Tybost
Generic: COBICISTAT
Basic Information
Manufacturer
Gilead Sciences, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
3784c35c-e87f-410c-900b-8fd6313c6010
Indications & Usage
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 in adults and in pediatric patients weighing at least 14 kg.
( 1.1 ) Limitations of Use : TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.
The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir.
( 1.2 , 5.4 ) Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions.
TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications.
( 1.2 , 5.3 , 7 , 12.3 ) 1.1 Indications Adult Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults [see Dosage and Administration (2.1) ].
Pediatric Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients weighing at least 14 kg [see Dosage and Administration (2.2) , and Drug Interactions (7.3) ].
1.2 Limitations of Use TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.
The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir [see Warnings and Precautions (5.4) ].
Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions.
TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications [see Warnings and Precautions (5.3) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].
( 1.1 ) Limitations of Use : TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.
The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir.
( 1.2 , 5.4 ) Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions.
TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications.
( 1.2 , 5.3 , 7 , 12.3 ) 1.1 Indications Adult Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults [see Dosage and Administration (2.1) ].
Pediatric Patients: TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients weighing at least 14 kg [see Dosage and Administration (2.2) , and Drug Interactions (7.3) ].
1.2 Limitations of Use TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.
The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir [see Warnings and Precautions (5.4) ].
Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions.
TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications [see Warnings and Precautions (5.3) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].
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.
Adverse Reactions from Clinical Trials Experience in Adults The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 antiretroviral treatment-naïve participants with HIV-1 received: TYBOST coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348).
The most common adverse reactions (Grades 2−4) and reported in >5% of participants in the TYBOST group were jaundice (6%) and rash (5%).
The proportion of participants who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups.
Table 4 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of participants in the TYBOST group in Trial 114.
Table 4 Selected Adverse Reactions Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs.
(Grades 2−4) Reported in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST Coadministered with Atazanavir + TRUVADA N=344 Ritonavir Coadministered with Atazanavir + TRUVADA N=348 Jaundice 6% 3% Rash Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.
5% 4% Ocular icterus 4% 2% Nausea 2% 2% Diarrhea 2% 1% Headache 2% 1% Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of participants receiving TYBOST coadministered with atazanavir and TRUVADA are listed below.
These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir.
Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.
Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of participants in the TYBOST group in Trial 114 is presented in Table 5 .
Table 5 Laboratory Abnormalities (Grades 3−4) in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Laboratory Parameter Abnormality N=344 N=348 Total Bilirubin (>2.5 × ULN) 73% 66% Creatine Kinase (≥10.0 × ULN) 8% 9% Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3% ALT (>5.0 × ULN) 6% 3% AST (>5.0 × ULN) 4% 3% GGT (>5.0 × ULN) 4% 2% Serum Amylase For participants with serum amylase >1.5 × upper limit of normal, lipase test was also performed.
The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively.
(>2.0 × ULN) 4% 2% Urine Glucose (Glycosuria) (≥1000 mg/dL) 3% 3% Neutrophils (<750/mm 3 ) 3% 2% Serum Glucose (Hyperglycemia) (>250 mg/dL) 2% 2% Increase in Serum Creatinine : TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .
In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized.
The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group.
Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 6 .
In both groups, mean values for serum lipids remained within the study reference range for each laboratory test.
The clinical significance of these changes is unknown.
Table 6 Lipid Values, Mean Change from Baseline, Reported in Treatment-Naïve Adults with HIV-1 Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Baseline Week 144 Baseline Week 144 mg/dL Change from baseline The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values.
Analysis excludes participants receiving an HMG-CoA reductase inhibitor drug.
mg/dL Change from baseline Total Cholesterol (fasted) 163 [N=219] +11 [N=219] 165 [N=227] +13 [N=227] HDL-cholesterol (fasted) 43 [N=218] +7 [N=218] 43 [N=228] +6 [N=228] LDL-cholesterol (fasted) 102 [N=218] +11 [N=218] 104 [N=228] +16 [N=228] Triglycerides (fasted) 130 [N=219] +14 [N=219] 131 [N=227] +14 [N=227] Adverse Reactions from Clinical Trials Experience in Pediatric Participants The safety of TYBOST was evaluated in an open-label clinical trial (Trial 128) of pediatric participants with HIV-1 administered TYBOST-boosted atazanavir or darunavir plus two nucleoside reverse transcriptase inhibitors; this study included 22 virologically-suppressed participants between the ages of 12 to less than 18 years (weighing ≥35 kg) administered atazanavir (N=14) or darunavir (N=7) through Week 48; 9 virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg to less than 40 kg administered darunavir (N=9) through Week 48; and 11 virologically-suppressed participants at least 2 years of age (weighing ≥14 kg to <25 kg) administered darunavir through Week 48 [see Drug Interactions (7.3) , Use in Specific Populations (8.4) , Clinical Studies (14.2) ] .
