NDC 61958-1401 Tybost

Cobicistat

NDC Product Code 61958-1401

NDC CODE: 61958-1401

Proprietary Name: Tybost What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Cobicistat What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This drug is used to increase ("boost") the levels of certain HIV protease inhibitors (atazanavir and darunavir). This helps them work better to help control HIV infection. Cobicistat is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, do all of the following: (1) continue to take all HIV medications exactly as prescribed by your doctor, (2) always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity, and (3) do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.

Product Characteristics

Color(s):
ORANGE (C48331)
Shape: ROUND (C48348)
Size(s):
10 MM
Imprint(s):
GSI
Score: 1

NDC Code Structure

  • 61958 - Gilead Sciences, Inc.

NDC 61958-1401-1

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Tybost with NDC 61958-1401 is a a human prescription drug product labeled by Gilead Sciences, Inc.. The generic name of Tybost is cobicistat. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Gilead Sciences, Inc.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Tybost Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • COBICISTAT 150 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • WATER (UNII: 059QF0KO0R)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • TALC (UNII: 7SEV7J4R1U)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • ALUMINUM OXIDE (UNII: LMI26O6933)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cytochrome P450 3A Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 3A Inhibitor - [EPC] (Established Pharmacologic Class)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2D6 Inhibitors - [MoA] (Mechanism of Action)
  • Organic Anion Transporting Polypeptide 1B1 Inhibitors - [MoA] (Mechanism of Action)
  • Organic Anion Transporting Polypeptide 1B3 Inhibitors - [MoA] (Mechanism of Action)
  • Breast Cancer Resistance Protein Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Gilead Sciences, Inc.
Labeler Code: 61958
FDA Application Number: NDA203094 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-24-2014 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Cobicistat

Cobicistat is pronounced as (koe bik' i stat)

Why is cobicistat medication prescribed?
Cobicistat is used to increase the amounts of atazanavir (Reyataz, in Evotaz ) or darunavir (Prezista, in Prezcobix ) in your blood when these medications are used to tre...
[Read More]

* Please review the disclaimer below.

Tybost Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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)].

Other

  • 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)].

Less Common Adverse ReactionsSelected 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 painGeneral Disorders and Administration Site Conditions: fatigueMusculoskeletal and Connective Tissue Disorders: rhabdomyolysisPsychiatric Disorders: depression, abnormal dreams, insomniaRenal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasisRefer 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 + TRUVADARitonavir + Atazanavir + TRUVADALaboratory Parameter AbnormalityN=344N=348Total 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 + TRUVADARitonavir + Atazanavir + TRUVADABaselineWeek 144BaselineWeek 144mg/dLChange 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/dLChange from baselineTotal 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]

Pregnancy Exposure RegistryThere 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 SummaryThere 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

Risk SummaryThere 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.

Effects on Pharmacokinetic EnhancementThe effect of TYBOST on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Study 114 in which HIV-1 infected subjects received atazanavir 300 mg coadministered with TYBOST 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady-state pharmacokinetic parameters of atazanavir were comparable when coadministered with TYBOST versus ritonavir groups as shown in Table 7 [see Clinical Studies (14)].Table 7 Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in HIV-1 Infected Treatment-Naïve Adults (Pharmacokinetic Substudy of Study 114)TYBOST + Atazanavir + TRUVADA Once DailyRitonavir + Atazanavir + TRUVADA Once DailyAtazanavir Pharmacokinetic ParametersN=22N=26AUCtau (mcg∙hr/mL)46.13 ± 26.1847.59 ± 24.38Cmax (mcg/mL)3.91 ± 1.944.76 ± 1.94Ctau (mcg/mL)0.80 ± 0.720.85 ± 0.72The effect of TYBOST on darunavir was evaluated in a clinical study (Study 115) in 31 healthy subjects who received darunavir 800 mg in combination with TYBOST 150 mg or ritonavir 100 mg, all once daily, for 10 days. With the exception of Ctau, the steady-state pharmacokinetic parameters of darunavir were comparable when coadministered with TYBOST versus ritonavir as shown in Table 8, and these results were similar to those reported in previous clinical trials of darunavir 800 mg with ritonavir 100 mg once daily (refer to prescribing information for darunavir).Table 8 Pharmacokinetic Parameters (Mean ± SD) of Darunavir in Healthy Adults (Study 115)TYBOST + Darunavir Once DailyRitonavir + Darunavir Once DailyDarunavir Pharmacokinetic ParametersN=31N=31AUCtau (mcg∙hr/mL)81.08 ± 25.1579.99 ± 27.20Cmax (mcg/mL)7.74 ± 1.697.46 ± 1.52C0h (mcg/mL)2.40 ± 1.222.48 ± 0.85Ctau (mcg/mL)1.33 ± 0.891.87 ± 1.56

