Tipranavir

1 INDICATIONS AND USAGE APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adults and pediatric patients weighing 36 kg or higher who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI) [see Use in Specific Populations (8.4) ] . This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy. The following points should be considered when initiating therapy with APTIVUS/ritonavir: The use of APTIVUS/ritonavir in treatment-naïve patients is not recommended [ see Warnings and Precautions (5.2) ]. The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response [ see Microbiology (12.4) and Clinical Studies (14) ]. Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir [ see Microbiology (12.4) ]. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir [ see Microbiology (12.4) ]. Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment [ see Warnings and Precautions (5.2) ]. Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment [ see Warnings and Precautions (5.2) ]. The drug-drug interaction potential of APTIVUS/ritonavir when co-administered with other drugs must be considered prior to and during APTIVUS/ritonavir use [ see Contraindications (4) and Drug Interactions (7) ]. Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding [ see Warnings and Precautions (5.5) ]. There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1. APTIVUS, a protease inhibitor, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult and pediatric patients weighing 36 kg or higher who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor ( 1 ) Do not use APTIVUS/ritonavir in treatment-naïve patients ( 1 )

2 DOSAGE AND ADMINISTRATION Adults: 500 mg APTIVUS, co-administered with 200 mg ritonavir, twice daily ( 2.2 ) Pediatric patients (weighing 36 kg or higher): 500 mg APTIVUS, co-administered with 200 mg ritonavir twice daily. ( 2.2 ) APTIVUS taken with ritonavir tablets must be taken with meals ( 2.1 ) APTIVUS capsules must be swallowed whole and must not be opened or chewed ( 2.1 ) Children should be assessed for their ability to swallow capsules before prescribing APTIVUS capsules. ( 2.1 ) Store unopened bottles of APTIVUS capsules in the refrigerator. ( 16 ) 2.1 Dosage and Administration Overview APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions [see Warnings and Precautions (5.1) ] . Children should be assessed for their ability to swallow capsules before prescribing APTIVUS capsules [see Use in Specific Populations (8.4) ] . APTIVUS co-administered with ritonavir tablets must only be taken with meals [see Clinical Pharmacology (12.3) ] . APTIVUS is supplied as capsules. APTIVUS capsules must be swallowed whole and must not be opened or chewed. Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information. 2.2 Recommended Dosage in Adults and Pediatric Patients Weighing 36 kg or Higher The recommended dosage in adults and pediatric patients weighing 36 kg or higher is 500 mg (two 250 mg capsules) of APTIVUS co-administered with 200 mg of ritonavir, twice daily.

6 ADVERSE REACTIONS The following adverse reactions are described, in greater detail, in other sections: Hepatic Impairment and Toxicity [ see Warnings and Precautions (5.2) ] Intracranial Hemorrhage [ see Warnings and Precautions (5.3) ] Rash [ see Warnings and Precautions (5.6) ] Due to the need for co-administration of APTIVUS with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions. 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 clinical practice. In adults the most frequent adverse reactions (incidence >4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. ( 6.1 ) In pediatric subjects the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric subjects than in adults. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials in Adults APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced subjects received the dose of 500 mg/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks [ see Clinical Studies (14) ]. In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated subjects and 10.8% for the comparator arm subjects. Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 - 4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below. Table 2 Adverse Reactions Reported in Randomized, Controlled Clinical Trials (1182.12 and 1182.48) Based on Treatment-Emergent Clinical Adverse Reactions of Moderate to Severe Intensity (Grades 2 - 4) in at least 2% of Treatment-Experienced Subjects in either Treatment Group a (48-week Analyses) Percentage of patients (rate per 100 patient-exposure years) APTIVUS/ritonavir (500/200 mg BID) + OBR c (n=749; 757.4 patient-exposure years) Comparator PI/ritonavir b + OBR (n=737; 503.9 patient-exposure years) a Excludes laboratory abnormalities that were Adverse Events b Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID c Optimized Background Regimen Blood and Lymphatic Disorders Anemia 3.3% (3.4) 2.3% (3.4) Neutropenia 2.0% (2.0) 1.0% (1.4) Gastrointestinal Disorders Diarrhea 15.0% (16.5) 13.4% (21.6) Nausea 8.5% (9.0) 6.4% (9.7) Vomiting 5.9% (6.0) 4.1% (6.1) Abdominal pain 4.4% (4.5) 3.4% (5.1) Abdominal pain upper 1.5% (1.5) 2.3% (3.4) General Disorders Pyrexia 7.5% (7.7) 5.4% (8.2) Fatigue 5.7% (5.9) 5.6% (8.4) Investigations Weight decreased 3.1% (3.1) 2.2% (3.2) ALT increased 2.0% (2.0) 0.5% (0.8) GGT increased 2.0% (2.0) 0.4% (0.6) Metabolism and Nutrition Disorders Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0) Hyperlipidemia 2.5% (2.6) 0.8% (1.2) Dehydration 2.1% (2.1) 1.1% (1.6) Musculoskeletal and Connective Tissue Disorders Myalgia 2.3% (2.3) 1.8% (2.6) Nervous System Disorders Headache 5.2% (5.3) 4.2% (6.3) Peripheral neuropathy 1.5% (1.5) 2.0% (3.0) Psychiatric Disorders Insomnia 1.7% (1.7) 3.7% (5.5) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 2.1% (2.1) 1.0% (1.4) Skin and Subcutaneous Tissue Disorders Rash 3.1% (3.1) 3.8% (5.7) Less Common Adverse Reactions Other adverse reactions reported in <2% of adult subjects (n=1474) treated with APTIVUS/ritonavir 500 mg/200 mg in Phase 2 and 3 clinical trials are listed below by body system: Blood and Lymphatic System Disorders: thrombocytopenia Gastrointestinal Disorders: abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis General Disorders: influenza-like illness, malaise Hepatobiliary Disorders: hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis Immune System Disorders: hypersensitivity Investigations: hepatic enzymes increased, liver function test abnormal, lipase increased Metabolism and Nutrition Disorders: anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity Musculoskeletal and Connective Tissue Disorders: muscle cramp Nervous System Disorders: dizziness, intracranial hemorrhage, somnolence Psychiatric Disorders: sleep disorder Renal and Urinary Disorders: renal insufficiency Skin and Subcutaneous System Disorders: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus Laboratory Abnormalities Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below. Table 3 Treatment-Emergent Laboratory Abnormalities Reported in ≥2% of Adult Patients (48-week Analyses) Randomized, Controlled Clinical Trials 1182.12 and 1182.48 Percentage of Patients (rate per 100 patient-exposure years) Limit APTIVUS/ritonavir (500/200 mg BID) + OBR (n=738) Comparator PI/ritonavir + OBR* (n=724) *Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID Hematology WBC count decrease Grade 3 <2.0 × 10 3 /µL 5.4% (5.6) 4.8% (7.7) Grade 4 <1.0 × 10 3 /µL 0.3% (0.3) 1.1% (1.7) Chemistry Amylase Grade 3 >2.5 × ULN 5.7% (5.9) 6.4% (10.4) Grade 4 >5 × ULN 0.3% (0.3) 0.7% (1.1) ALT Grade 2 >2.5-5 × ULN 14.9% (16.5) 7.5% (12.4) Grade 3 >5-10 × ULN 5.6% (5.7) 1.7% (2.6) Grade 4 >10 × ULN 4.1% (4.1) 0.4% (0.7) AST Grade 2 >2.5-5 × ULN 9.9% (10.5) 8.0% (13.3) Grade 3 >5-10 × ULN 4.5% (4.6) 1.4% (2.2) Grade 4 >10 × ULN 1.6% (1.6) 0.4% (0.6) ALT and/or AST Grade 2-4 >2.5 × ULN 26.0% (31.5) 13.7% (23.8) Cholesterol Grade 2 >300 – 400 mg/dL 15.6% (17.7) 6.4% (10.5) Grade 3 >400 – 500 mg/dL 3.3% (3.3) 0.3% (0.4) Grade 4 >500 mg/dL 0.9% (1.0) 0.1% (0.2) Triglycerides Grade 2 400 – 750 mg/dL 35.9% (49.9) 26.8% (51.0) Grade 3 >750 – 1200 mg/dL 16.9% (19.4) 8.7% (14.6) Grade 4 >1200 mg/dL 8.0% (8.4) 4.3% (7.0) In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of subjects who developed Grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 32.1% at week 96 with APTIVUS/ritonavir. The risk of developing transaminase elevations is greater during the first year of therapy. 6.2 Clinical Trials in Pediatrics APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric subjects as combination therapy. Study 1182.14 enrolled HIV-1 infected, treatment-experienced pediatric subjects (with the exception of 3 treatment-naïve subjects), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) subjects were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 subjects were enrolled in other clinical studies including Expanded Access and Emergency Use Programs. The adverse reactions profile seen in Study 1182.14 was similar to adults. However, rash (5.5%), was reported more frequently in pediatric subjects than in adults. The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%).

