS 30 TABLETS (NDC 61958-1201-1), A SILICA GEL DESICCANT, AND CLOSED WITH A CHILD-RESISTANT CLOSURE.
STORE AT 25 °C (77 °F), EXCURSIONS PERMITTED TO 15-30 °C (59-86 °F) (SEE USP CONTROLLED ROOM TEMPERATURE).
" KEEP CONTAINER TIGHTLY CLOSED.
" DISPENSE ONLY IN ORIGINAL CONTAINER.
" DO NOT USE IF SEAL OVER BOTTLE OPENING IS BROKEN OR MISSING.
MANUFACTURED AND DISTRIBUTED BY: GILEAD SCIENCES, INC. FOSTER CITY, CA 94404. REVISED: DECEMBER 2014
DOSAGE AND ADMINISTRATION
DOSAGE INFORMATION
THE RECOMMENDED DOSAGE OF STRIBILD IS ONE TABLET TAKEN ORALLY ONCE DAILY WITH FOOD [SEE CLINICAL PHARMACOLOGY].
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 MINUTE DURING TREATMENT WITH STRIBILD, AS THE DOSE INTERVAL ADJUSTMENT REQUIRED FOR EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE (DF) CANNOT BE ACHIEVED [SEE WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, USE IN SPECIFIC POPULATIONS, CLINICAL PHARMACOLOGY, AND CLINICAL STUDIES].
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 AND CLINICAL PHARMACOLOGY].
TESTING PRIOR TO INITIATION OF STRIBILD
PRIOR TO INITIATION OF STRIBILD, PATIENTS SHOULD BE TESTED FOR HEPATITIS B INFECTION [SEE WARNINGS AND PRECAUTIONS] AND ESTIMATED CREATININE CLEARANCE, URINE GLUCOSE AND URINE PROTEIN SHOULD BE DOCUMENTED IN ALL PATIENTS [SEE WARNINGS AND PRECAUTIONS].
SIDE EFFECTS
THE FOLLOWING ADVERSE DRUG REACTIONS ARE DISCUSSED IN OTHER SECTIONS OF THE LABELING:
" LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS [SEE BOXED WARNING, WARNINGS AND PRECAUTIONS].
" SEVERE ACUTE EXACERBATIONS OF HEPATITIS B [SEE BOXED WARNING, WARNINGS AND PRECAUTIONS].
" NEW ONSET OR WORSENING RENAL IMPAIRMENT [SEE WARNINGS AND PRECAUTIONS].
" BONE EFFECTS OF TENOFOVIR DF [SEE WARNINGS AND PRECAUTIONS].
" IMMUNE RECONSTITUTION SYNDROME [SEE WARNINGS AND PRECAUTIONS].
ADVERSE REACTIONS FROM CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
IN HIV-1-INFECTED SUBJECTS WITH NO ANTIRETROVIRAL TREATMENT HISTORY
THE SAFETY ASSESSMENT OF STRIBILD IS BASED ON THE WEEK 144 POOLED DATA FROM 1408 SUBJECTS IN TWO RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIALS, STUDY 102 AND STUDY 103, IN ANTIRETROVIRAL TREATMENT-NAÏVE HIV-1 INFECTED ADULT SUBJECTS [SEE CLINICAL STUDIES]. A TOTAL OF 701 SUBJECTS RECEIVED STRIBILD ONCE DAILY IN THESE TWO STUDIES.
THE PROPORTION OF SUBJECTS WHO DISCONTINUED TREATMENT WITH STRIBILD (ELVITEGRAVIR 150 MG/COBICISTAT 150 MG/EMTRICITABINE 200 MG/TENOFOVIR DF 300 MG); ATRIPLA (EFAVIRENZ 600 MG/EMTRICITABINE 200 MG/TENOFOVIR DF 300 MG); OR ATAZANAVIR (ATV) + RITONAVIR (RTV) + TRUVADA (EMTRICITABINE 200 MG/TENOFOVIR DF 300 MG) DUE TO ADVERSE EVENTS, REGARDLESS OF SEVERITY, WAS 6.0%, 7.4% AND 8.5%, RESPECTIVELY. STRIBILD DISPLAYS THE FREQUENCY OF ADVERSE DRUG REACTIONS GREATER THAN OR EQUAL TO 5% OF SUBJECTS IN ANY TREATMENT ARM.
STRIBILD : ADVERSE DRUG REACTIONSA (ALL GRADES) REPORTED IN ? 5% OF SUBJECTS IN ANY TREATMENT ARM IN STUDIES 102 AND 103 (WEEK 144 ANALYSIS).
STRIBILD
N=701 ATRIPLA
N=352 ATV + RTV + TRUVADA
N=355
EYE DISORDERS
OCULAR ICTERUS < 1% 0% 13%
GASTROINTESTINAL DISORDERS
DIARRHEA 12% 11% 17%
FLATULENCE 2% < 1% 8%
NAUSEA 16% 9% 14%
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
FATIGUE 4% 8% 6%
HEPATOBILIARY DISORDERS
JAUNDICE 0% < 1% 9%
NERVOUS SYSTEM DISORDERS
SOMNOLENCE 1% 7% 1%
HEADACHE 7% 4% 6%
DIZZINESS 3% 21% 5%
PSYCHIATRIC DISORDERS
INSOMNIA 3% 9% 1%
ABNORMAL DREAMS 9% 27% 4%
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
RASHB 4% 15% 6%
A FREQUENCIES OF ADVERSE REACTIONS ARE BASED ON ALL TREATMENT-EMERGENT ADVERSE EVENTS, ATTRIBUTED TO STUDY DRUGS.