Cardiac ElectrophysiologyThe effect of a single dose of cobicistat 250 mg and 400 mg (approximately 1.7 and 2.7 times the recommended dose, respectively) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-period crossover thorough QT study in 48 healthy subjects. In this study, no significant QTc prolongation effect of cobicistat was detected. The dose of 400 mg TYBOST is expected to cover a high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving TYBOST in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg of cobicistat.

Effects on Serum CreatinineThe effect of TYBOST on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with TYBOST among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.1)].

AbsorptionIn a trial where subjects were instructed to take coadministered TYBOST and darunavir with food, median cobicistat peak plasma concentrations were observed approximately 3.5 hours postdose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD) values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg*hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.

Effect of Food on Oral AbsorptionA food-effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents [see Clinical Studies (14)] under fed conditions, in accordance with the prescribing information for these agents. It is recommended that TYBOST coadministered with atazanavir or darunavir be administered with food [see Dosage and Administration (2.1)].

DistributionCobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

MetabolismCobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

EliminationThe terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for 6 days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

Specific Populations

Patients with Hepatic Impairment No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7)].

Patients with Renal Impairment No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min) and healthy subjects [see Use in Specific Populations (8.6)].

Race and GenderNo clinically relevant differences in the pharmacokinetics of cobicistat were observed based on race or gender.

Assessment of Drug InteractionsDrug interaction trials were conducted with TYBOST (as a single entity) and desipramine, digoxin, and efavirenz. Drug interaction trials of TYBOST coadministered with atazanavir or darunavir included atorvastatin, drospirenone/ethinyl estradiol, and rosuvastatin. Drug interaction trials of TYBOST coadministered with elvitegravir included rosuvastatin and rifabutin. The effects of cobicistat on the exposure of coadministered drugs are shown in Table 9.Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information.Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of CobicistatAll interaction studies conducted in healthy subjects.Coadministered DrugDose of Coadministered Drug (mg)TYBOST Dose (mg)NMean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI);No effect = 1.00CmaxAUCAtorvastatin10 single dose150 once daily1618.85Study conducted in the presence of 300 mg atazanavir.(13.53, 26.27)9.22(7.58, 11.22)4.19Study conducted in the presence of 800 mg darunavir.(3.67, 4.78)3.90(3.52, 4.32)Desipramine50 single dose150 once daily81.24(1.08, 1.44)1.65(1.36, 2.02)Digoxin0.5 single dose150 once daily221.41(1.29, 1.55)1.08(1.00, 1.17)Drospirenone/ethinyl estradiol3 drospirenone single dose150 once daily141.12(1.05, 1.19)2.30(2.00, 2.64)0.02 ethinyl estradiol single dose0.82(0.76, 0.89)0.78(0.73, 0.85)3 drospirenone single dose150 once daily151.15(1.05, 1.26)1.58(1.47, 1.71)0.02 ethinyl estradiol single dose0.86(0.77, 0.95)0.70(0.63, 0.77)Efavirenz600 single dose150 once daily170.87(0.80, 0.94)0.93(0.89, 0.97)Rosuvastatin10 single dose150 once daily 1610.58(8.72, 12.83)3.42(2.87, 4.07)3.77(3.29, 4.32)1.93(1.70, 2.20)

Antiviral ActivityCobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.

ResistanceIn an analysis of treatment-failure subjects who received TYBOST coadministered with atazanavir and TRUVADA in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the TYBOST group [6%, 21/344]. Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures [5%, 19/348]. Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir or protease inhibitor associated resistance substitutions.

CarcinogenesisIn a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.

MutagenesisCobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays.

Impairment of FertilityCobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose.Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

Drug InteractionInform patients that TYBOST coadministered with atazanavir or darunavir may interact with many drugs with potential serious implications and that some drugs are contraindicated with TYBOST coadministered with atazanavir or darunavir. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication, including acid-modifying medications or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.3) and Drug Interactions (7)].

New Onset or Worsening Renal ImpairmentInform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST is used in combination with a tenofovir DF containing regimen [see Warnings and Precautions (5.2)].

