cobicistat 150 MG Oral Tablet [Tybost]

INDICATIONS 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 [see Dosage and Administration (2.1) ]. 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 [see Warnings and Precautions (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 [see Warnings and Precautions (5.3) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].

DOSAGE 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 [see Drug Interactions (7) ]. 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 [see Drug Interactions (7) ]. 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 [see Warnings and Precautions (5.1) ]. 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 [see Warnings and Precautions (5.2) ]. 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 [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . 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 [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . 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.

WARNINGS AND PRECAUTIONS • Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. Consider ECG monitoring in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. ( 5.1 , 6 , 7.3 , 12.2 , 17 ) • Severe skin reactions: Discontinue if severe rash develops. ( 5.2 , 6.1 , 17 ) • Assess creatinine clearance (CLcr) before initiating treatment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. ( 5.3 ) • When cobicistat, a component of EVOTAZ, is used in combination with a tenofovir disoproxil fumarate (tenofovir DF)-containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. ( 5.4 ) • When used with tenofovir DF, assess urine glucose and urine protein at baseline and monitor CLcr, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. Coadministration with tenofovir DF is not recommended in patients with CLcr below 70 mL/min or in patients also receiving a nephrotoxic agent. ( 5.4 ) • Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment with EVOTAZ. Consider discontinuation of EVOTAZ in patients with progressive renal disease. ( 5.5 ) • Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. ( 5.6 , 6 ) • Hepatotoxicity: Patients with hepatitis B or C are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. ( 2.5 , 5.7 , 8.7 ) • Antiretrovirals that are not recommended: EVOTAZ is not recommended for use with ritonavir or products containing ritonavir, or in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other protease inhibitors and elvitegravir). ( 5.9 ) • Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. ( 5.10 , 6 ) • Patients receiving EVOTAZ may develop immune reconstitution syndrome ( 5.11 ), new onset or exacerbations of diabetes mellitus/hyperglycemia ( 5.12 , 6 ), and redistribution/accumulation of body fat ( 5.13 ). • Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. ( 5.14 ) 5.1 Cardiac Conduction Abnormalities Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.1) and Overdosage (10) ] . In clinical trials of atazanavir in participants with HIV-1 that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of participants treated with atazanavir (n=920) and 5% of participants (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block), consider ECG monitoring in these patients [see Clinical Pharmacology (12.2) ] . 5.2 Severe Skin Reactions Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [see Contraindications (4) and Adverse Reactions (6.1) ] . EVOTAZ should be discontinued if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation. 5.3 Effects on Serum Creatinine Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance [see Dosage and Administration (2.1) ] . Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment [see Adverse Reactions (6.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.2) ] . Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. 5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir DF Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min [see Dosage and Administration (2.3) ] . • When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment. • Measure serum phosphorus in patients with or at risk for renal impairment. • Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. In a clinical trial over 144 weeks (N=692), 10 (2.9%) participants treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) participants treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants treated with cobicistat, with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any participant. 5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy w

CONTRAINDICATIONS The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Warnings and Precautions (5.8 , 5.9) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]. EVOTAZ is contraindicated: • in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product [see Warnings and Precautions (5.2) ] . • when coadministered with drugs that strongly induce CYP3A4, which may lead to lower exposure of EVOTAZ resulting in potential loss of efficacy and development of possible resistance (Table 5). • when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 5). For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [see Drug Interactions (7.3) ] . Coadministration is contraindicated with, but not limited to, the following drugs: Table 1: Drugs Contraindicated with EVOTAZ Drug Class Drugs within class that are contraindicated with EVOTAZ a Refer to Table 5 for sildenafil when administered for erectile dysfunction [see Drug Interactions (7.3) ]. b Refer to Table 5 for parenterally administered midazolam [see Drug Interactions (7.3) ]. Alpha 1-adrenoreceptor antagonist alfuzosin Antianginal ranolazine Antiarrhythmics dronedarone Anticonvulsants carbamazepine, phenobarbital, phenytoin Antigout colchicine (when used in patients with hepatic and/or renal impairment) Antimycobacterials rifampin Antineoplastics apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics lurasidone, pimozide Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine Hepatitis C Direct-Acting Antivirals elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum ) Hormonal Contraceptives drospirenone/ethinyl estradiol Lipid-modifying Agents lomitapide, lovastatin, simvastatin Non-nucleoside Reverse Transcriptase Inhibitor nevirapine Phosphodiesterase-5 (PDE-5) Inhibitor sildenafil a when administered for the treatment of pulmonary arterial hypertension Protease Inhibitors indinavir Sedative/hypnotics triazolam, orally administered midazolam b • EVOTAZ is contraindicated in patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4) • EVOTAZ is contraindicated with drugs that are strong inducers of CYP3A4 due to the potential for loss of therapeutic effect and development of possible resistance. (4) • EVOTAZ is contraindicated with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4)

Mechanism of Action GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4) ] . Mechanism of Action Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II. Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism. Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ. Tenofovir Alafenamide (TAF): TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in cell culture based on several assays including mitochondrial DNA analyses.