B RASH EVENT INCLUDES DERMATITIS, DRUG ERUPTION, ECZEMA, PRURITUS, PRURITUS GENERALIZED, RASH, RASH ERYTHEMATOUS, RASH GENERALIZED, RASH MACULAR, RASH MACULO-PAPULAR, RASH MORBILLIFORM, RASH PAPULAR, RASH PRURITIC, AND URTICARIA.
SEE WARNINGS AND PRECAUTIONS, FOR A DISCUSSION OF RENAL ADVERSE REACTIONS FROM CLINICAL TRIALS EXPERIENCE WITH STRIBILD.
ADDITIONAL ADVERSE DRUG REACTIONS OBSERVED WITH STRIBILD INCLUDED SUICIDAL IDEATION AND SUICIDE ATTEMPT (0.3%), ALL IN SUBJECTS WITH A PRE-EXISTING HISTORY OF DEPRESSION OR PSYCHIATRIC ILLNESS.
IN VIROLOGICALLY-SUPPRESSED HIV-1-INFECTED SUBJECTS
NO NEW ADVERSE REACTIONS TO STRIBILD THROUGH WEEK 48 WERE IDENTIFIED IN 584 VIROLOGICALLY STABLY SUPPRESSED SUBJECTS SWITCHING TO STRIBILD FROM A REGIMEN CONTAINING A RTV-BOOSTED PROTEASE INHIBITOR (PI) OR A NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI). IN A COMBINED ANALYSIS OF STUDIES 115 AND 121, THE FREQUENCY OF ADVERSE REACTIONS (ALL GRADES) WAS 24% IN SUBJECTS SWITCHING TO STRIBILD COMPARED TO 6% OF SUBJECTS IN EITHER GROUP WHO STAYED ON THEIR BASELINE ANTIRETROVIRAL REGIMEN, RTV-BOOSTED PI + TRUVADA OR NNRTI + TRUVADA. COMMON ADVERSE REACTIONS THAT OCCURRED IN GREATER THAN OR EQUAL TO 2% OF SUBJECTS SWITCHING TO STRIBILD WERE NAUSEA (4%), FLATULENCE (2%), AND HEADACHE (2%). THE PROPORTION OF SUBJECTS WHO DISCONTINUED TREATMENT WITH STRIBILD, THE RTV-BOOSTED PI, OR THE NNRTI DUE TO ADVERSE EVENTS, WAS 2%, 3% AND 1%, RESPECTIVELY.
ADVERSE REACTIONS FROM CLINICAL TRIALS OF THE COMPONENTS OF STRIBILD
EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE: IN ADDITION TO THE ADVERSE REACTIONS OBSERVED WITH STRIBILD, THE FOLLOWING ADVERSE REACTIONS OCCURRED IN AT LEAST 5% OF TREATMENT-EXPERIENCED OR TREATMENT-NAÏVE SUBJECTS RECEIVING EMTRICITABINE OR TENOFOVIR DF WITH OTHER ANTIRETROVIRAL AGENTS IN OTHER CLINICAL TRIALS: DEPRESSION, ABDOMINAL PAIN, DYSPEPSIA, VOMITING, FEVER, PAIN, NASOPHARYNGITIS, PNEUMONIA, SINUSITIS, UPPER RESPIRATORY TRACT INFECTION, ARTHRALGIA, BACK PAIN, MYALGIA, PARESTHESIA, PERIPHERAL NEUROPATHY (INCLUDING PERIPHERAL NEURITIS AND NEUROPATHY), ANXIETY, INCREASED COUGH, AND RHINITIS.
SKIN DISCOLORATION HAS BEEN REPORTED WITH HIGHER FREQUENCY AMONG EMTRICITABINE-TREATED SUBJECTS; IT WAS MANIFESTED BY HYPERPIGMENTATION ON THE PALMS AND/OR SOLES AND WAS GENERALLY MILD AND ASYMPTOMATIC. THE MECHANISM AND CLINICAL SIGNIFICANCE ARE UNKNOWN.
LABORATORY ABNORMALITIES
THE FREQUENCY OF LABORATORY ABNORMALITIES (GRADES 3-4) OCCURRING IN AT LEAST 2% OF SUBJECTS RECEIVING STRIBILD IN STUDIES 102 AND 103 ARE PRESENTED IN TABLE 3.
TABLE 3 : LABORATORY ABNORMALITIES (GRADES 3-4) REPORTED IN ? 2% OF SUBJECTS RECEIVING STRIBILD IN STUDIES 102 AND 103 (WEEK 144 ANALYSIS)
STRIBILD ATRIPLA ATV + RTV + TRUVADA
LABORATORY PARAMETER ABNORMALITYA,B N=701 N=352 N=355
AST ( > 5.0 X ULN) 3% 6% 6%
ALT ( > 3.0 X ULN) 2% 5% 4%
AMYLASEA ( > 2.0 X ULN) 3% 3% 5%
CREATINE KINASE ( ? 10.0 X ULN) 8% 15% 11%
URINE RBC (HEMATURIA) ( > 75 RBC/HPF) 4% 2% 4%
A FREQUENCIES ARE BASED ON TREATMENT-EMERGENT LABORATORY ABNORMALITIES.
B FOR SUBJECTS WITH SERUM AMYLASE > 1.5 X UPPER LIMIT OF NORMAL, LIPASE TEST WAS ALSO PERFORMED. THE FREQUENCY OF INCREASED LIPASE (GRADES 3-4) OCCURRING IN STRIBILD (N=69), ATRIPLA (N=40), AND ATV +RTV + TRUVADA (N=38) WAS 17%, 15%, AND 24%, RESPECTIVELY.