Pregnancy RegistryInform patients that there is a pregnancy exposure registry that monitors fetal outcomes in women exposed to TYBOST during pregnancy [see Use in Specific Populations (8.1)].

LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Dosing InstructionsInform patients that TYBOST must be taken at the same time as atazanavir or darunavir and with food once daily as prescribed. It is important to take TYBOST and atazanavir or darunavir together on a regular dosing schedule and to avoid missing doses. Counsel patients about the risks of developing resistance to their HIV-1 medications.

© 2017 Gilead Sciences, Inc. All rights reserved.TYBOST, GSI, and TRUVADA are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks are the property of their respective owners.

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 RegimensTYBOST DosageCoadministered Agent DosagePatient Populations150 mg orally once dailyatazanavir 300 mg orally once dailyTreatment-naïve or experienceddarunavir 800 mg orally once dailyTreatment-naïveTreatment-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)].

3 Dosage Forms And Strengths

Orange, round, biconvex, film-coated tablets debossed with "GSI" on one side and plain faced on the other side providing 150 mg of cobicistat.

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 DarunavirDrug ClassDrugs within Class that are ContraindicatedClinical CommentAlpha 1-Adrenoreceptor AntagonistalfuzosinPotential for increased alfuzosin concentrations, which can result in serious or life-threatening reactions such as hypotension.AntianginalranolazinePotential for serious and/or life-threatening reactions.AntiarrhythmicdronedaronePotential for increased dronedarone concentrations.Anticonvulsantscarbamazepine, phenobarbital, phenytoinPotential for decreased atazanavir or darunavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.Anti-goutcolchicineContraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions.AntimycobacterialrifampinRifampin 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.AntineoplasticsirinotecanContraindicated with TYBOST coadministered with atazanavir only: Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicity.AntipsychoticslurasidonepimozidePotential for serious and/or life-threatening reactions.Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.Ergot Derivativesdihydroergotamine, ergotamine, methylergonovinePotential 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 AgentcisapridePotential for serious and/or life-threatening reactions such as cardiac arrhythmias.Herbal ProductsSt. 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 Inhibitorslovastatin, simvastatinPotential for serious reactions such as myopathy including rhabdomyolysis.Hormonal Contraceptivesdrospirenone/ethinyl estradiolContraindicated with TYBOST coadministered with atazanavir only: Potential for increased drospirenone concentrations, which can result in hyperkalemia.Non-nucleoside Reverse Transcriptase InhibitornevirapineContraindicated 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) InhibitorsildenafilSee Drug Interactions (7), Table 6 for sildenafil when dosed as Viagra for erectile dysfunction. when administered as Revatio® for the treatment of pulmonary arterial hypertensionPotential for sildenafil-associated adverse reactions (which include visual disturbances, hypotension, priapism, and syncope).Protease InhibitorindinavirContraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.Sedative/hypnoticstriazolam, 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.

5.1 Effects On Serum Creatinine

TYBOST 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 TYBOST, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.2)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-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 TYBOST 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.

5.2 New Onset Or Worsening Renal Impairment When Used With Tenofovir Disoproxil Fumarate

  • Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST was used in an antiretroviral regimen that contained tenofovir DF.Coadministration of TYBOST and 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 Dosage and Administration (2.2, 2.3)].Document urine glucose and urine protein at baseline [see Dosage and Administration (2.2)] and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when TYBOST is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.Coadministration of TYBOST and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) subjects treated with TYBOST coadministered with atazanavir and TRUVADA® and 11 (3.2%) subjects treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any subject.

5.3 Risk Of Serious Adverse Reactions Or Loss Of Virologic Response Due To Drug Interactions

  • Initiation of TYBOST, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving TYBOST may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of TYBOST with atazanavir or darunavir.Increased concentrations may lead to:clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications.clinically significant adverse reactions from higher exposures of TYBOST and atazanavir or darunavir.Decreased antiretroviral concentrations may lead to:loss of therapeutic effect of TYBOST with atazanavir or darunavir and possible development of resistance.See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].TYBOST or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions [see Drug Interactions (7), and Clinical Pharmacology (12.3)].
  • The following antiretrovirals are not recommended in combination with TYBOST because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor in combination with elvitegravir)Darunavir in combination with efavirenz, nevirapine, or etravirineAtazanavir in combination with etravirineAtazanavir in combination with efavirenz in treatment-experienced patientsDarunavir 600 mg twice dailyOther HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavirTYBOST in combination with fixed-dose combination tablets that contain cobicistat is not recommended.TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of TYBOST and ritonavir on CYP3A.

