Tipranavir

12.1 Mechanism of Action Tipranavir is an antiretroviral drug [ see Microbiology (12.4) ].

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 I

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 c

7 DRUG INTERACTIONS Co-administration of APTIVUS can alter the concentrations of other drugs and other drugs may alter the concentration of tipranavir. The potential for drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.4 , 7 ) 7.1 Potential for APTIVUS/ritonavir to Affect Other Drugs APTIVUS co-administered with ritonavir at the recommended dose is a net inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Thus, co-administration of APTIVUS/ritonavir 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 [see Contraindications (4) ] . Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring [see Drug Interactions (7) ] . Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below. A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of APTIVUS co-administered with 200 mg of ritonavir twice daily in capsule form. There was no net effect on CYP2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP1A2, but there was moderate induction at steady state. There was modest inhibition of CYP2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP2D6 and both hepatic and intestinal CYP3A4/5 activities were observed after first dose and steady state. Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of APTIVUS/ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established. 7.2 Potential for Other Drugs to Affect Tipranavir Tipranavir is a CYP3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir with drugs that inhibit CYP3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of APTIVUS/ritonavir 500 mg/200 mg twice daily. Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below [see Contraindications (4) , Warnings and Precautions (5.4) , and Clinical Pharmacology (12.3) ] . Table 4 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug name Effect on Concentration of Tipranavir or Concomitant Drug Clinical Comment ↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict HIV-1 Antiviral Agents Fusion Inhibitors: Enfuvirtide ↑ Tipranavir At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended. Non-Nucleoside Reverse Transcriptase Inhibitors: Etravirine ↓ Etravirine APTIVUS/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavir should not be coadministered. Rilpivirine The use of rilpivirine co-administered with APTIVUS/ritonavir has not been studied. Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir. Nucleoside Reverse Transcriptase Inhibitors: Abacavir ↓ Abacavir AUC by approximately 40% Clinical relevance of reduction in abacavir levels not established. Dose adjustment