COBICISTAT: 347 Adverse Event Reports & Safety Profile

GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. EVG is an HIV-1 integrase strand transfer inhibitor. COBI is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (equivalent to 11.2 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing FD&C Blue No. 2/indigo carmine aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. 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 447.88. 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 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3 R ,6 R ,9 S )-. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.02. It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.

Chemical Structure

Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2 R -hydroxymethyl-1,3-oxathiolan-5 S -yl)-(1 H )-pyrimidin-2-one. 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 247.24. It has the following structural formula: Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Chemical Structure

Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[( S )-[[(1 R )-2-(6-amino-9 H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2 E )-2-butenedioate (2:1). It has an empirical formula of C 21 H 29 O 5 N 6 P∙½(C 4 H 4 O 4 ) and a formula weight of 534.5. It has the following structural formula: Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

Chemical

Structure

AND USAGE TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 14 kg. ( 1.1 ) Limitations of Use : TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir. ( 1.2 , 5.4 ) Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions. TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. ( 1.2 , 5.3 , 7 , 12.3 )

1.1 Indications Adult Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>.

Pediatric

Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients weighing at least 14 kg [see Dosage and Administration (2.2) , and Drug Interactions (7.3) ].

1.2 Limitations of Use TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions. TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]</span>.

AND ADMINISTRATION TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents. ( 2.1 , 2.2 ) Recommended dosage in adults: ( 2.1 )

Adult Patient Populations Coadministered Agent

Dosage TYBOST Dosage Treatment-naïve or treatment-experienced atazanavir 300 mg orally once daily 150 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions darunavir 800 mg orally once daily Recommended dosage in pediatric patients: TYBOST 150 mg or TYBOST 90 mg orally once daily based on body weight. For dosage recommendations for TYBOST and the coadministered protease inhibitor atazanavir or darunavir in pediatric patients, refer to Table 2 and Table 3 of the full prescribing information respectively. ( 2.2 ) Prior to starting TYBOST, assess estimated creatinine clearance. ( 2.3 ) Coadministration with tenofovir disoproxil fumarate (TDF): assess estimated creatinine clearance, urine glucose, and urine protein at baseline. ( 2.3 ) TYBOST coadministered with TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST. ( 2.4 )

2.1 Recommended Dosage in Adults Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1 . TYBOST must be coadministered at the same time as atazanavir or darunavir <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Consult the prescribing information for atazanavir or darunavir.

Table

1 Recommended Dosing Regimens in Treatment-Naïve or Treatment-Experienced Adults Patient Populations Coadministered Agent Dosage TYBOST Dosage Treatment-naïve or treatment-experienced atazanavir 300 mg orally once daily 150 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions darunavir 800 mg orally once daily

2.2 Recommended Dosage in Pediatric Patients Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of pediatric patients with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are based on weight and presented in Table 2 and Table 3 , respectively. TYBOST must be coadministered at the same time as atazanavir or darunavir <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Consult the prescribing information for atazanavir or darunavir.

Table

2 Recommended Dosing Regimen in Treatment-Naïve or Treatment-Experienced Pediatric Patients in Combination with Atazanavir Body Weight Atazanavir Dosage TYBOST Dosage Weighing at least 14 kg to less than 25 kg 200 mg orally once daily 90 mg orally once daily Weighing at least 25 kg to less than 35 kg 200 mg orally once daily 150 mg orally once daily Weighing at least 35 kg 300 mg orally once daily Table 3 Recommended Dosing Regimen in Treatment-Naïve or Treatment-Experienced Pediatric Patients with no Darunavir Resistance-Associated Substitutions in Combination with Darunavir Body Weight Darunavir Dosage TYBOST Dosage Weighing at least 15 kg to less than 25 kg 600 mg orally once daily 90 mg orally once daily Weighing at least 25 kg to less than 30 kg 600 mg orally once daily 150 mg orally once daily Weighing at least 30 kg to less than 40 kg 675 mg orally once daily Weighing at least 40 kg 800 mg orally once daily

2.3 Testing Prior to Initiation of TYBOST Prior to or when initiating TYBOST and during treatment with TYBOST, on a clinically appropriate schedule, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. When coadministering TYBOST with TDF, assess estimated creatinine clearance, urine glucose, and urine protein at baseline. In patients with chronic kidney disease, also assess serum phosphorus <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

2.4 Renal Impairment TYBOST coadministered with TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ]</span> .

2.5 Not Recommended During Pregnancy TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ]</span> . TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ]</span> . TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.