In this trial, the safety profile of TYBOST was similar to that in adults.
The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2−4) are jaundice and rash.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc.
at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions from Clinical Trials Experience in Adults The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 antiretroviral treatment-naïve participants with HIV-1 received: TYBOST coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348).
The most common adverse reactions (Grades 2−4) and reported in >5% of participants in the TYBOST group were jaundice (6%) and rash (5%).
The proportion of participants who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups.
Table 4 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of participants in the TYBOST group in Trial 114.
Table 4 Selected Adverse Reactions Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs.
(Grades 2−4) Reported in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST Coadministered with Atazanavir + TRUVADA N=344 Ritonavir Coadministered with Atazanavir + TRUVADA N=348 Jaundice 6% 3% Rash Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.
5% 4% Ocular icterus 4% 2% Nausea 2% 2% Diarrhea 2% 1% Headache 2% 1% Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of participants receiving TYBOST coadministered with atazanavir and TRUVADA are listed below.
These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir.
Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.
Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of participants in the TYBOST group in Trial 114 is presented in Table 5 .
Table 5 Laboratory Abnormalities (Grades 3−4) in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Laboratory Parameter Abnormality N=344 N=348 Total Bilirubin (>2.5 × ULN) 73% 66% Creatine Kinase (≥10.0 × ULN) 8% 9% Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3% ALT (>5.0 × ULN) 6% 3% AST (>5.0 × ULN) 4% 3% GGT (>5.0 × ULN) 4% 2% Serum Amylase For participants with serum amylase >1.5 × upper limit of normal, lipase test was also performed.
The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively.
(>2.0 × ULN) 4% 2% Urine Glucose (Glycosuria) (≥1000 mg/dL) 3% 3% Neutrophils (<750/mm 3 ) 3% 2% Serum Glucose (Hyperglycemia) (>250 mg/dL) 2% 2% Increase in Serum Creatinine : TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .
In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized.
The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group.
Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 6 .
In both groups, mean values for serum lipids remained within the study reference range for each laboratory test.
The clinical significance of these changes is unknown.
Table 6 Lipid Values, Mean Change from Baseline, Reported in Treatment-Naïve Adults with HIV-1 Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Baseline Week 144 Baseline Week 144 mg/dL Change from baseline The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values.
Analysis excludes participants receiving an HMG-CoA reductase inhibitor drug.
mg/dL Change from baseline Total Cholesterol (fasted) 163 [N=219] +11 [N=219] 165 [N=227] +13 [N=227] HDL-cholesterol (fasted) 43 [N=218] +7 [N=218] 43 [N=228] +6 [N=228] LDL-cholesterol (fasted) 102 [N=218] +11 [N=218] 104 [N=228] +16 [N=228] Triglycerides (fasted) 130 [N=219] +14 [N=219] 131 [N=227] +14 [N=227] Adverse Reactions from Clinical Trials Experience in Pediatric Participants The safety of TYBOST was evaluated in an open-label clinical trial (Trial 128) of pediatric participants with HIV-1 administered TYBOST-boosted atazanavir or darunavir plus two nucleoside reverse transcriptase inhibitors; this study included 22 virologically-suppressed participants between the ages of 12 to less than 18 years (weighing ≥35 kg) administered atazanavir (N=14) or darunavir (N=7) through Week 48; 9 virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg to less than 40 kg administered darunavir (N=9) through Week 48; and 11 virologically-suppressed participants at least 2 years of age (weighing ≥14 kg to <25 kg) administered darunavir through Week 48 [see Drug Interactions (7.3) , Use in Specific Populations (8.4) , Clinical Studies (14.2) ] .
In this trial, the safety profile of TYBOST was similar to that in adults.