TYBOST

TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0. It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20 °C. TYBOST tablets are for oral administration. Each tablet contains 150 mg or 90 mg of cobicistat. The 150 mg and 90 mg tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 150 mg tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow. The 90 mg tablets are film-coated with a coating material containing the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Chemical Structure

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) ].

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.

The concomitant use of TYBOST with atazanavir or darunavir and the following drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Alpha 1-adrenoreceptor antagonist: alfuzosin Antianginal: ranolazine Antiarrhythmic: dronedarone Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-gout: colchicine Antimycobacterial: rifampin Antineoplastics: irinotecan These contraindications apply only to TYBOST coadministered with atazanavir Antipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine 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 when administered as Revatio ® for the treatment of pulmonary arterial hypertension Protease Inhibitor: indinavir Sedative/hypnotics triazolam, orally administered midazolam Coadministration with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. ( 4 )

The following adverse reaction is described in greater detail in another section of the labeling: New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2) ]. The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2−4) are jaundice and rash. ( 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. Adverse Reactions from Clinical Trials Experience in Adults The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 antiretroviral treatment-naïve participants with HIV-1 received: TYBOST coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348). The most common adverse reactions (Grades 2−4) and reported in >5% of participants in the TYBOST group were jaundice (6%) and rash (5%). The proportion of participants who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 4 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of participants in the TYBOST group in Trial 114. Table 4 Selected Adverse Reactions Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs. (Grades 2−4) Reported in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST Coadministered with Atazanavir + TRUVADA N=344 Ritonavir Coadministered with Atazanavir + TRUVADA N=348 Jaundice 6% 3% Rash Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria. 5% 4% Ocular icterus 4% 2% Nausea 2% 2% Diarrhea 2% 1% Headache 2% 1% Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of participants receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir. Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of participants in the TYBOST group in Trial 114 is presented in Table 5 . Table 5 Laboratory Abnormalities (Grades 3−4) in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Laboratory Parameter Abnormality N=344 N=348 Total Bilirubin (>2.5 × ULN) 73% 66% Creatine Kinase (≥10.0 × ULN) 8% 9% Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3% ALT (>5.0 × ULN) 6% 3% AST (>5.0 × ULN) 4% 3% GGT (>5.0 × ULN) 4% 2% Serum Amylase For participants with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively. (>2.0 × ULN) 4% 2% Urine Glucose (Glycosuria) (≥1000 mg/dL) 3% 3% Neutrophils (<750/mm 3 ) 3% 2% Serum Glucose (Hyperglycemia) (>250 mg/dL) 2% 2% Increase in Serum Creatinine : TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group. Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 6 . In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown. Table 6 Lipid Values, Mean Change from Baseline, Reported in Treatment-Naïve Adults with HIV-1 Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Baseline Week 144 Baseline Week 144 mg/dL Change from baseline The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes participants receiving an HMG-CoA reductase inhibitor drug. mg/dL Change from baseline Total Cholesterol (fasted) 163 [N=219] +11 [N=219] 165 [N=227] +13 [N=227] HDL-cholesterol (fasted) 43 [N=218] +7 [N=218] 43 [N=228] +6 [N=228] LDL-cholesterol (fasted) 102 [N=218] +11 [N=218] 104 [N=228] +16 [N=228] Triglycerides (fasted) 130 [N=219] +14 [N=219] 131 [N=227] +14 [N=227] Adverse Reactions from Clinical Trials Experience in Pediatric Participants The safety of TYBOST was evaluated in an open-label clinical trial (Trial 128) of pediatric participants with HIV-1 administered TYBOST-boosted atazanavir or darunavir plus two nucleoside reverse transcriptase inhibitors; this study included 22 virologically-suppressed participants between the ages of 12 to less than 18 years (weighing ≥35 kg) administered atazanavir (N=14) or darunavir (N=7) through Week 48; 9 virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg to less than 40 kg administered darunavir (N=9) through Week 48; and 11 virologically-suppressed participants at least 2 years of age (weighing ≥14 kg to <25 kg) administered darunavir through Week 48 [see Drug Interactions (7.3) , Use in Specific Populations (8.4) , Clinical Studies (14.2) ] . In this trial, the safety profile of TYBOST was similar to that in adults.

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.

TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with “GSI” on one side and plain faced on the other side. (NDC 61958-1401-1). TYBOST tablets, 90 mg, are white, round, biconvex, film-coated, and debossed with “TYB” on one side and “ 90 ” on the other side. (NDC 61958-1402-1). Store at 25 °C (77 °F); excursions permitted to 15°C –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.