IN STUDY 103, BMD WAS ASSESSED BY DEXA IN A NON-RANDOM SUBSET OF 120 SUBJECTS (STRIBILD GROUP N = 54; ATV + RTV + TRUVADA GROUP N = 66). MEAN PERCENTAGE DECREASES IN BMD FROM BASELINE TO WEEK 144 IN THE STRIBILD GROUP WERE COMPARABLE TO THE ATV + RTV + TRUVADA GROUP AT THE LUMBAR SPINE (-1.43% VERSUS -3.68%, RESPECTIVELY) AND AT THE HIP (-2.83% VERSUS -3.77%, RESPECTIVELY). IN STUDIES 102 AND 103, BONE FRACTURES OCCURRED IN 27 SUBJECTS (3.9%) IN THE STRIBILD GROUP, 8 SUBJECTS (2.3%) IN THE ATRIPLA GROUP, AND 19 SUBJECTS (5.4%) IN THE ATV + RTV + TRUVADA GROUP. THESE FINDINGS WERE CONSISTENT WITH DATA FROM AN EARLIER 144-WEEK TRIAL OF TREATMENT-NAÏVE SUBJECTS RECEIVING TENOFOVIR DF + LAMIVUDINE + EFAVIRENZ.
PROTEINURIA (ALL GRADES) OCCURRED IN 52% OF SUBJECTS RECEIVING STRIBILD, 41% OF SUBJECTS RECEIVING ATRIPLA, AND 42% OF SUBJECTS RECEIVING ATV + RTV + TRUVADA.
THE COBICISTAT COMPONENT OF STRIBILD HAS BEEN SHOWN TO INCREASE SERUM CREATININE AND DECREASE ESTIMATED CREATININE CLEARANCE DUE TO INHIBITION OF TUBULAR SECRETION OF CREATININE WITHOUT AFFECTING RENAL GLOMERULAR FUNCTION. IN STUDIES 102 AND 103, INCREASES IN SERUM CREATININE AND DECREASES IN ESTIMATED CREATININE CLEARANCE OCCURRED EARLY IN TREATMENT WITH STRIBILD, AFTER WHICH THEY STABILIZED. TABLE 4 DISPLAYS THE MEAN CHANGES IN SERUM CREATININE AND EGFR LEVELS AT WEEK 144 AND THE PERCENTAGE OF SUBJECTS WITH ELEVATIONS IN SERUM CREATININE (ALL GRADES).
TABLE 4 : CHANGE FROM BASELINE IN SERUM CREATININE AND EGFR AND INCIDENCE OF ELEVATED SERUM CREATININE (ALL GRADES) IN STUDIES 102 AND 103 AT WEEK 144
STRIBILD
(N=701) ATRIPLA
(N=352) ATV + RTV + TRUVADA
(N=355)
SERUM CREATININE (MG/DL)A 0.14 (± 0.14) 0.01 (± 0.12) 0.09 (± 0.15)
EGFR BY COCKCROFT-GAULT (ML/MINUTE)A -14.0 (± 16.6) -1.9 (± 17.9) -9.8 (± 19.4)
SUBJECTS WITH ELEVATIONS IN SERUM CREATININE (ALL GRADES) (%) 12 2 6
A MEAN CHANGE ±SD
EMTRICITABINE OR TENOFOVIR DF: IN ADDITION TO THE LABORATORY ABNORMALITIES OBSERVED WITH STRIBILD, THE FOLLOWING LABORATORY ABNORMALITIES HAVE BEEN PREVIOUSLY REPORTED IN SUBJECTS TREATED WITH EMTRICITABINE OR TENOFOVIR DF WITH OTHER ANTIRETROVIRAL AGENTS IN OTHER CLINICAL TRIALS: GRADE 3 OR 4 LABORATORY ABNORMALITIES OF ALT (M: GREATER THAN 215 U PER L; F: GREATER THAN 170 U PER L), ALKALINE PHOSPHATASE (GREATER THAN 550 U PER L), BILIRUBIN (GREATER THAN 2.5 X ULN), SERUM GLUCOSE (LESS THAN 40 OR GREATER THAN 250 MG PER DL), GLYCOSURIA (GREATER THAN OR EQUAL TO 3+), NEUTROPHILS (LESS THAN 750 PER MM³), FASTING CHOLESTEROL (GREATER THAN 240 MG PER DL), AND FASTING TRIGLYCERIDES (GREATER THAN 750 MG PER DL).
SERUM LIPIDS: IN THE CLINICAL TRIALS OF STRIBILD, A SIMILAR PERCENTAGE OF SUBJECTS RECEIVING STRIBILD, ATRIPLA, AND ATV + RTV + TRUVADA WERE ON LIPID LOWERING AGENTS AT BASELINE (12%, 12%, AND 13%, RESPECTIVELY). WHILE RECEIVING STUDY DRUG THROUGH WEEK 144, AN ADDITIONAL 11% OF STRIBILD SUBJECTS WERE STARTED ON LIPID LOWERING AGENTS, COMPARED TO 13% OF ATRIPLA AND 12% OF ATV + RTV + TRUVADA SUBJECTS.
CHANGES FROM BASELINE IN TOTAL CHOLESTEROL, HDL-CHOLESTEROL, LDL-CHOLESTEROL, AND TRIGLYCERIDES ARE PRESENTED IN TABLE 5.