4.

Contraindications

Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of SYMTUZA with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance. Examples of drugs that are contraindicated for co-administration with SYMTUZA due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.5) ] are listed below.

Alpha

1-adrenoreceptor antagonist: alfuzosin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine Herbal product: St. John's wort ( Hypericum perforatum ) Hepatitis C direct acting antiviral: elbasvir/grazoprevir Lipid modifying agents: lomitapide, lovastatin, simvastatin Opioid Antagonist: naloxegol PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension Sedatives/hypnotics: orally administered midazolam, triazolam SYMTUZA is contraindicated to be co-administered with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. ( 4 )

REACTIONS The following adverse drug reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [see Warnings and Precautions (5.1) ]

Immune Reconstitution

Syndrome [see Warnings and Precautions (5.3) ]

New

Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ]

Lactic Acidosis/Severe

Hepatomegaly with Steatosis [see Warnings and Precautions (5.5) ] Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

Clinical

Trials in Treatment-Naïve Adults The primary safety assessment of GENVOYA was based on Week 144 pooled data from 1,733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of GENVOYA once daily [see Clinical Studies (14.2) ] . The most common adverse reaction (all Grades) reported in at least 10% of subjects in the GENVOYA group was nausea. The proportion of subjects who discontinued treatment with GENVOYA or STRIBILD ® due to adverse events, regardless of severity, was 1% and 2%, respectively.

Table

1 displays the frequency of adverse reactions (all Grades) greater than or equal to 5% in the GENVOYA group.

Table

1 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator. (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment-Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis) GENVOYA N=866 STRIBILD N=867 Nausea 11% 13% Diarrhea 7% 9% Headache 6% 5% Fatigue 5% 4% The majority of events presented in Table 1 occurred at severity Grade 1.

Clinical

Trials in Virologically Suppressed Adults The safety of GENVOYA in virologically-suppressed adults was based on Week 96 data from 959 subjects in a randomized, open-label, active-controlled trial (Study 109) in which virologically-suppressed subjects were switched from a TDF-containing combination regimen to GENVOYA. Overall, the safety profile of GENVOYA in subjects in this study was similar to that of treatment-naïve subjects [see Clinical Studies (14.3) ] . Additional adverse reactions observed with GENVOYA in Study 109 included suicidal ideation, suicidal behavior, and suicide attempt (<1% combined); all of these events were serious and all occurred in subjects with a preexisting history of depression or psychiatric illness.

Clinical

Trials in Adult Subjects with Renal Impairment In an open-label trial (Study 112), 248 HIV-1 infected subjects with estimated creatinine clearance between 30 and 69 mL per minute (by Cockcroft-Gault method) were treated with GENVOYA for a median duration of 144 weeks. Of these subjects, 65% had previously been on a stable TDF-containing regimen. A total of 5 subjects permanently discontinued GENVOYA due to the development of renal adverse events through Week 96. Three of these five were among the 80 subjects with baseline estimated creatinine clearance of less than 50 mL/min and two subjects were among the 162 subjects with baseline estimated creatinine clearance of greater than or equal to 50 mL/min. There were no further renal discontinuations between Weeks 96 and 144. Overall, renally impaired subjects receiving GENVOYA in this study had a mean serum creatinine of 1.5 mg/dL at baseline and 1.4 mg/dL at Week 144. Otherwise, the safety profile of GENVOYA in subjects in this study was similar to that of subjects with normal renal function. Virologically-Suppressed Adults with End Stage Renal Disease (ESRD)

Receiving Chronic Hemodialysis

The safety of GENVOYA in subjects with end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis was assessed in 55 subjects (Study 1825) [see Clinical Studies (14.4) ]. The most commonly reported adverse reaction (adverse event assessed as causally related by investigator and all grades) was nausea (7%). Serious adverse events were reported in 53% of subjects and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%).

Overall

5% of subjects permanently discontinued treatment due to an adverse event.

Renal Laboratory

Tests and Renal Safety Treatment-Naïve Adults: Cobicistat (a component of GENVOYA) has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Clinical Pharmacology (12.2) ] . Increases in serum creatinine occurred by Week 2 of treatment and remained stable through 144 weeks. In two 144-week randomized, controlled trials in a total of 1,733 treatment-naïve adults with a median baseline estimated creatinine clearance of 115 mL per minute, mean serum creatinine increased by less than 0.1 mg per dL in the GENVOYA group and by 0.1 mg per dL in the STRIBILD group from baseline to Week 144.