12.3 Pharmacokinetics In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with ritonavir is essential [ see Dosage and Administration (2) ]. Ritonavir inhibits hepatic cytochrome P450 3A (CYP3A), the intestinal P-gp efflux pump and possibly intestinal CYP3A. In a dose-ranging evaluation in 113 HIV-1 negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following APTIVUS co-administered with low-dose ritonavir (500 mg/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of APTIVUS was similar to the concentrations observed when 100 mg was given with the other protease inhibitors. Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV-1 infected adult subjects dosed with 500 mg/200 mg tipranavir/ritonavir for 14 days. Figure 1 Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500 mg/200 mg BID) Figure 1 Absorption and Bioavailability Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. In vivo data suggest that tipranavir/ritonavir, at the dose of 500 mg/200 mg, is a P-gp inhibitor after the first dose and induction of P-gp occurs over time. Tipranavir trough concentrations at steady-state are about 70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing. Dosing APTIVUS 500 mg with 200 mg ritonavir capsules twice daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic parameters for male and female HIV-1 positive subjects presented in Table 5. Table 5 Pharmacokinetic Parameters a of tipranavir/ritonavir 500 mg/200 mg for HIV-1 Positive Subjects by Gender Parameter Females (n=14) Males (n=106) a Population pharmacokinetic parameters reported as mean ± standard deviation Cp trough (µM) 41.6 ± 24.3 35.6 ± 16.7 C max (µM) 94.8 ± 22.8 77.6 ± 16.6 T max (h) 2.9 3.0 AUC 0-12h (µM∙h) 851 ± 309 710 ± 207 CL (L/h) 1.15 1.27 V (L) 7.7 10.2 t 1/2 (h) 5.5 6.0 Effects of Food on Oral Absorption For APTIVUS capsules co-administered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir C max , Cp12h, and AUC were observed under fed conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted conditions [ see Dosage and Administration (2) ]. The effect of food on tipranavir exposure when APTIVUS capsules is co-administered with ritonavir tablets has not been evaluated [ see Dosage and Administration (2) ]. For information on the effect of food on the bioavailability of ritonavir tablets, please refer to the ritonavir tablet prescribing information. Distribution Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and α-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive subjects. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 µM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range. No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen. Metabolism In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP enzyme involved in tipranavir metabolism. The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver. The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. Administration of 14 C-tipranavir to subjects that received APTIVUS/ritonavir 500 mg/200 mg dosed to steady-state demonstrated that unchanged tipranavir accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In feces, unchanged tipranavir represented the majority of fecal radioactivity (79.9% of fecal radioactivity). The most abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir. Elimination Administration of 14 C-tipranavir to subjects (n=8) that received APTIVUS/ritonavir 500 mg/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult subjects (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500 mg/200 mg twice daily with a light meal. Special Populations Renal Impairment APTIVUS pharmacokinetics has not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency. Hepatic Impairment In a study comparing 9 HIV-1 negative subjects with mild (Child-Pugh Class A) hepatic impairment to 9 HIV-1 negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in subjects with hepatic impairment, but were within the range observed in clinical trials. No dosing adjustment is required in patients with mild hepatic impairment. The influence of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated [ see Dosage and Administration (2) , Contraindications (4) , and Warnings and Precautions (5.2) ]. Gender Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS/ritonavir 500 mg/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. The difference in concentrations does not warrant a dose adjustment. Race Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. Geriatric Patients Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly. Pediatric Patients Among pediatric subjects in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. The exposure differences between pediatric subjects and adults are not considered to be clinically significant based on the activity and safety data. Drug Interactions Drug interaction studies were performed with APTIVUS capsules co-administered with ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir on the AUC, C max , and C min of tipranavir or the co-administered drug, are summarized in Tables 6 and 7, respectively. For information regarding clinical recommendations see Drug Interactions (7.2) . Table 6 Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs Co-administered Drug Co-administered Drug Dose (Schedule) tipranavir/ ritonavir Drug Dose (Schedule) n PK Ratio (90% Confidence Interval) of Tipranavir Pharmacokinetic Parameters with/without Co-administered Drug; No Effect = 1.00 C max AUC C min *steady state comparison to historical data (n) ↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict Antacids (Maalox®) 20 mL (1 dose) 500 mg/200 mg (1 dose) 23 ↓ 0.75 (0.63, 0.88) 0.73 (0.64, 0.84) - Atazanavir/ritonavir 300 mg/100 mg QD (9 doses) 