TABLE 5 : LIPID VALUES, MEAN CHANGE FROM BASELINE AT WEEK 144 IN SUBJECTS RECEIVING STRIBILD OR COMPARATOR IN STUDIES 102 AND 103
STRIBILD
N=701 ATRIPLA
N=352 ATV + RTV + TRUVADA
N=355
BASELINE MG/DL WEEK 144 CHANGEA BASELINE MG/DL WEEK 144 CHANGEA BASELINE MG/DL WEEK 144 CHANGEA
TOTAL CHOLESTEROL (FASTED) 166 [N=675] +17 [N=535] 161 [N=343] +22 [N=262] 168 [N=337] +16 [N=243]
HDL- CHOLESTEROL (FASTED) 43 [N=675] +7 [N=535] 43 [N=343] +9 [N=262] 42 [N=335] +7 [N=242]
LDL- CHOLESTEROL (FASTED) 100 [N=675] +15 [N=535] 97 [N=343] +19 [N=262] 101 [N=337] +18 [N=242]
TRIGLYCERIDES (FASTED) 122 [N=675] +12 [N=535] 121 [N=343] +5 [N=262] 132 [N=337] +22 [N=242]
A THE CHANGE FROM BASELINE IS THE MEAN OF WITHIN-PATIENT CHANGES FROM BASELINE FOR PATIENTS WITH BOTH BASELINE AND WEEK 144 VALUES.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST APPROVAL USE OF TENOFOVIR DF. BECAUSE POSTMARKETING REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE. NO ADDITIONAL POSTMARKETING ADVERSE REACTIONS SPECIFIC FOR EMTRICITABINE HAVE BEEN IDENTIFIED.
IMMUNE SYSTEM DISORDERS
ALLERGIC REACTION, INCLUDING ANGIOEDEMA
METABOLISM AND NUTRITION DISORDERS
LACTIC ACIDOSIS, HYPOKALEMIA, HYPOPHOSPHATEMIA
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
DYSPNEA
GASTROINTESTINAL DISORDERS
PANCREATITIS, INCREASED AMYLASE, ABDOMINAL PAIN
HEPATOBILIARY DISORDERS
HEPATIC STEATOSIS, HEPATITIS, INCREASED LIVER ENZYMES (MOST COMMONLY AST, ALT GAMMA GT)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
RASH
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
RHABDOMYOLYSIS, OSTEOMALACIA (MANIFESTED AS BONE PAIN AND WHICH MAY CONTRIBUTE TO FRACTURES), MUSCULAR WEAKNESS, MYOPATHY
RENAL AND URINARY DISORDERS
ACUTE RENAL FAILURE, RENAL FAILURE, ACUTE TUBULAR NECROSIS, FANCONI SYNDROME, PROXIMAL RENAL TUBULOPATHY, INTERSTITIAL NEPHRITIS (INCLUDING ACUTE CASES), NEPHROGENIC DIABETES INSIPIDUS, RENAL INSUFFICIENCY, INCREASED CREATININE, PROTEINURIA, POLYURIA
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
ASTHENIA
THE FOLLOWING ADVERSE REACTIONS, LISTED UNDER THE BODY SYSTEM HEADINGS ABOVE, MAY OCCUR AS A CONSEQUENCE OF PROXIMAL RENAL TUBULOPATHY: RHABDOMYOLYSIS, OSTEOMALACIA, HYPOKALEMIA, MUSCULAR WEAKNESS, MYOPATHY, HYPOPHOSPHATEMIA.
READ THE STRIBILD (ELVITEGRAVIR, COBICISTAT, EMTRICITABINE, TENOFOVIR DF) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
DRUG INTERACTIONS
SEE ALSO CONTRAINDICATIONS 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 SIGNIFICANTA 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 CONCENTRATIONB CLINICAL COMMENT
ACID REDUCING AGENTS: ANTACIDS* (FOR EXAMPLE ALUMINUM AND MAGNESIUM HYDROXIDE) ?ELVITEGRAVIR 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 CAUTION IS WARRANTED AND THERAPEUTIC CONCENTRATION MONITORING, IF AVAILABLE, IS RECOMMENDED FOR ANTIARRHYTHMICS WHEN COADMINISTERED WITH STRIBILD.
ANTIBACTERIALS: CLARITHROMYCIN ?CLARITHROMYCIN
?COBICISTAT PATIENTS WITH CLCR GREATER THAN OR EQUAL TO 60 ML/MINUTE:
NO DOSE ADJUSTMENT OF CLARITHROMYCIN IS REQUIRED.
PATIENTS WITH CLCR BETWEEN 50 ML/MINUTE AND 60ML/MINUTE:
THE DOSE OF CLARITHROMYCIN SHOULD BE REDUCED BY 50%.
ANTICOAGULANTS: WARFARIN EFFECT ON WARFARIN UNKNOWN MONITOR INTERNATIONAL NORMALIZED RATIO (INR) UPON COADMINISTRATION OF WARFARIN WITH STRIBILD.
ANTICONVULSANTS: OXCARBAZEPINE
CLONAZEPAM
ETHOSUXIMIDE ?ELVITEGRAVIR
?COBICISTAT
?CLONAZEPAM
? ETHOSUXIMIDE ALTERNATIVE ANTICONVULSANTS SHOULD BE CONSIDERED WHEN STRIBILD IS COADMINISTERED WITH OXCARBAZEPINE. CLINICAL MONITORING IS RECOMMENDED UPON COADMINISTRATION OF CLONAZEPAM OR ETHOSUXIMIDE WITH STRIBILD.
ANTIDEPRESSANTS: SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) E.G., PAROXETINE TRICYCLIC ANTIDEPRESSANTS (TCAS) E.G., AMITRIPTYLINE
DESIPRAMINE
IMIPRAMINE
NORTRIPTYLINE
BUPROPION
TRAZODONE ? SSRIS
? TCAS
?TRAZODONE CAREFUL DOSE TITRATION OF THE ANTIDEPRESSANT AND MONITORING FOR ANTIDEPRESSANT RESPONSE ARE RECOMMENDED WHEN COADMINISTERED WITH STRIBILD.