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)]

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 + TRUVADAN=344Ritonavir Coadministered with Atazanavir + TRUVADAN=348Jaundice6%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 icterus4%2%Nausea2%2%Diarrhea2%1%Headache2%1%

7 Drug Interactions

See also Dosage and Administration (2), Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (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 regimenPatients on a TYBOST-containing regimen who initiate a new concomitant medicationPatients initiating a TYBOST-containing regimen and a new concomitant medication simultaneouslyUnder 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 InteractionConcomitant Drug Class: Drug Name Potential Effect↑ = Increase, ↓ = Decrease, ↔ = No changeClinical CommentAntiretroviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)efavirenz↓ cobicistat↓ darunavir↓ atazanavirTYBOST 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↓ cobicistatdarunavir: effect unknown↓ atazanavirCoadministration with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir or darunavir.nevirapine↓ cobicistatdarunavir: effect unknownTYBOST 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 Antagonistsmaraviroc↑ maravirocMaraviroc 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)↓ atazanavirTYBOST coadministered with atazanavir:With concomitant use, administer a minimum of 2 hours apart.Antiarrhythmics:e.g.,amiodaronedisopyramideflecainidemexiletinepropafenonequinidine↑ antiarrhythmicsContraindicated antiarrhythmics [see Contraindications (4)]Clinical monitoring is recommended upon coadministration with antiarrhythmics.digoxin↑ digoxinWhen coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.Antibacterials (macrolide or ketolide antibiotics):clarithromycinerythromycintelithromycin↑ clarithromycin↑ erythromycin↑ telithromycin↑ cobicistat↑ atazanavir↑ darunavirConsider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir.Anticancer Agents:dasatinibnilotinibvinblastinevincristine↑ anticancer agentsA 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:warfarinwarfarin: effect unknownMonitor the international normalized ratio (INR) when coadministering with warfarin.rivaroxaban↑ rivaroxabanAvoid 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↓ atazanavirdarunavir: effect unknownContraindicated 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)↑ clonazepamClinical monitoring of anticonvulsants is recommended.Antidepressants:Selective Serotonin Reuptake Inhibitors (SSRIs)e.g.,paroxetineTricyclicAntidepressants (TCAs)e.g.,amitriptylinedesipramineimipraminenortriptylineOther antidepressants:trazodoneSSRIs: effects unknown↑ TCAs↑ trazodoneWhen 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:itraconazoleketoconazole↑ itraconazole↑ ketoconazoleSpecific dosing recommendations are not available for coadministration with itraconazole or ketoconazole.voriconazole Voriconazole: effects unknown↑ cobicistat↑ atazanavir↑ darunavirCoadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.Anti-gout:colchicine↑ colchicineCoadministration 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↑ rifabutincobicistat: effects unknowndarunavir: effects unknownatazanavir: effects unknownContraindicated 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.,perphenazinerisperidonethioridazine↑ antipsychoticContraindicated antipsychotics [see Contraindications (4)]A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration.quetiapine↑ quetiapineInitiation 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.,metoprololcarvediloltimolol↑ beta-blockersClinical monitoring is recommended for coadministration with beta-blockers that are metabolized by CYP2D6.Calcium Channel Blockers:e.g.,amlodipinediltiazemfelodipinenifedipineverapamil↑ calcium channel blockersClinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A.Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids:e.g.,betamethasonebudesonide ciclesonidedexamethasone fluticasonemethylprednisolonemometasonetriamcinolone↓ cobicistat↓ atazanavir ↓ darunavir↑ corticosteroidsCoadministration 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↓ atazanavirInitiation 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↓ atazanavirTYBOST 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:boceprevirdarunavir: effects unknownatazanavir: effects unknownboceprevir: effects unknownNo drug interaction data are available. Coadministration with boceprevir or simeprevir is not recommended.simeprevir↑ simeprevirHMG-CoA Reductase Inhibitors: e.g.,atorvastatinrosuvastatin↑ HMG-CoA reductase inhibitorsContraindicated 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 mgTYBOST coadministered with darunavir: Atorvastatin dosage should not exceed 20 mgRosuvastatin dosage should not exceed 20 mgHormonal Contraceptives:drospirenone/ethinyl estradioldarunavir:↑ drospirenone↓ ethinyl estradiolContraindicated Hormonal Contraceptives [see Contraindications (4)] TYBOST coadministered with darunavir:For coadministration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.Otherprogestin/estrogen contraceptivesprogestin: effects unknownestrogen: effects unknownNo 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:cyclosporineeverolimussirolimustacrolimus↑ immuno-suppressantsThese immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended if coadministered.Inhaled Beta Agonist:salmeterol↑ salmeterolCoadministration 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 AnalgesicsFor treatment of opioid dependence:buprenorphinebuprenorphine/naloxonemethadonebuprenorphine or buprenorphine/ naloxone: effects unknownmethadone: effects unknownInitiation 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↑ fentanylCareful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.tramadol↑ tramadolA dose decrease may be needed for tramadol with concomitant use.Phosphodiesterase-5 (PDE-5) Inhibitors: avanafilsildenafiltadalafilvardenafil↑ PDE-5 inhibitorsContraindicated 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↓ atazanavirTYBOST 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.,buspironediazepamparenterally-administered midazolam ↑ sedatives/hypnoticsContraindicated 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.