Virologically Suppressed

Adults: In a study of 1,436 virologically-suppressed TDF-treated adults with a mean baseline estimated creatinine clearance of 112 mL per minute who were randomized to continue their treatment regimen or switch to GENVOYA, at Week 96 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to GENVOYA. Across these trials, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA.

Bone Mineral Density Effects

Treatment-Naïve Adults: In a pooled analysis of Studies 104 and 111, the effects of GENVOYA compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 144 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 144 was −0.92% with GENVOYA compared to −2.95% with STRIBILD at the lumbar spine and −0.75% compared to −3.36% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known.

Virologically Suppressed

Adults: In Study 109, TDF-treated subjects were randomized to continue their TDF-based regimen or switch to GENVOYA; changes in BMD from baseline to Week 96 were assessed by DXA. Mean BMD increased in subjects who switched to GENVOYA (2.12% lumbar spine, 2.44% total hip) and decreased slightly in subjects who continued their baseline regimen (−0.09% lumbar spine, −0.46% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2% of GENVOYA subjects and 6% of subjects who continued their TDF-based regimen. BMD declines of 7% or greater at the femoral neck were experienced by 2% of GENVOYA subjects and 7% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known.

Laboratory

Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving GENVOYA in Studies 104 and 111 are presented in Table 2.

Table

2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)

Laboratory Parameter Abnormality

Frequencies are based on treatment-emergent laboratory abnormalities. GENVOYA N=866 STRIBILD N=867 Creatine Kinase (≥10.0 × ULN) 11% 10% LDL-cholesterol (fasted) (>190 mg/dL) 11% 5% Total cholesterol (fasted) (>300mg/dL) 4% 3% Amylase 3% 5% ALT 3% 3% AST 3% 4% Urine RBC (Hematuria) (>75 RBC/HPF) 3% 3% Serum Lipids: Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD. Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 3.

Table

3 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Trials 104 and 111 Excludes subjects who received lipid lowering agents during the treatment period. GENVOYA N=866 STRIBILD N=867 Baseline Week 144 Baseline Week 144 mg/dL Change The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values. mg/dL Change Total Cholesterol (fasted) 162 [N=647] +31 [N=647] 165 [N=627] +14 [N=627] Triglycerides (fasted) 111 [N=647] +29 [N=647] 115 [N=627] +17 [N=627] LDL-cholesterol (fasted) 103 [N=647] +20 [N=643] 107 [N=628] +8 [N=628] HDL-cholesterol (fasted) 47 [N=647] +7 [N=647] 46 [N=627] +3 [N=627]

Total

Cholesterol to HDL ratio 3.7 [N=647] 0.2 [N=647] 3.8 [N=627] 0.1 [N=627]

Clinical

Trials in Pediatric Subjects: Safety in Pediatric Patients The safety of GENVOYA in HIV-1 infected pediatric subjects was evaluated in treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), and in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=52) through Week 48 (cohort 2) in an open-label clinical trial (Study 106) [see Clinical Studies (14.5) ] . With the exception of a decrease in the mean CD4+ cell count observed in cohort 2 of Study 106, the safety profile in pediatric subjects who received treatment with GENVOYA was similar to that in adults.

One

13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.

Bone Mineral Density Effects Cohort

1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg) Among the subjects in cohort 1 receiving GENVOYA, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were −0.07 for lumbar spine and −0.20 for TBLH at Week 48. One GENVOYA subject had significant (at least 4%) lumbar spine BMD loss at Week 48.

Cohort

2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg) Among the subjects in cohort 2 receiving GENVOYA, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. Six GENVOYA subjects had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 subjects also had at least 4% TBLH BMD loss at Week 48. Change from Baseline in CD4+ cell counts Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Cohort

2 of Study 106 evaluated pediatric subjects (N=52) who were virologically-suppressed and who switched from their antiretroviral regimen to GENVOYA. Although all subjects had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 4. All subjects maintained their CD4+ cell counts above 400 cells/mm 3 [see Pediatric Use (8.4) and Clinical Studies (14.5) ].

Table

4 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to GENVOYA Baseline Mean Change from Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 (275.5) Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 (6.4) +0.3% -0.1% -0.8% -0.8% -1.0% -0.6%

6.2 Postmarketing Experience The following events have been identified during post approval use of products containing TAF, including GENVOYA. Because these events 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. Skin and Subcutaneous Tissue Disorders Angioedema, urticaria, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

5.