ANTIFUNGALS:
ITRACONAZOLE
KETOCONAZOLE*
VORICONAZOLE ?ELVITEGRAVIR
?COBICISTAT
? ITRACONAZOLE
?KETOCONAZOLE
? TVORICONAZOLE WHEN COADMINISTERED 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) X 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 STRIBILD WITH RIFABUTIN OR RIFAPENTINE IS NOT RECOMMENDED.
BETA-BLOCKERS: E.G., METOPROLOL
TIMOLOL ?BETA-BLOCKERS 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 CAUTION IS WARRANTED AND CLINICAL MONITORING IS RECOMMENDED UPON COADMINISTRATION OF CALCIUM CHANNEL BLOCKERS WITH STRIBILD.
CORTICOSTEROID: SYSTEMIC: DEXAMETHASONE ? ELVITEGRAVIR
?COBICISTAT ALTERNATIVE CORTICOSTEROIDS SHOULD BE CONSIDERED.
CORTICOSTEROID: INHALED/NASAL: FLUTICASONE ?FLUTICASONE CONCOMITANT USE OF STRIBILD WITH INHALED OR NASAL FLUTICASONE MAY REDUCE 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 ?IMMUNOSUPPRESSANTS THERAPEUTIC MONITORING OF THE IMMUNOSUPPRESSIVE AGENTS IS RECOMMENDED UPON COADMINISTRATION WITH STRIBILD.
NARCOTIC ANALGESICS: BUPRENORPHINE/ NALOXONE* ? BUPRENORPHINE
?NORBUPRENORPHINE
? NALOXONE 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 BECAUSE IT 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 (PDE-5) INHIBITORS: SILDENAFIL
TADALAFIL
VARDENAFIL ?PDE-5 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 TADALAFIL FOR PULMONARY ARTERIAL HYPERTENSION (PAH):
" 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: THE BELOW PDE-5 INHIBITORS CAN BE USED ALONG WITH INCREASED MONITORING FOR PDE-5 INHIBITOR ASSOCIATED WITH ADVERSE EVENTS:
" SILDENAFIL AT A SINGLE DOSE NOT EXCEEDING 25 MG IN 48 HOURS OR,
" TADALAFIL AT A SINGLE DOSE NOT EXCEEDING 10 MG IN 72 HOURS, OR
" VARDENAFIL AT A SINGLE DOSE NOT EXCEEDING 2.5 MG IN 72 HOURS
SEDATIVE/HYPNOTICS: BENZODIAZEPINES: E.G., PARENTERALLY ADMINISTERED MIDAZOLAM
CLORAZEPATE
DIAZEPAM
ESTAZOLAM
FLURAZEPAM
BUSPIRONE
ZOLPIDEM ? SEDATIVES/HYPNOTICS COADMINISTRATION OF PARENTERAL MIDAZOLAM WITH STRIBILD 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. WITH OTHER SEDATIVE/HYPNOTICS, DOSE REDUCTION MAY BE NECESSARY AND CLINICAL MONITORING IS RECOMMENDED.
* INDICATES THAT A DRUG-DRUG INTERACTION TRIAL WAS CONDUCTED.
A THIS TABLE IS NOT ALL INCLUSIVE.
B ?= INCREASE, ? = DECREASE, ? = NO EFFECT
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.
READ THE STRIBILD DRUG INTERACTIONS CENTER FOR A COMPLETE GUIDE TO POSSIBLE INTERACTIONS
PRECAUTIONS
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).
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.
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].
IN THE CLINICAL TRIALS OF STRIBILD OVER 144 WEEKS, 13 (1.9%) SUBJECTS IN THE STRIBILD GROUP (N=701), 8 (2.3%) SUBJECTS IN THE ATV + RTV + TRUVADA GROUP (N=355) AND NO SUBJECTS IN THE ATRIPLA GROUP (N = 352) DISCONTINUED STUDY DRUG DUE TO A RENAL ADVERSE REACTION. OF THESE DISCONTINUATIONS, 8 IN THE STRIBILD GROUP AND 1 IN THE ATV + RTV + TRUVADA GROUP OCCURRED DURING THE FIRST 48 WEEKS. FOUR (0.6%) SUBJECTS WHO RECEIVED STRIBILD DEVELOPED LABORATORY FINDINGS CONSISTENT WITH PROXIMAL RENAL TUBULAR DYSFUNCTION LEADING TO DISCONTINUATION OF STRIBILD DURING THE FIRST 48 WEEKS OF TREATMENT. TWO OF THE 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 IMPROVED BUT DID NOT COMPLETELY RESOLVE IN ALL SUBJECTS UPON DISCONTINUATION OF STRIBILD. RENAL REPLACEMENT THERAPY WAS NOT REQUIRED FOR THESE SUBJECTS. ONE (0.3%) SUBJECT WHO RECEIVED ATV + RTV + TRUVADA DEVELOPED LABORATORY FINDINGS CONSISTENT WITH PROXIMAL RENAL TUBULAR DYSFUNCTION LEADING TO DISCONTINUATION OF ATV + RTV + TRUVADA AFTER WEEK 96.
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]. 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.
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.
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], 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.
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:
" COBICISTAT (TYBOST);
" ELVITEGRAVIR (VITEKTA);
" PRODUCTS CONTAINING EMTRICITABINE OR TENOFOVIR DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD);
" PRODUCTS CONTAINING LAMIVUDINE (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIUMEQ, TRIZIVIR);
" ADEFOVIR DIPIVOXIL (HEPSERA);
" PRODUCTS CONTAINING RITONAVIR (NORVIR, KALETRA)
RISK OF ADVERSE REACTIONS OR LOSS OF VIROLOGIC RESPONSE DUE TO DRUG INTERACTIONS
THE CONCOMITANT USE OF STRIBILD AND OTHER DRUGS MAY RESULT IN KNOWN OR POTENTIALLY SIGNIFICANT DRUG INTERACTIONS, SOME OF WHICH MAY LEAD TO [SEE CONTRAINDICATIONS, DRUG INTERACTIONS]:
" LOSS OF THERAPEUTIC EFFECT OF STRIBILD AND POSSIBLE DEVELOPMENT OF RESISTANCE.
