Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 15 August 2018

Indication(s)

1 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 [see Dosage and Administration (2.1)]. 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. (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. (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. (5.3, 7, 12.3) 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)].

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Advisory information

contraindications
4 CONTRAINDICATIONS The concomitant use of TYBOST with atazanavir or darunavir and the following drugs (see Table 2) is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.1, 7.2)]. Table 2 Drugs that are Contraindicated with Concomitant use with TYBOST and Atazanavir or Darunavir Drug Class Drugs within Class that are Contraindicated Clinical Comment Alpha 1-Adrenoreceptor Antagonist alfuzosin Potential for increased alfuzosin concentrations, which can result in serious or life-threatening reactions such as hypotension. Antianginal ranolazine Potential for serious and/or life-threatening reactions. Antiarrhythmic dronedarone Potential for increased dronedarone concentrations. Anticonvulsants carbamazepine, phenobarbital, phenytoin Potential for decreased atazanavir or darunavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Anti-gout colchicine Contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. Antimycobacterial rifampin Rifampin is a potent inducer of CYP metabolism and coadministration may cause a significant decrease in the plasma concentrations of atazanavir or darunavir and result in loss of therapeutic effect and development of resistance. Antineoplastics irinotecan Contraindicated with TYBOST coadministered with atazanavir only: Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicity. Antipsychotics lurasidone pimozide Potential for serious and/or life-threatening reactions. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine 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. GI Motility Agent cisapride Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Herbal Products St. John's wort (Hypericum perforatum) Products containing St. John's wort may result in reduced plasma concentrations of atazanavir or darunavir, which may result in loss of therapeutic effect and development of resistance. HMG-CoA Reductase Inhibitors lovastatin, simvastatin Potential for serious reactions such as myopathy including rhabdomyolysis. Hormonal Contraceptives drospirenone/ethinyl estradiol Contraindicated with TYBOST coadministered with atazanavir only: Potential for increased drospirenone concentrations, which can result in hyperkalemia. Non-nucleoside Reverse Transcriptase Inhibitor nevirapine Contraindicated with TYBOST coadministered with atazanavir only: Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures. Phosphodiesterase-5 (PDE-5) Inhibitor sildenafilSee Drug Interactions (7), Table 6 for sildenafil when dosed as Viagra for erectile dysfunction. when administered as Revatio® for the treatment of pulmonary arterial hypertension Potential for sildenafil-associated adverse reactions (which include visual disturbances, hypotension, priapism, and syncope). Protease Inhibitor indinavir Contraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Sedative/hypnotics triazolam, orally administered midazolamSee Drug Interactions (7), Table 6 for parenterally administered midazolam. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Co-administration of triazolam or orally administered midazolam may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life-threatening benzodiazepine reactions such as prolonged or increased sedation or respiratory depression. Coadministration with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4)
Adverse reactions
6 ADVERSE REACTIONS 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. The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received: TYBOST coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=344) or; ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=348). The most common adverse reactions (Grades 2–4) and reported in >5% of subjects in the TYBOST group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 3 displays the frequency of adverse reactions (Grades 2–4) occurring in at least 2% of subjects in the TYBOST group in Study 114. Table 3 Selected Adverse ReactionsFrequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs. (Grades 2–4) Reported in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Study 114 (Week 144 Analysis) TYBOST Coadministered with Atazanavir + TRUVADA N=344 Ritonavir Coadministered with Atazanavir + TRUVADA N=348 Jaundice 6% 3% RashRash 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 subjects 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 subjects in the TYBOST group in Study 114 is presented in Table 4. Table 4 Laboratory Abnormalities (Grades 3–4) in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Study 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 AmylaseFor subjects 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/mm3) 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 Study 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 5. 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 5 Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Study 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Baseline Week 144 Baseline Week 144 mg/dL Change from baselineThe change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes subjects 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]