Teratogenic Effects

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.

8.4 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)].

10 Overdosage

If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with TYBOST consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

11 Description

TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor.The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20 °C.TYBOST tablets are for oral administration. Each tablet contains 150 mg of cobicistat. The tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 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.

12.1 Mechanism Of Action

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.

14 Clinical Studies

The activity of TYBOST as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with TYBOST 150 mg was consistent with those observed with ritonavir 100 mg [see Clinical Pharmacology (12.2)]. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.The safety and efficacy of TYBOST coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naïve subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg + TYBOST 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).The mean age of subjects was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm3 (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm3.Virologic outcomes in Study 114 through Week 144 are presented in Table 10. In Study 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm3 in the TYBOST group and 297 cells/mm3 in the ritonavir group.Table 10 Virologic Outcome of Randomized Treatment of Study 114 in HIV-1 Infected Treatment Naïve Adults at Week 144Week 144 window was between Day 967 and 1050 (inclusive).TYBOST + Atazanavir + TRUVADA(N=344)Ritonavir + Atazanavir + TRUVADA(N=348)HIV-1 RNA <50 copies/mL72%74%  Treatment Difference–2.1% (95% CI = –8.7%, 4.5%)HIV RNA ≥50 copies/mLIncluded subjects who had ≥50 copies/mL in the Week 144 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.8%5%No Virologic Data at Week 144 Window20%21%  Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.11%11%  Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, lost to follow-up, etc.8%10%  Missing Data During Window but on Study Drug<1%<1%

16 How Supplied/Storage And Handling

TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with "GSI" on one side and plain faced on the other side.Each bottle contains 30 tablets (NDC 61958-1401-1) and a silica gel desiccant, with a child-resistant closure.

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.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Spl Patient Package Insert