" POSSIBLE CLINICALLY SIGNIFICANT ADVERSE REACTIONS FROM GREATER EXPOSURES OF CONCOMITANT DRUGS.
SEE TABLE 6 FOR STEPS TO PREVENT OR MANAGE THESE POSSIBLE AND KNOWN SIGNIFICANT DRUG INTERACTIONS, INCLUDING DOSING RECOMMENDATIONS [SEE DRUG INTERACTIONS]. CONSIDER THE POTENTIAL FOR DRUG INTERACTIONS PRIOR TO AND DURING STRIBILD THERAPY; REVIEW CONCOMITANT MEDICATIONS DURING STRIBILD THERAPY; AND MONITOR FOR THE ADVERSE REACTIONS ASSOCIATED WITH THE CONCOMITANT DRUGS.
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 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]. 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 NEW ONSET OR WORSENING RENAL IMPAIRMENT].
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.
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.
PATIENT COUNSELING INFORMATION
ADVISE THE PATIENT TO READ THE 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.
o DO NOT SHARE NEEDLES OR OTHER INJECTION EQUIPMENT.
o DO NOT SHARE PERSONAL ITEMS THAT CAN HAVE BLOOD OR BODY FLUIDS ON THEM, LIKE TOOTHBRUSHES AND RAZOR BLADES.
o 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.
o 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.
o IT IS IMPORTANT TO TAKE STRIBILD ON A REGULAR DOSING SCHEDULE WITH FOOD AND TO AVOID MISSING DOSES.
o 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].
" 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]. 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].
" 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 AND DRUG INTERACTIONS].
" STRIBILD SHOULD NOT BE ADMINISTERED IN COMBINATION WITH ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, TYBOST, VIREAD, OR VITEKTA; WITH DRUGS CONTAINING LAMIVUDINE, INCLUDING COMBIVIR, EPIVIR OR EPIVIR-HBV, EPZICOM, TRIUMEQ, OR TRIZIVIR; WITH DRUGS CONTAINING RTV OR REGIMENS CONTAINING RTV; OR WITH HEPSERA [SEE WARNINGS AND PRECAUTIONS].
" 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].
" 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].
" 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].
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
ELVITEGRAVIR: LONG-TERM CARCINOGENICITY STUDIES OF ELVITEGRAVIR WERE CARRIED OUT IN MICE (104 WEEKS) AND IN RATS FOR UP TO 88 WEEKS (MALES) AND 90 WEEKS (FEMALES). NO DRUG-RELATED INCREASES IN TUMOR INCIDENCE WERE FOUND IN MICE AT DOSES UP TO 2000 MG PER KG PER DAY ALONE OR IN COMBINATION WITH 25 MG PER KG PER DAY RTV AT EXPOSURES 3- AND 14-FOLD, RESPECTIVELY, THE HUMAN SYSTEMIC EXPOSURE AT THE RECOMMENDED DAILY DOSE OF 150 MG. NO DRUG-RELATED INCREASES IN TUMOR INCIDENCE WERE FOUND IN RATS AT DOSES UP TO 2000 MG PER KG PER DAY AT EXPOSURES 12- TO 27-FOLD, RESPECTIVELY IN MALE AND FEMALE, THE HUMAN SYSTEMIC EXPOSURE.
ELVITEGRAVIR WAS NOT GENOTOXIC IN THE REVERSE MUTATION BACTERIAL TEST (AMES TEST) AND THE RAT MICRONUCLEUS ASSAY. IN AN IN VITRO CHROMOSOMAL ABERRATION TEST, ELVITEGRAVIR WAS NEGATIVE WITH METABOLIC ACTIVATION; HOWEVER, AN EQUIVOCAL RESPONSE WAS OBSERVED WITHOUT ACTIVATION.
ELVITEGRAVIR DID NOT AFFECT FERTILITY IN MALE AND FEMALE RATS AT APPROXIMATELY 16- AND 30-FOLD HIGHER EXPOSURES (AUC), RESPECTIVELY, THAN IN HUMANS AT THE THERAPEUTIC 150 MG DAILY DOSE.
FERTILITY WAS NORMAL IN THE OFFSPRING OF RATS EXPOSED DAILY FROM BEFORE BIRTH (IN UTERO) THROUGH SEXUAL MATURITY AT DAILY EXPOSURES (AUC) OF APPROXIMATELY 18-FOLD HIGHER THAN HUMAN EXPOSURES AT THE RECOMMENDED 150 MG DAILY DOSE.
COBICISTAT: IN A LONG-TERM CARCINOGENICITY STUDY IN MICE, NO DRUG-RELATED INCREASES IN TUMOR INCIDENCE WERE OBSERVED AT DOSES UP TO 50 AND 100 MG/KG/DAY (MALES AND FEMALES, RESPECTIVELY). COBICISTAT EXPOSURES AT THESE DOSES WERE APPROXIMATELY 7 (MALE) AND 16 (FEMALES) TIMES, RESPECTIVELY, THE HUMAN SYSTEMIC EXPOSURE AT THE THERAPEUTIC DAILY DOSE. IN A LONG-TERM CARCINOGENICITY STUDY OF COBICISTAT IN RATS, AN INCREASED INCIDENCE OF FOLLICULAR CELL ADENOMAS AND/OR CARCINOMAS IN THE THYROID GLAND WAS OBSERVED AT DOSES OF 25 AND 50 MG/KG/DAY IN MALES, AND AT 30 MG/KG/DAY IN FEMALES. THE FOLLICULAR CELL FINDINGS ARE CONSIDERED TO BE RAT-SPECIFIC, SECONDARY TO HEPATIC MICROSOMAL ENZYME INDUCTION AND THYROID HORMONE IMBALANCE, AND ARE NOT RELEVANT FOR HUMANS. AT THE HIGHEST DOSES TESTED IN THE RAT CARCINOGENICITY STUDY, SYSTEMIC EXPOSURES WERE APPROXIMATELY 2 TIMES THE HUMAN SYSTEMIC EXPOSURE AT THE THERAPEUTIC DAILY DOSE.