Warnings And Precautions

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) including some fatalities can occur with SYMTUZA. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. ( 5.2 ) Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis may occur with SYMTUZA. Discontinue treatment if severe skin reaction develops. ( 5.3 ) Patients receiving SYMTUZA may develop new onset or exacerbations of immune reconstitution syndrome. ( 5.5 ) Monitor in patients with a known sulfonamide allergy. ( 5.7 ) Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.8 ) Patients receiving SYMTUZA may develop new onset or exacerbation of diabetes mellitus/hyperglycemia and redistribution/accumulation of body fat. ( 5.9 , 5.10 ) Patients with hemophilia may develop increase bleeding events. ( 5.11 )

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions. Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA.

5.3 Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia. Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

5.4 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions (7.5) ]</span> : Clinically significant adverse reactions from greater exposures of concomitant drugs. Clinically significant adverse reactions from greater exposures of SYMTUZA. Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s). Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA.

See Table

4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] .

5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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&apos; disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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 antiretroviral treatment.

5.6 New Onset or Worsening Renal Impairment Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2) ]</span> . SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

5.7 Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

5.8 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 emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA 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).

5.9 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

5.10 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &quot;cushingoid appearance&quot; 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.

5.11 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

INTERACTIONS TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.3 , 7 , 12.3 )

7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are coadministered with TYBOST. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data. Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 7 .

7.2 Potential Effect of Concomitant Drugs on the Pharmacokinetics of Cobicistat (Coadministered with Atazanavir or Darunavir) Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A. Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and development of resistance (see Table 7 ). Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir, and darunavir (see Table 7 ).

7.3 Established and Other Potentially Significant Interactions Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.

Table

7 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see Contraindications (4) , Warnings and Precautions (5.3 , 5.4) , and Clinical Pharmacology (12.3) ].

In Table

7 , if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see Clinical Pharmacology (12.3) ] . In addition to the drug interactions noted in Table 7 , TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4) ]. Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in: Patients on a stable concomitant medication who initiate or switch to a TYBOST-containing regimen Patients on a TYBOST-containing regimen who initiate a new concomitant medication Patients initiating a TYBOST-containing regimen and a new concomitant medication simultaneously Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate. No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.

Table

7 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 Potential Effect ↑ = Increase, ↓ = Decrease, ↔ = No change Clinical Comment Antiretroviral Agents: Nucleotide Reverse Transcriptase Inhibitor (NRTI) tenofovir alafenamide ↔tenofovir alafenamide ↑tenofovir alafenamide TYBOST coadministered with darunavir in pediatric patients weighing at least 15 kg: No dose adjustment. TYBOST coadministered with atazanavir in pediatric patients weighing 14 to less than 35 kg: Coadministration is not recommended [see Use in Specific Populations (8.4) ].

Antiretroviral

Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) efavirenz ↓ cobicistat ↓ darunavir ↓ atazanavir TYBOST coadministered with darunavir: Coadministration of darunavir and TYBOST with efavirenz is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir. TYBOST coadministered with atazanavir: In treatment-naïve adult patients: Atazanavir 400 mg with TYBOST 150 mg should be coadministered once daily as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced adult patients: Coadministration of atazanavir and TYBOST with efavirenz in treatment-experienced patients is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir. etravirine ↓ cobicistat darunavir: effect unknown ↓ atazanavir Coadministration with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir or darunavir. nevirapine ↓ atazanavir ↑ nevirapine ↓ cobicistat darunavir: effect unknown Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions. TYBOST coadministered with darunavir: TYBOST coadministration with nevirapine and darunavir is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir.

Antiretroviral

Agents: CCR5 Antagonists maraviroc ↑ maraviroc Maraviroc is a substrate of CYP3A. When coadministering with maraviroc, adult patients should receive maraviroc 150 mg twice daily.

Antiretroviral

Agents: Protease Inhibitors indinavir Contraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

Other

Agents: Alpha 1- adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antianginal ranolazine ↑ ranolazine Coadministration with ranolazine is contraindicated due to potential for serious and/or life-threatening reactions. Antacids: e.g., aluminum and magnesium hydroxide (please also see H2-Receptor Antagonists and Proton Pump Inhibitors below) ↓ atazanavir TYBOST coadministered with atazanavir: With concomitant use, administer a minimum of 2 hours apart. Antiarrhythmics: dronedarone ↑ dronedarone Coadministration with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. digoxin ↑ digoxin When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. Other antiarrhythmics: e.g., amiodarone disopyramide flecainide mexiletine propafenone quinidine ↑ antiarrhythmics Clinical monitoring is recommended upon coadministration with antiarrhythmics. Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin ↑ clarithromycin ↑ erythromycin ↑ telithromycin ↑ cobicistat ↑ atazanavir ↑ darunavir Consider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir.