  • This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 08/2017Patient Information TYBOST® (TYE-bost)(cobicistat)tabletsImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with TYBOST. For more information, see the section "What should I tell my healthcare provider before taking TYBOST?"Read this Patient Information before you start taking TYBOST and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.Also read the Patient Information for atazanavir (REYATAZ®) or darunavir (PREZISTA®) prescribed by your healthcare provider when taking TYBOST.What is TYBOST? TYBOST is a prescription medicine used in adults 1 time each day with the antiretroviral Human Immunodeficiency Virus-1 (HIV-1) medicines atazanavir (REYATAZ®) or darunavir (PREZISTA®) to increase the amount of those medicines in your blood.TYBOST is not an antiretroviral medicine and does not treat the HIV-1 virus. You must also take all the antiretroviral HIV-1 medicines prescribed by your healthcare provider even if you take TYBOST and atazanavir (REYATAZ®) or darunavir (PREZISTA®).TYBOST should not be used if you take darunavir (PREZISTA) when prescribed by your healthcare provider to be taken 2 times each day, or if you take other HIV-1 protease inhibitor medicines, including fosamprenavir (LEXIVA®), saquinavir (INVIRASE®), or tipranavir (APTIVUS®).It is not known if TYBOST is safe and effective in children under 18 years of age.Do not take TYBOST combined with atazanavir or darunavir if you also take any of the following medicines:alfuzosin hydrochloride (UROXATRAL®)carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®)cisapride (PROPULSID®, PROPULSID® QUICKSOLV)colchicine (COLCRYS , MITIGARE™), if you have liver or kidney problemsdronedarone hydrochloride (MULTAQ®)ergot-containing medicines: dihydroergotamine mesylate (D.H.E. 45®, MIGRANAL®)ergotamine tartrate (CAFERGOT®, MIGERGOT®, ERGOSTAT®, MEDIHALER ERGOTAMINE®, WIGRAINE®, WIGRETTES®)methylergonovine maleate (ERGOTRATE®, METHERGINE®)lovastatin (ADVICOR®, ALTOPREV®, MEVACOR®)lurasidone (LATUDA®)midazolam (VERSED®), when taken by mouthphenobarbital (LUMINAL®)phenytoin (DILANTIN®, PHENYTEX®)pimozide (ORAP®)ranolazine (RANEXA®)rifampin (RIFADIN®, RIFAMATE®, RIFATER®, RIMACTANE®)sildenafil (REVATIO®), when used for treating the lung problem pulmonary arterial hypertension (PAH)simvastatin (SIMCOR®, VYTORIN®, ZOCOR®)St. John's wort (Hypericum perforatum) or a product that contains St. John's worttriazolam (HALCION®)Do not take TYBOST with atazanavir if you also take any of the following medicines: drospirenone/ethinyl estradiol (BEYAZ®, SAFYRAL®, YASMIN®, YAZ®)indinavir (CRIXIVAN®)irinotecan (CAMPTOSAR®)nevirapine (VIRAMUNE®, VIRAMUNE XR®)What should I tell my healthcare provider before taking TYBOST?Before you take TYBOST, tell your healthcare provider if you:have kidney problemshave liver problemshave any other medical conditionsare pregnant or plan to become pregnant. It is not known if TYBOST can harm your unborn baby. Tell your healthcare provider if you become pregnant while taking TYBOST. Pregnancy Registry: There is a pregnancy registry for women who take TYBOST during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take TYBOST. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if TYBOST can pass to your baby in your breast milk.Talk to your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TYBOST with atazanavir or darunavir may affect the way other medicines work, and other medicines may affect how TYBOST with atazanavir or darunavir works. Taking TYBOST with atazanavir or darunavir, along with certain other medicines can lead to severe or life threatening side effects, or could lead to death. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.You can ask your healthcare provider or pharmacist for a list of medicines that interact when taken with TYBOST with atazanavir or darunavir.Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TYBOST with atazanavir or darunavir, along with other medicines.How should I take TYBOST? Take TYBOST exactly as your healthcare provider tells you.Do not change your dose or stop taking TYBOST without first talking with your healthcare provider.Stay under the care of your healthcare provider during treatment with TYBOST. See your healthcare provider regularly while taking TYBOST.Take TYBOST 1 time each day at the same time you take atazanavir (REYATAZ®) or darunavir (PREZISTA®). It is important to take these medicines on a regular dosing schedule.Take TYBOST with atazanavir or TYBOST with darunavir, along with food.If you take too much TYBOST, call your healthcare provider or go to the nearest hospital emergency room right away.Do not run out of TYBOST. The virus in your blood may become resistant to the HIV-1 medicine atazanavir (REYATAZ®) or darunavir (PREZISTA®) if TYBOST is stopped for even a short time. When your supply starts to run low, get more from your healthcare provider or pharmacy.What are the possible side effects of TYBOST?TYBOST when taken with certain other medicines can cause new or worse kidney problems, including kidney failure. Your healthcare provider should check your kidneys before you start and while you are taking TYBOST.The most common side effects of TYBOST with atazanavir (REYATAZ®) include yellowing of the skin and rash.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of TYBOST. For more information, ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store TYBOST?Store TYBOST at room temperature between 68 °F to 77 °F (20 °C to 25 °C).Do not use TYBOST if the seal over the bottle opening is broken or missing.Keep TYBOST in its original container.Keep the container tightly closed.Keep TYBOST and all medicines out of reach of children.General information about TYBOSTMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TYBOST for a condition for which it was not prescribed. Do not give TYBOST to other people, even if they have the same symptoms you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TYBOST that is written for health professionals.For more information, call 1-800-445-3235 or go to www.GILEAD.com.What are the ingredients in TYBOST?Active ingredient: cobicistatInactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablets are film-coated with a coating material containing polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow.Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404© 2017 Gilead Sciences, Inc. All rights reserved.TYBOST, GSI, and TRUVADA are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks are the property of their respective owners.203094-GS-004

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