COBICISTAT WAS NOT GENOTOXIC IN THE REVERSE MUTATION BACTERIAL TEST (AMES TEST), MOUSE LYMPHOMA OR RAT MICRONUCLEUS ASSAYS.
COBICISTAT DID NOT AFFECT FERTILITY IN MALE OR FEMALE RATS AT DAILY EXPOSURES (AUC) APPROXIMATELY 4-FOLD HIGHER THAN HUMAN EXPOSURES AT THE RECOMMENDED 150 MG DAILY DOSE.38
FERTILITY WAS NORMAL IN THE OFFSPRING OF RATS EXPOSED DAILY FROM BEFORE BIRTH (IN UTERO) THROUGH SEXUAL MATURITY AT DAILY EXPOSURES (AUC) OF APPROXIMATELY 1.2-FOLD HIGHER THAN HUMAN EXPOSURES AT THE RECOMMENDED 150 MG DAILY DOSE.
EMTRICITABINE: IN LONG-TERM CARCINOGENICITY STUDIES OF EMTRICITABINE, NO DRUG-RELATED INCREASES IN TUMOR INCIDENCE WERE FOUND IN MICE AT DOSES UP TO 750 MG PER KG PER DAY (23 TIMES THE HUMAN SYSTEMIC EXPOSURE AT THE THERAPEUTIC DOSE OF 200 MG PER DAY) OR IN RATS AT DOSES UP TO 600 MG PER KG PER DAY (28 TIMES THE HUMAN SYSTEMIC EXPOSURE AT THE THERAPEUTIC DOSE).
EMTRICITABINE WAS NOT GENOTOXIC IN THE REVERSE MUTATION BACTERIAL TEST (AMES TEST), MOUSE LYMPHOMA OR MOUSE MICRONUCLEUS ASSAYS.
EMTRICITABINE DID NOT AFFECT FERTILITY IN MALE RATS AT APPROXIMATELY 140-FOLD OR IN MALE AND FEMALE MICE AT APPROXIMATELY 60-FOLD HIGHER EXPOSURES (AUC) THAN IN HUMANS GIVEN THE RECOMMENDED 200 MG DAILY DOSE. FERTILITY WAS NORMAL IN THE OFFSPRING OF MICE EXPOSED DAILY FROM BEFORE BIRTH (IN UTERO) THROUGH SEXUAL MATURITY AT DAILY EXPOSURES (AUC) OF APPROXIMATELY 60-FOLD HIGHER THAN HUMAN EXPOSURES AT THE RECOMMENDED 200 MG DAILY DOSE.
TENOFOVIR DISOPROXIL FUMARATE: LONG-TERM ORAL CARCINOGENICITY STUDIES OF TENOFOVIR DF IN MICE AND RATS WERE CARRIED OUT AT EXPOSURES UP TO APPROXIMATELY 10 TIMES (MICE) AND 4 TIMES (RATS) THOSE OBSERVED IN HUMANS AT THE THERAPEUTIC DOSE FOR HIV-1 INFECTION. AT THE HIGH DOSE IN FEMALE MICE, LIVER ADENOMAS WERE INCREASED AT EXPOSURES 10 TIMES OF THAT IN HUMANS. IN RATS, THE STUDY WAS NEGATIVE FOR CARCINOGENIC FINDINGS AT EXPOSURES UP TO 4 TIMES THAT OBSERVED IN HUMANS AT THE THERAPEUTIC DOSE.
TENOFOVIR DF WAS MUTAGENIC IN THE IN VITRO MOUSE LYMPHOMA ASSAY AND NEGATIVE IN AN IN VITRO BACTERIAL MUTAGENICITY TEST (AMES TEST). IN AN IN VIVO MOUSE MICRONUCLEUS ASSAY, TENOFOVIR DF WAS NEGATIVE WHEN ADMINISTERED TO MALE MICE.
THERE WERE NO EFFECTS ON FERTILITY, MATING PERFORMANCE OR EARLY EMBRYONIC DEVELOPMENT WHEN TENOFOVIR DF WAS ADMINISTERED TO MALE RATS AT A DOSE EQUIVALENT TO 10 TIMES THE HUMAN DOSE BASED ON BODY SURFACE AREA COMPARISONS FOR 28 DAYS PRIOR TO MATING AND TO FEMALE RATS FOR 15 DAYS PRIOR TO MATING THROUGH DAY SEVEN OF GESTATION. THERE WAS, HOWEVER, AN ALTERATION OF THE ESTROUS CYCLE IN FEMALE RATS.
USE IN SPECIFIC POPULATIONS
PREGNANCY
PREGNANCY CATEGORY B
THERE ARE NO ADEQUATE AND WELL-CONTROLLED STUDIES IN PREGNANT WOMEN. BECAUSE ANIMAL REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE, STRIBILD SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENEFIT JUSTIFIES THE POTENTIAL RISK TO THE FETUS.