Usage information

Dosing and administration
2 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) Recommended dosage: (2.1) TYBOST Dosage Coadministered Agent Dosage Patient Populations 150 mg orally once daily atazanavir 300 mg orally once daily Treatment-naïve or experienced darunavir 800 mg orally once daily Treatment-naïve Treatment-experienced with no darunavir resistance associated substitutions Prior to starting TYBOST, assess estimated creatinine clearance. (2.2) Coadministration with tenofovir DF: assess estimated creatinine clearance, urine glucose, and urine protein at baseline. (2.2) TYBOST coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST. (2.3) 2.1 Recommended Dosage 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 TYBOST Dosage Coadministered Agent Dosage Patient Populations 150 mg orally once daily atazanavir 300 mg orally once daily Treatment-naïve or experienced darunavir 800 mg orally once daily Treatment-naïve Treatment-experienced with no darunavir resistance associated substitutions 2.2 Testing Prior to Initiation of TYBOST Prior to starting TYBOST, 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 tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions 5.2]. 2.3 Renal Impairment TYBOST coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1) Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors fetal outcomes in women exposed to TYBOST during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry 1-800-258-4263. Risk Summary There are no data with TYBOST in pregnant women to inform a drug-associated risk. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of cobicistat during organogenesis at doses that produced exposures up to 1.4 and 3.3 times, respectively, the maximal recommended human dose (MRHD) of 150 mg [see Data]. Consider the benefits and risks of TYBOST when prescribing TYBOST to a pregnant woman. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Because TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs, also refer to the prescribing information of each drug for information about pregnancy. Data Animal Data Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17. Maternal toxicity (adverse clinical signs, decreased body weight and food consumption) was noted at 125 mg/kg/day and was associated with increases in postimplantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females was 1.4-fold higher than the exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3-fold higher than exposures at the MRHD. In a pre- and postnatal developmental study, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were slightly lower than (0.9-fold) the MRHD. 8.2 Lactation Risk Summary There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. 8.4 Pediatric Use Safety and effectiveness of TYBOST in pediatric patients younger than 18 years of age have not been established. 8.5 Geriatric Use Clinical trials of TYBOST did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6 Renal Impairment No dosage adjustment of TYBOST is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. TYBOST is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment [see Clinical Pharmacology (12.3)]. TYBOST has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with TYBOST [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)]. 8.7 Hepatic Impairment No dosing adjustment of TYBOST is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS See also Dosage and Administration (2), Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3). 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 other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6. 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 6). 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 6). 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 6 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. In Table 6, 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 6, 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 tenofovir DF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir. Table 6 Established and Other Potentially SignificantThis 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: 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 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 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 ↓ cobicistat darunavir: effect unknown TYBOST coadministered with atazanavir: TYBOST coadministration with nevirapine and atazanavir is contraindicated [see Contraindications (4)] 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, patients should receive maraviroc 150 mg twice daily. Other Agents: 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: e.g., amiodarone disopyramide flecainide mexiletine propafenone quinidine ↑ antiarrhythmics Contraindicated antiarrhythmics [see Contraindications (4)] Clinical monitoring is recommended upon coadministration with antiarrhythmics. digoxin ↑ digoxin When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. 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: 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: warfarin warfarin: effect unknown Monitor the international normalized ratio (INR) when coadministering with warfarin. rivaroxaban ↑ rivaroxaban Avoid coadministration with rivaroxaban which may result in increased exposure of rivaroxaban and increased risk of bleeding. Anticonvulsants: Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine) ↓ cobicistat ↓ atazanavir darunavir: effect unknown Contraindicated anticonvulsants [see Contraindications (4)] 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 in patients with renal or hepatic impairment is contraindicated [see Contraindications (4)]. Treatment of gout flares – coadministration of colchicine: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout flares – coadministration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifabutin ↑ rifabutin cobicistat: effects unknown darunavir: effects unknown atazanavir: effects unknown Contraindicated antimycobacterials [see Contraindications (4)] The recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin associated adverse reactions including neutropenia and uveitis. Antipsychotics: e.g., perphenazine risperidone thioridazine ↑ antipsychotic Contraindicated antipsychotics [see Contraindications (4)] A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration. 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. 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. Systemic/Inhaled/ Nasal/Ophthalmic 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 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 [see Drug Interactions (7.4)]. Endothelin Receptor Antagonists: bosentan ↑ bosentan ↓ cobicistat ↓ darunavir ↓ atazanavir Initiation of bosentan in 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 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. H2-Receptor Antagonists: e.g., famotidine ↓ atazanavir TYBOST coadministered with atazanavir: Administer atazanavir/TYBOST either at the same time or a minimum of 10 hours after administering H2-receptor antagonists. The dose of the H2-receptor antagonist should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naïve patients or 20 mg twice daily in treatment-experienced patients. TYBOST coadministered with atazanavir and tenofovir DF: Treatment-experienced patients: The recommended once daily dosage regimen is TYBOST 150 mg coadministered with atazanavir 400 mg with concomitant use of H2-receptor antagonists and tenofovir. HCV Protease Inhibitors: boceprevir darunavir: effects unknown atazanavir: effects unknown boceprevir: effects unknown No drug interaction data are available. Coadministration with boceprevir or simeprevir is not recommended. simeprevir ↑ simeprevir HMG-CoA Reductase Inhibitors: e.g., atorvastatin rosuvastatin ↑ HMG-CoA reductase inhibitors Contraindicated HMG-CoA Reductase Inhibitors [see Contraindications (4)] 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: Rosuvastatin dosage should not exceed 10 mg TYBOST coadministered with darunavir: Atorvastatin dosage should not exceed 20 mg Rosuvastatin dosage should not exceed 20 mg Hormonal Contraceptives: drospirenone/ethinyl estradiol darunavir: ↑ drospirenone ↓ ethinyl estradiol Contraindicated Hormonal Contraceptives [see Contraindications (4)] 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. Additional or alternative (non-hormonal) forms of contraception should be considered. 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. 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 Contraindicated PDE-5 Inhibitors [see Contraindications (4)] 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 [see Contraindications (4)]. The following dose adjustments are recommended for tadalafil concomitant use: Initiation of tadalafil in patients taking TYBOST coadministered with atazanavir or darunavir: In 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 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: 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 treatment-naïve 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 patients, coadministration with PPIs, with or without tenofovir, is not recommended. Sedative/Hypnotics: e.g., buspirone diazepam parenterally-administered midazolam ↑ sedatives/hypnotics Contraindicated Sedative/Hypnotics [see Contraindications (4)] 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. Concomitant use with oral midazolam is contraindicated [see Contraindications (4)]. With other sedatives/hypnotics that are CYP3A metabolized, dose reduction may be necessary and clinical monitoring is recommended.

More information

Category Value
Authorisation number NDA203094
Agency product number LW2E03M5PG
Orphan designation No
Product NDC 61958-1401
Date Last Revised 31-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1551999
Storage and handling Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature). Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
Marketing authorisation holder Gilead Sciences, Inc.