Cobicistat

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) ].

2 DOSAGE AND ADMINISTRATION TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents. ( 2.1 , 2.2 ) Recommended dosage in adults: ( 2.1 ) Adult Patient Populations Coadministered Agent Dosage TYBOST Dosage Treatment-naïve or treatment-experienced atazanavir 300 mg orally once daily 150 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions darunavir 800 mg orally once daily Recommended dosage in pediatric patients: TYBOST 150 mg or TYBOST 90 mg orally once daily based on body weight. For dosage recommendations for TYBOST and the coadministered protease inhibitor atazanavir or darunavir in pediatric patients, refer to Table 2 and Table 3 of the full prescribing information respectively. ( 2.2 ) Prior to starting TYBOST, assess estimated creatinine clearance. ( 2.3 ) Coadministration with tenofovir disoproxil fumarate (TDF): assess estimated creatinine clearance, urine glucose, and urine protein at baseline. ( 2.3 ) TYBOST coadministered with TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST. ( 2.4 ) 2.1 Recommended Dosage in Adults Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1 . TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7) ]. Consult the prescribing information for atazanavir or darunavir. Table 1 Recommended Dosing Regimens in Treatment-Naïve or Treatment-Experienced Adults Patient Populations Coadministered Agent Dosage TYBOST Dosage Treatment-naïve or treatment-experienced atazanavir 300 mg orally once daily 150 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions darunavir 800 mg orally once daily 2.2 Recommended Dosage in Pediatric Patients Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of pediatric patients with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are based on weight and presented in Table 2 and Table 3 , respectively. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7) ]. Consult the prescribing information for atazanavir or darunavir. Table 2 Recommended Dosing Regimen in Treatment-Naïve or Treatment-Experienced Pediatric Patients in Combination with Atazanavir Body Weight Atazanavir Dosage TYBOST Dosage Weighing at least 14 kg to less than 25 kg 200 mg orally once daily 90 mg orally once daily Weighing at least 25 kg to less than 35 kg 200 mg orally once daily 150 mg orally once daily Weighing at least 35 kg 300 mg orally once daily Table 3 Recommended Dosing Regimen in Treatment-Naïve or Treatment-Experienced Pediatric Patients with no Darunavir Resistance-Associated Substitutions in Combination with Darunavir Body Weight Darunavir Dosage TYBOST Dosage Weighing at least 15 kg to less than 25 kg 600 mg orally once daily 90 mg orally once daily Weighing at least 25 kg to less than 30 kg 600 mg orally once daily 150 mg orally once daily Weighing at least 30 kg to less than 40 kg 675 mg orally once daily Weighing at least 40 kg 800 mg orally once daily 2.3 Testing Prior to Initiation of TYBOST Prior to or when initiating TYBOST and during treatment with TYBOST, on a clinically appropriate schedule, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) ]. When coadministering TYBOST with TDF, assess estimated creatinine clearance, urine glucose, and urine protein at baseline. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2) ]. 2.4 Renal Impairment TYBOST coadministered with TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . 2.5 Not Recommended During Pregnancy TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.

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.