500 mg/100 mg BID (34 doses) 13 ↑ 1.08 (0.98, 1.20) 1.20 (1.09, 1.32) 1.75 (1.39, 2.20) Atorvastatin 10 mg (1 dose) 500 mg/200 mg BID (14 doses) 22 ↔ 0.96 (0.86, 1.07) 1.08 (1.00, 1.15) 1.04 (0.89, 1.22) Clarithromycin 500 mg BID (25 doses) 500 mg/200 mg BID* 24 (68) ↑ 1.40 (1.24, 1.47) 1.66 (1.43, 1.73) 2.00 (1.58, 2.47) Didanosine 400 mg (1 dose) 500 mg/100 mg BID (27 doses) 5 ↓ 1.32 (1.09, 1.60) 1.08 (0.82, 1.42) 0.66 (0.31, 1.43) Efavirenz 600 mg QD (8 doses) 500 mg/100 mg BID* 21 (89) ↓ 0.79 (0.69, 0.89) 0.69 (0.57, 0.83) 0.58 (0.36, 0.86) 750 mg/200 mg BID* 25 (100) ↔ 0.97 (0.85, 1.09) 1.01 (0.85, 1.18) 0.97 (0.69, 1.28) Ethinyl estradiol /Norethindrone 0.035 mg/1.0 mg (1 dose) 500 mg/100 mg BID (21 doses) 21 ↓ 1.10 (0.98, 1.24) 0.98 (0.88, 1.11) 0.73 (0.59, 0.90) 750 mg/200 mg BID (21 doses) 13 ↔ 1.01 (0.96, 1.06) 0.98 (0.90, 1.07) 0.91 (0.69, 1.20) Fluconazole 100 mg QD (12 doses) 500 mg/200 mg BID* 20 (68) ↑ 1.32 (1.18, 1.47) 1.50 (1.29, 1.73) 1.69 (1.33, 2.09) Loperamide 16 mg (1 dose) 750 mg/200 mg BID (21 doses) 24 ↓ 1.03 (0.92, 1.17) 0.98 (0.86, 1.12) 0.74 (0.62, 0.88) Rifabutin 150 mg (1 dose) 500 mg/200 mg BID (15 doses) 21 ↔ 0.99 (0.93, 1.07) 1.00 (0.96, 1.04) 1.16 (1.07, 1.27) Rosuvastatin 10 mg (1 dose) 500 mg/200 mg BID (24 doses) 16 ↔ 1.08 (1.00, 1.17) 1.06 (0.97, 1.15) 0.99 (0.88, 1.11) Tadalafil 10 mg (1 dose) 500 mg/200 mg BID (17 doses) 17 ↔ 0.90 (0.80, 1.01) 0.85 (0.74, 0.97) 0.81 (0.70, 0.94) Tenofovir 300 mg (1 dose) 500 mg/100 mg BID 22 ↓ 0.83 (0.74, 0.94) 0.82 (0.75, 0.91) 0.79 (0.70, 0.90) 750 mg/200 mg BID (23 doses) 20 ↔ 0.89 (0.84, 0.96) 0.91 (0.85, 0.97) 0.88 (0.78, 1.00) Valacyclovir 500 mg (1 dose) 500 mg/200 mg BID (23 doses) 26 ↔ 1.02 (0.95, 1.10) 1.01 (0.96, 1.06) 0.98 (0.93, 1.04) Zidovudine 300 mg (1 dose) 500 mg/100 mg BID 29 ↓ 0.87 (0.80, 0.94) 0.82 (0.76, 0.89) 0.77 (0.68, 0.87) 750 mg/200 mg BID (23 doses) 25 ↔ 1.02 (0.94, 1.10) 1.02 (0.92, 1.13) 1.07 (0.86, 1.34) Table 7 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of APTIVUS/ritonavir Co-administered Drug Co-administered Drug Dose (Schedule) tipranavir/ ritonavir Drug Dose (Schedule) n PK Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without tipranavir/ritonavir; No Effect = 1.00 C max AUC C min a HIV-1 positive subjects b Buprenorphine/Naloxone maintenance subjects c HIV-1 positive subjects (tipranavir/ritonavir 250 mg/200 mg, 750 mg/200 mg and 1250 mg/100 mg) and healthy volunteers (tipranavir/ritonavir 500 mg/100 mg and 750 mg/200 mg) d Normalized sum of parent drug (rifabutin) and active metabolite (25-O-desacetyl-rifabutin) e Intensive PK analysis f Drug levels obtained at 8-16 hrs post-dose g n = 14 for C min h Administered as Valacyclovir ↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict Abacavir a 300 mg BID (43 doses) 250 mg/200 mg BID 750 mg/100 mg BID 1250 mg/100 mg BID (42 doses) 28 14 11 ↓ ↓ ↓ 0.56 (0.48, 0.66) 0.54 (0.47, 0.63) 0.48 (0.42, 0.53) 0.56 (0.49, 0.63) 0.64 (0.55, 0.74) 0.65 (0.55, 0.76) - - - Acyclovir h 500 mg (1 dose) 500 mg/200 mg BID (23 doses) 26 ↔ 0.95 (0.88, 1.02) 1.07 (1.04, 1.09) - Amprenavir/ritonavir a 600 mg/100 mg BID (27 doses) 500 mg/200 mg BID (28 doses) 16 74 ↓ ↓ 0.61 (0.51, 0.73) e 0.56 (0.49, 0.64) e - 0.45 (0.38, 0.53) e 0.44 (0.39, 0.49) f Atazanavir/ritonavir 300 mg/100 mg QD (9 doses) 500 mg/100 mg BID (34 doses) 13 ↓ 0.43 (0.38, 0.50) 0.32 (0.29, 0.36) 0.19 (0.15, 0.24) Atorvastatin 10 mg (1 dose) 500 mg/200 mg BID (17 doses) 22 ↑ 8.61 (7.25, 10.21) 9.36 (8.02, 10.94) 5.19 (4.21, 6.40) Orthohydroxy-atorvastatin Parahydroxy-atorvastatin 21, 12, 17 ↓ 0.02 (0.02, 0.03) 0.11 (0.08, 0.17) 0.07 (0.06, 0.08) 13, 22, 1 ↓ 1.04 (0.87, 1.25) 0.18 (0.14, 0.24) 0.33 (NA) Buprenorphine/Naloxone b 16 mg/4 mg 24 mg/6 mg (daily) 500 mg/200 mg BID (16 doses) Buprenorphine 10 ↔ 0.86 (0.68, 1.10) 0.99 (0.80, 1.23) 0.94 (0.74, 1.19) Carbamazepine 100 mg BID (29 doses) 500 mg/200 mg (1 dose) 7 ↔ 1.04 (1.00, 1.07) 1.05 (1.02, 1.09) 1.17 (1.11, 1.24) (43 doses) (15 doses) 7 ↔ 1.10 (0.85, 1.42) 1.08 (0.91, 1.27) 1.07 (0.90, 1.27) 200 mg BID (29 doses) 500 mg/200 mg (1 dose) 17 ↔ 1.00 (0.96, 1.04) 1.04 (1.00, 1.08) 1.16 (1.11, 1.22) (43 doses) (15 doses) 17 ↑ 1.22 (1.11, 1.34) 1.26 (1.15, 1.38) 1.35 (1.22, 1.50) Clarithromycin 500 mg BID (25 doses) 500 mg/200 mg BID (15 doses) 21 ↑ 0.95 (0.83, 1.09) 1.19 (1.04, 1.37) 1.68 (1.42, 1.98) 14-OH-clarithromycin 21 ↓ 0.03 (0.02, 0.04) 0.03 (0.02, 0.04) 0.05 (0.04, 0.07) Didanosine c 200 mg BID, ≥60 kg 125 mg BID, <60 kg (43 doses) 250 mg/200 mg BID 750 mg/100 mg BID 1250 mg/100 mg BID (42 doses) 10 8 9 ↓ ↔ ↔ 0.57 (0.42, 0.79) 0.76 (0.49, 1.17) 0.77 (0.47, 1.26) 0.67 (0.51, 0.88) 0.97 (0.64, 1.47) 0.87 (0.47, 1.65) - - - 400 mg (1 dose) 500 mg/100 mg BID (27 doses) 5 ↔ 0.80 (0.63, 1.02) 0.90 (0.72, 1.11) 1.17 (0.62, 2.20) Dolutegravir 50 mg QD 500 mg/200 mg BID 14 ↓ 0.54 (0.50-0.57) 0.41 (0.38-0.44) 0.24 (0.21-0.27) Efavirenz c 600 mg QD (15 doses) 500 mg/100 mg BID 750 mg/200 mg BID (15 doses) 24 22 ↔ ↔ 1.09 (0.99, 1.19) 1.12 (0.98, 1.28) 1.04 (0.97, 1.12) 1.00 (0.93, 1.09) 1.02 (0.92, 1.12) 0.94 (0.84, 1.04) Ethinyl estradiol 0.035 mg (1 dose) 500 mg/100 mg BID 750 mg/200 mg BID (21 doses) 21 13 ↓ ↓ 0.52 (0.47, 0.57) 0.48 (0.42, 0.57) 0.52 (0.48, 0.56) 0.57 (0.54, 0.60) - - Fluconazole 200 mg (Day 1) then 100 mg QD (6 or 12 doses) 500 mg/200 mg BID (2 or 14 doses) 19 19 ↔ ↔ 0.97 (0.94, 1.01) 0.94 (0.91, 0.98) 0.99 (0.97, 1.02) 0.92 (0.88, 0.95) 0.98 (0.94, 1.02) 0.89 (0.85, 0.92) Lopinavir/ritonavir a 400 mg/100 mg BID (27 doses) 500 mg/200 mg BID (28 doses) 21 69 ↓ ↓ 0.53 (0.40, 0.69) e - 0.45 (0.32, 0.63) e - 0.30 (0.17, 0.51) e 0.48 (0.40, 0.58) f Loperamide 16 mg (1 dose) 750 mg/200 mg BID (21 doses) 24 ↓ 0.39 (0.31, 0.48) 0.49 (0.40, 0.61) - N-Demethyl-Loperamide 