Anticancer

Agents: irinotecan ↑ irinotecan Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with irinotecan is contraindicated due to potential for increased irinotecan toxicity. dasatinib nilotinib vinblastine vincristine ↑ anticancer agents A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with TYBOST coadministered with atazanavir or darunavir. Consult the dasatinib and nilotinib prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects. Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban ↑ apixaban TYBOST coadministered with atazanavir or darunavir: Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with TYBOST depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. ↑ rivaroxaban Coadministration of rivaroxaban with TYBOST is not recommended because it may lead to an increased bleeding risk. atazanavir: ↑ betrixaban ↑ dabigatran ↑ edoxaban TYBOST coadministered with atazanavir: Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as TYBOST coadministered with atazanavir depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. darunavir: ↔ betrixaban ↔ dabigatran ↔ edoxaban TYBOST coadministered with darunavir: No dose adjustment. warfarin warfarin: effect unknown Monitor the international normalized ratio (INR) upon coadministration of TYBOST with warfarin. Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ atazanavir ↓ darunavir ↓ cobicistat Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated e.g., eslicarbazepine, oxcarbazepine ↓ cobicistat ↓ atazanavir darunavir: effect unknown Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response. Anticonvulsants that are metabolized by CYP3A e.g., clonazepam ↑ clonazepam Clinical monitoring of anticonvulsants is recommended. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline Other antidepressants: trazodone SSRIs: effects unknown ↑ TCAs ↑ trazodone When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. Antifungals: itraconazole ketoconazole ↑ itraconazole ↑ ketoconazole Specific dosing recommendations are not available for coadministration with itraconazole or ketoconazole. voriconazole Voriconazole: effects unknown ↑ cobicistat ↑ atazanavir ↑ darunavir Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole. Anti-gout: colchicine ↑ colchicine Coadministration with colchicine is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. Treatment of gout flares in adult patients – coadministration of colchicine: 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 in adult patients – coadministration of colchicine: 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 in adult patients – coadministration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifampin ↓ atazanavir ↓ darunavir ↓ cobicistat Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin ↑ rifabutin cobicistat: effects unknown darunavir: effects unknown atazanavir: effects unknown The recommended adult dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin associated adverse reactions including neutropenia and uveitis. Antiplatelets: ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended. clopidogrel ↓ clopidogrel active metabolite Coadministration with clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. prasugrel ↔ prasugrel active metabolite No dose adjustment is needed when prasugrel is co-administered with TYBOST. Antipsychotics: lurasidone ↑ lurasidone Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. quetiapine ↑ quetiapine Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking TYBOST coadministered with atazanavir or darunavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Other antipsychotics: e.g., perphenazine risperidone thioridazine ↑ antipsychotic A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration. Beta-Blockers: e.g., metoprolol carvedilol timolol ↑ beta-blockers Clinical monitoring is recommended for coadministration with beta-blockers that are metabolized by CYP2D6.

Calcium Channel

Blockers: e.g., amlodipine diltiazem felodipine nifedipine verapamil ↑ calcium channel blockers Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone ↓ cobicistat ↓ atazanavir ↓ darunavir ↑ corticosteroids Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir or darunavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use .

Endothelin Receptor

Antagonists: bosentan ↑ bosentan ↓ cobicistat ↓ darunavir ↓ atazanavir Initiation of bosentan in adult patients taking TYBOST coadministered with atazanavir or darunavir: In patients who have been receiving TYBOST coadministered with atazanavir or darunavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of TYBOST coadministered with atazanavir or darunavir in adult patients taking bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of TYBOST coadministered with atazanavir or darunavir. After at least 10 days following the initiation of TYBOST combined with atazanavir or darunavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from ritonavir to TYBOST coadministered with atazanavir or darunavir: Maintain bosentan dose.