12.3 Pharmacokinetics Absorption In a trial where participants 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 C max , AUC tau, and C tau (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 Absorption A food-effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents [see Clinical Studies (14.1) ] 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 , 2.2) ] . Distribution Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Metabolism Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. Elimination The terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [ 14 C] 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 Race and Gender No clinically relevant differences in the pharmacokinetics of cobicistat were observed based on race or gender. Pediatric Patients In pediatric participants aged 12 to less than 18 years who received TYBOST 150 mg coadministered with atazanavir 300 mg (N=12), geometric mean atazanavir C max and AUC tau and cobicistat AUC tau values were approximately 20-30% higher than in adults and geometric mean atazanavir and cobicistat C tau values were approximately 60% to 160% higher than in adults; the increases were not considered clinically significant. In pediatric participants aged 12 to less than 18 years who received TYBOST 150 mg coadministered with darunavir 800 mg (N=7), geometric mean darunavir C max and AUC tau values were similar between adults and adolescents. Geometric mean darunavir AUC tau and C tau values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in adolescent participants relative to adults, respectively. This difference was not considered clinically significant based on exposure-response relationships. Geometric mean cobicistat AUC tau, C max, and C tau values were comparable in adolescents and adults ( Table 10 ). In pediatric participants aged 6 to less than 12 years (weighing ≥25 kg to <40 kg) who received TYBOST 150 mg coadministered with atazanavir (N=14) or darunavir (N=9), AUC tau and C max values were similar to those in adults, while the C trough was 33% higher for atazanavir and 44% higher for darunavir than in adults. In this study, exposures of cobicistat (AUC tau, C max, and C trough ) in the combined groups were 88%, 52%, and 192%, respectively, higher than in adults ( Table 10 ). However, the increases were not considered clinically significant. In pediatric participants at least 2 years of age (weighing ≥14 kg to <25 kg) who received TYBOST 90 mg coadministered with atazanavir (N=15) or darunavir (N=11), exposures (AUC tau, C max, and C trough ) were higher for atazanavir (46%, 72% and 42%, respectively) and darunavir (49%, 88%, and 66%, respectively) as compared to exposures in adults. Exposures of cobicistat (AUC tau, C max, and C trough ) in the combined groups were 58%, 29%, and 126%, respectively, higher than in adults ( Table 10 ). However, the increases were not considered clinically significant. Table 10 Multiple-Dose PK Parameters of Cobicistat, Atazanavir, and Darunavir Following Administration of TYBOST with Atazanavir or Darunavir in Pediatric Participants with HIV-1 Weighing at Least 14 kg From Intensive PK analysis of Trial 128. Parameter Mean (CV%) Cobicistat Atazanavir Darunavir Treatment Administered TYBOST + Atazanavir TYBOST + Darunavir TYBOST + Atazanavir TYBOST + Darunavir CV=Coefficient of Variation Pediatric Participants 12 to less than 18 years of age (weighing ≥35 kg) , Values are geometric means N=12 N=7 N=12 N=7 AUC tau (mcg∙hr/mL) 12.11 (44.7) 8.33 (34.9) 49.48 (49.1) 77.22 (29.5) C max (mcg/mL) 1.28 (31.7) 1.10 (20.0) 4.32 (49.9) 7.32 (21.7) C tau (mcg/mL) 0.09 (156.2) 0.02 (123.9) N=5; Data from two participants who had undetectable TYBOST C tau concentrations were excluded from summary statistics. 0.91 (96.4) 0.68 (91.6) Pediatric Participants 6 to less than 12 years of age (weighing ≥25 to < 40 kg) , Values are arithmetic means N=14 N=9 N=14 N=9 AUC tau (mcg∙hr/mL) 21.03 (21.7) N=13 13.67 (39.8) 47.48 (38.4) 110.51 (30.8) C max (mcg/mL) 2.62 (20.5) 1.64 (29.8) 4.19 (38.9) 9.10 (23.9) C tau (mcg/mL) 0.10 (118.4) 0.06 (109.7) 0.92 (66.4) 3.78 (43.2) Pediatric Participants at least 2 years of age (weighing ≥14 to < 25 kg) , N=15 N=11 N=15 N=11 AUC tau (mcg∙hr/mL) 15.14 (39.3) 16.07 (46.9) 65.51 (50.8) 160.53 (54.0) C max (mcg/mL) 1.95 (37.1) 2.08 (36.0) 6.78 (52.0) 15.02 (38.0) C tau (mcg/mL) 0.06 (114.0) 0.06 (138.6) 0.95 (58.0) 2.79 (92.1) Adults From pooled Intensive PK analysis of trials with TYBOST + atazanavir. , From Intensive PK analysis of Trial GS-US-299-0102 with TYBOST + darunavir. , N=30 N=21 N=30 N=21 AUC tau (mcg∙hr/mL) 9.65 (41.8) 7.69 (43.9) 39.96 (52.1) 90.56 (45.3) C max (mcg/mL) 1.28 (35.6) 1.04 (35.3) 3.54 (45.8) 8.34 (33.3) C tau (mcg/mL) 0.04 (112.7) 0.02 (135.1) N=18. 0.58 (84.7) 1.00 (108.0) Patients with Renal Impairment No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with severe renal impairment (estimated creatinine clearance below 30 mL/min) and healthy participants [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with moderate hepatic impairment (Child-Pugh Class B) and healthy participants. 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) ]. Pregnancy and Postpartum The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 11 and Figure 1 ). Table 11: Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy, and Postpartum Pharmacokinetics of total darunavir (mean ± SD) 2 nd Trimester of pregnancy N=7 3 rd Trimester of pregnancy N=6 Postpartum (6–12 weeks) N=6 C max , ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199 AUC 24h , ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862 C min , ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344 Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e. second or third trimester / postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25. Figure 1: Pharmacokinetic Results (Within-participant Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd and 3 rd Trimester of Pregnancy Compared to Postpartum Figure 1 Assessment of Drug Interactions Drug 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 12 . Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat All interaction studies conducted in healthy participants. 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. Coadministered Drug Dose of Coadministered Drug (mg) TYBOST Dose (mg) N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC Atorvastatin 10 single dose 150 once daily 16 18.85 Study conducted in the presence of 300 mg atazanavir. (13.53, 26.27) 9.22 (7.58, 11.22) 4.19 Study conducted in the presence of 800 mg darunavir. (3.67, 4.78) 3.90 (3.52, 4.32) Desipramine 50 single dose 150 once daily 8 1.24 (1.08, 1.44) 1.65 (1.36, 2.02) Digoxin 0.5 single dose 150 once daily 22 1.41 (1.29, 1.55) 1.08 (1.00, 1.17) Drospirenone/ ethinyl estradiol 3 drospirenone single dose 150 once daily 14 1.12 (1.05, 1.19) 2.30 (2.00, 2.64) 0.02 ethinyl estradiol single dose 0.82 (0.76, 0.89) 0.78 (0.73, 0.85) 3 drospirenone single dose 150 once daily 15 1.15 (1.05, 1.26) 1.58 (1.47, 1.71) 0.02 ethinyl estradiol single dose 0.86 (0.77, 0.95) 0.70 (0.63, 0.77) Efavirenz 600 single dose 150 once daily 17 0.87 (0.80, 0.94) 0.93 (0.89, 0.97) Rosuvastatin 10 single dose 150 once daily 16 10.58 (8.72, 12.83) 3.42 (2.87, 4.07) 3.77 (3.29, 4.32) 1.93 (1.70, 2.20)