24 ↓ 0.21 (0.17, 0.25) 0.23 (0.19, 0.27) - Lamivudine a 150 mg BID (43 doses) 250 mg/200 mg BID 750 mg/100 mg BID 1250 mg/100 mg BID (42 doses) 64 46 35 ↔ ↔ ↔ 0.96 (0.89, 1.03) 0.86 (0.78, 0.94) 0.71 (0.62, 0.81) 0.95 (0.89, 1.02) 0.96 (0.90, 1.03) 0.82 (0.66, 1.00) - - - Methadone 5 mg (1 dose) 500 mg/200 mg BID (16 doses) 14 ↓ 0.45 (0.41, 0.49) 0.47 (0.44, 0.51) 0.50 (0.46, 0.54) R-methadone 0.54 (0.50, 0.58) 0.52 (0.49, 0.56) - S-methadone 0.38 (0.35, 0.43) 0.37 (0.34, 0.41) - Nevirapine a 200 mg BID (43 doses) 250 mg/200 mg BID 750 mg/100 mg BID 1250 mg/100 mg BID (42 doses) 26 22 17 ↔ ↔ ↔ 0.97 (0.90, 1.04) 0.86 (0.76, 0.97) 0.71 (0.62, 0.82) 0.97 (0.91, 1.04) 0.89 (0.78, 1.01) 0.76 (0.63, 0.91) 0.96 (0.87, 1.05) 0.93 (0.80, 1.08) 0.77 (0.64, 0.92) Norethindrone 1.0 mg (1 dose) 500 mg/100 mg BID 750 mg/200 mg BID (21 doses) 21 13 ↔ ↔ 1.03 (0.94, 1.13) 1.08 (0.97, 1.20) 1.14 (1.06, 1.22) 1.27 (1.13, 1.43) - - Raltegravir 400 mg BID 500 mg/200 mg BID 15 ↓ 0.82 (0.46, 1.46) 0.76 (0.49, 1.19) 0.45 (0.31, 0.66) g Rifabutin 150 mg (1 dose) 500 mg/200 mg BID (15 doses) 20 ↑ 1.70 (1.49, 1.94) 2.90 (2.59, 3.26) 2.14 (1.90, 2.41) 25-O-desacetyl-rifabutin 20 ↑ 3.20 (2.78, 3.68) 20.71 (17.66, 24.28) 7.83 (6.70, 9.14) Rifabutin + 25-O-desacetyl-rifabutin d 20 ↑ 1.86 (1.63, 2.12) 4.33 (3.86, 4.86) 2.76 (2.44, 3.12) Rosuvastatin 10 mg (1 dose) 500 mg/200 mg BID (24 doses) 16 ↑ 2.23 (1.83, 2.72) 1.26 (1.08, 1.46) 1.06 (0.93, 1.20) Saquinavir/ritonavir a 600 mg/100 mg BID (27 doses) 500 mg/200 mg BID (28 doses) 20 68 ↓ ↓ 0.30 (0.23, 0.40) e - 0.24 (0.19, 0.32) e - 0.18 (0.13, 0.26) e 0.20 (0.16, 0.25) f Stavudine a 40 mg BID ≥60 kg 30 mg BID <60 kg (43 doses) 250 mg/200 mg BID 750 mg/100 mg BID 1250 mg/100 mg BID (42 doses) 26 22 19 ↔ ↔ ↔ 0.90 (0.81, 1.02) 0.76 (0.66, 0.89) 0.74 (0.69, 0.80) 1.00 (0.91, 1.11) 0.84 (0.74, 0.96) 0.93 (0.83, 1.05) - - - Tadalafil 10 mg (1 dose) 500 mg/200 mg (1 dose) 17 ↑ 0.78 (0.72, 0.84) 2.33 (2.02, 2.69) - 10 mg (1 dose) 500 mg/200 mg BID (17 doses) 17 ↔ 0.70 (0.63, 0.78) 1.01 (0.83, 1.21) - Tenofovir 300 mg (1 dose) 500 mg/100 mg BID 750 mg/200 mg BID (23 doses) 22 20 ↓ ↓ 0.77 (0.68, 0.87) 0.62 (0.54, 0.71) 0.98 (0.91, 1.05) 1.02 (0.94, 1.10) 1.07 (0.98, 1.17) 1.14 (1.01, 1.27) Zidovudine c 300 mg BID 250 mg/200 mg BID 48 ↓ 0.54 (0.47, 0.62) 0.58 (0.51, 0.66) - 300 mg BID 750 mg/100 mg BID 31 ↓ 0.51 (0.44, 0.60) 0.64 (0.55, 0.75) - 300 mg BID (43 doses) 1250 mg/100 mg BID (42 doses) 23 ↓ 0.49 (0.40, 0.59) 0.69 (0.49, 0.97) - 300 mg (1 dose) 500 mg/100 mg BID 750 mg/200 mg BID (23 doses) 29 25 ↓ ↔ 0.39 (0.33, 0.45) 0.44 (0.36, 0.54) 0.57 (0.52, 0.63) 0.67 (0.62, 0.73) 0.89 (0.81, 0.99) 1.25 (1.08, 1.44) Zidovudine glucuronide 500 mg/100 mg BID 750 mg/200 mg BID (23 doses) 29 25 ↑ ↑ 0.82 (0.74, 0.90) 0.82 (0.73, 0.92) 1.02 (0.97, 1.06) 1.09 (1.05, 1.14) 1.52 (1.34, 1.71) 1.94 (1.62, 2.31)