Ergot

Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. H 2 -Receptor Antagonists: e.g., famotidine ↓ atazanavir TYBOST coadministered with atazanavir in adult patients: Administer atazanavir/TYBOST either at the same time or a minimum of 10 hours after administering H 2 -receptor antagonists. The dose of the H 2 -receptor antagonist should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naïve adult patients or 20 mg twice daily in treatment-experienced adult patients. TYBOST coadministered with atazanavir and TDF in adult patients: Treatment-experienced adult patients: The recommended once daily dosage regimen is TYBOST 150 mg coadministered with atazanavir 400 mg with concomitant use of H 2 -receptor antagonists and tenofovir DF.

Herbal

Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir ↓ darunavir ↓ cobicistat Coadministration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Hormonal

Contraceptives: Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with TYBOST and atazanavir or darunavir. drospirenone/ethinyl estradiol atazanavir: ↑ drospirenone Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with drospirenone is contraindicated due to potential for drospirenone-associated hyperkalemia. darunavir: ↑ drospirenone ↓ ethinyl estradiol TYBOST coadministered with darunavir: For coadministration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. Other progestin/estrogen contraceptives progestin: effects unknown estrogen: effects unknown No data are available to make recommendations on the coadministration of TYBOST and atazanavir or darunavir with other hormonal contraceptives. Immuno-suppressants: cyclosporine everolimus sirolimus tacrolimus ↑ immuno-suppressants These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended if coadministered.

Inhaled Beta

Agonist: salmeterol ↑ salmeterol Coadministration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Lipid-modifying Agents: HMG-CoA reductase inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. Other HMG-CoA reductase inhibitors: e.g., atorvastatin rosuvastatin ↑ HMG-CoA reductase inhibitors Coadministration of atazanavir and TYBOST with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with TYBOST coadministered with atazanavir or darunavir, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows. TYBOST coadministered with atazanavir in adult patients: Rosuvastatin dosage should not exceed 10 mg TYBOST coadministered with darunavir in adult patients: Atorvastatin dosage should not exceed 20 mg Rosuvastatin dosage should not exceed 20 mg Other lipid-modifying agents: lomitapide ↑ lomitapide Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases.

Narcotic Analgesics

For treatment of opioid dependence: buprenorphine buprenorphine/ naloxone methadone buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown Initiation of buprenorphine, buprenorphine/naloxone, or methadone in patients taking TYBOST coadministered with atazanavir or darunavir: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone, or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking buprenorphine, buprenorphine/naloxone, or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms. fentanyl ↑ fentanyl Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration. tramadol ↑ tramadol A dose decrease may be needed for tramadol with concomitant use. Phosphodiesterase-5 (PDE-5) Inhibitors: avanafil sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors Coadministration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Coadministration with TYBOST coadministered with atazanavir or darunavir may result in an increase in PDE-5 inhibitor associated adverse events, 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 PAH due to potential for sildenafil-associated adverse reactions (which include visual disturbances, hypotension, priapism, and syncope) . The following dose adjustments are recommended for tadalafil concomitant use: Initiation of tadalafil in adult patients taking TYBOST coadministered with atazanavir or darunavir: In adult patients taking TYBOST coadministered with atazanavir or darunavir for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Initiation of TYBOST coadministered with atazanavir or darunavir in adult patients taking tadalafil: Avoid use of tadalafil during the initiation of TYBOST coadministered with atazanavir or darunavir. Stop tadalafil at least 24 hours prior to starting TYBOST coadministered with atazanavir or darunavir. After at least one week following initiation of TYBOST coadministered with atazanavir or darunavir, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Patients switching from ritonavir to TYBOST coadministered with atazanavir or darunavir: Maintain tadalafil dose. Use of PDE-5 inhibitors for erectile dysfunction in adult patients: Sildenafil at a single dose not exceeding 25 mg in 48 hours, 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 can be used with increased monitoring for PDE-5 inhibitor associated adverse events. Proton-pump Inhibitors (PPIs) e.g., omeprazole ↓ atazanavir TYBOST coadministered with atazanavir in adult patients: In treatment-naïve adult patients, administer TYBOST with atazanavir a minimum of 12 hours after administering PPIs. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced adult patients, coadministration with PPIs, with or without tenofovir, is not recommended. Sedative/Hypnotics: midazolam (oral), triazolam ↑ midazolam ↑ triazolam Coadministration with triazolam or oral administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with TYBOST may cause large increases in the concentrations of these benzodiazepines. Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam ↑ sedatives/hypnotics Coadministration with parenteral midazolam 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. Dosing reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. buspirone zolpidem With other sedatives/hypnotics that are CYP3A metabolized, dose reduction may be necessary and clinical monitoring is recommended.