ANTIRETROVIRAL PREGNANCY REGISTRY
TO MONITOR FETAL OUTCOMES OF PREGNANT WOMEN EXPOSED TO STRIBILD, AN ANTIRETROVIRAL PREGNANCY REGISTRY HAS BEEN ESTABLISHED. HEALTHCARE PROVIDERS ARE ENCOURAGED TO REGISTER PATIENTS BY CALLING 1-800-258-4263.
ANIMAL DATA
ELVITEGRAVIR: STUDIES IN ANIMALS HAVE SHOWN NO EVIDENCE OF TERATOGENICITY OR AN EFFECT ON REPRODUCTIVE FUNCTION. IN OFFSPRING FROM RAT AND RABBIT DAMS TREATED WITH ELVITEGRAVIR DURING PREGNANCY, THERE WERE NO TOXICOLOGICALLY SIGNIFICANT EFFECTS ON DEVELOPMENTAL ENDPOINTS. THE EXPOSURES (AUC) AT THE EMBRYO-FETAL NO OBSERVED ADVERSE EFFECTS LEVELS (NOAELS) IN RATS AND RABBITS WERE RESPECTIVELY 23 AND 0.2 TIMES HIGHER THAN THE EXPOSURE IN HUMANS AT THE RECOMMENDED DAILY DOSE OF 150 MG.
COBICISTAT: STUDIES IN ANIMALS HAVE SHOWN NO EVIDENCE OF TERATOGENICITY OR AN EFFECT ON REPRODUCTIVE FUNCTION. IN OFFSPRING FROM RAT AND RABBIT DAMS TREATED WITH COBICISTAT DURING PREGNANCY, THERE WERE NO TOXICOLOGICALLY SIGNIFICANT EFFECTS ON DEVELOPMENTAL ENDPOINTS. THE EXPOSURES (AUC) AT THE EMBRYO-FETAL NOAELS IN RATS AND RABBITS WERE RESPECTIVELY 1.8 AND 4.3 TIMES HIGHER THAN THE EXPOSURE IN HUMANS AT THE RECOMMENDED DAILY DOSE OF 150 MG.
EMTRICITABINE: THE INCIDENCE OF FETAL VARIATIONS AND MALFORMATIONS WAS NOT INCREASED IN EMBRYO-FETAL TOXICITY STUDIES PERFORMED WITH EMTRICITABINE IN MICE AT EXPOSURES (AUC) APPROXIMATELY 60 TIMES HIGHER AND IN RABBITS AT APPROXIMATELY 120 TIMES HIGHER THAN HUMAN EXPOSURES AT THE RECOMMENDED DAILY DOSE.
TENOFOVIR DF: REPRODUCTION STUDIES HAVE BEEN PERFORMED IN RATS AND RABBITS AT DOSES UP TO 14 AND 19 TIMES THE HUMAN DOSE BASED ON BODY SURFACE AREA COMPARISONS AND REVEALED NO EVIDENCE OF IMPAIRED FERTILITY OR HARM TO THE FETUS DUE TO TENOFOVIR.
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.
PEDIATRIC USE
SAFETY AND EFFECTIVENESS OF STRIBILD IN PEDIATRIC PATIENTS LESS THAN 18 YEARS OF AGE HAVE NOT BEEN ESTABLISHED [SEE CLINICAL PHARMACOLOGY].
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].
RENAL IMPAIRMENT
INITIATION OF STRIBILD IN PATIENTS WITH ESTIMATED CREATININE CLEARANCE BELOW 70 ML PER MIN IS NOT RECOMMENDED. BECAUSE STRIBILD IS A FIXED-DOSE COMBINATION TABLET, STRIBILD SHOULD BE DISCONTINUED IF ESTIMATED CREATININE CLEARANCE DECLINES BELOW 50 ML PER MINUTE DURING TREATMENT WITH STRIBILD AS DOSE INTERVAL ADJUSTMENT REQUIRED FOR EMTRICITABINE AND TENOFOVIR DF CANNOT BE ACHIEVED [SEE WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, AND CLINICAL STUDIES].
CLINICAL TRIALS IN SUBJECTS WITH MILD TO MODERATE RENAL IMPAIRMENT
IN STUDY 118, 33 HIV-1 INFECTED TREATMENT NAÏVE SUBJECTS WITH MILD TO MODERATE RENAL IMPAIRMENT (EGFR BY COCKCROFT-GAULT METHOD BETWEEN 50 AND 89 ML/MINUTE) WERE STUDIED IN AN OPEN-LABEL CLINICAL TRIAL EVALUATING THE SAFETY OF 48 WEEKS OF TREATMENT WITH STRIBILD. AFTER 48 WEEKS OF TREATMENT, THE MEAN CHANGE IN SERUM CREATININE WAS 0.17 ± 0.14 MG/DL AND THE MEAN CHANGE IN EGFR BY COCKCROFT-GAULT METHOD WAS -6.9 ± 9.0 ML/MINUTE FOR SUBJECTS TREATED WITH STRIBILD.
TWELVE OF THE 33 SUBJECTS STUDIED HAD BASELINE EGFR BETWEEN 50 AND 70 ML/MINUTE. THREE SUBJECTS, ALL WITH BASELINE EGFR BETWEEN 50-60 ML/MINUTE, DISCONTINUED STRIBLD DUE TO A RENAL ADVERSE EVENT. THE SAFETY OF STRIBILD AMONG 21 OF THE 33 SUBJECTS WITH BASELINE EGFR GREATER THAN OR EQUAL TO 70 ML/MINUTE WAS CONSISTENT WITH THE SAFETY PROFILE IN STUDIES 102 AND 103.
HEPATIC IMPAIRMENT
NO DOSE 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 DOSAGE AND ADMINISTRATION AND CLINICAL PHARMACOLOGY].