FULL PRESCRIBING INFORMAT

* ON: CONTENTS

I

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

1. Hepatic Impairment

2. Drug Interactions

WARNINGS AND PRECAUTIONS

1. Hepatic Impairment and Toxicity

2. Intracranial Hemorrhage

3. Drug Interactions

4. Effects on Platelet Aggregation and Coagulation

5. Rash

6. Sulfa Allergy

7. Diabetes Mellitus/Hyperglycemia

8. Immune Reconstitution Syndrome

9. Fat Redistribution

10. Elevated Lipids

11. Patients with Hemophilia

12. Resistance/Cross Resistance

DRUG INTERACTIONS

1. Potential for APTIVUS/ritonavir to Affect Other Drugs

2. Potential for Other Drugs to Affect Tipranavir

USE IN SPECIFIC POPULATIONS

1. Pregnancy

-------------------------WARNINGS AND PRECAUTIONS-----------------

Hepatic Impairment: Discontinue for signs and symptoms of clinical hepatitis or asymptomatic increases in ALT/AST > 10 times ULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitant increases in total bilirubin. Monitor liver function tests prior to therapy and frequently (5.1). Intracranial Hemorrhage/Platelet Aggregation and Coagulation: Use with caution in patients at risk for increased bleeding or who are receiving medications that increase the risk of bleeding (5.2, 5.4) Drug Interactions: Consider drug-drug interaction potential to reduce risk of serious or life-threatening adverse reactions (5.3) Rash: Discontinue and initiate appropriate treatment if severe skin reaction occurs or is suspected (5.5). Use with caution in patients with a known sulfonamide allergy (5.6). Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.7), immune reconstitution syndrome (5.8), redistribution/accumulation of body fat (5.9), and elevated lipids (5.10). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.11)

--------------------------ADVERSE REACTIONS------------------------------

Most frequent adverse reactions (incidence > 4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain (6)

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-------------------------DRUG INTERACTIONS-------------------------------

Coadministration 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 (4.2, 5.3, 7).

-------------------------USE IN SPECIFIC POPULATIONS----------------------

The risk-benefit has not been established in pediatric patients (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-

approved patient labeling.

Revised: 10/2007

Nursing MothersPediatric UseGeriatric UseHepatic Impairment

OVERDOSAGE

DESCRIPTION

CLINICAL PHARMACOLOGY

1. Mechanism of Action

2. Pharmacodynamics

3. Pharmacokinetics

4. Microbiology

NONCLINICAL TOXICOLOGY

1. Carcinogenesis, Mutagenesis, Impairment of Fertility

2. Animal Toxicology and/or Pharmacology

CLINICAL STUDIES

HOW SUPPLIED/STORAGE AND HANDLING

PATIENT COUNSELING INFORMATION

1. Hepatic Impairment and Toxicity

2. Intracranial Hemorrhage

3. Drug Interactions

4. Rash

5. Sulfa Allergy

6. Contraceptives

7. Fat Redistribution

8. Administration

9. FDA-Approved Patient Labeling

* Sections or sub-sections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

Hepatotoxicity:

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity [see Warnings and Precautions (5.1)].

Intracranial Hemorrhage:

Both fatal and non-fatal intracranial hemorrhage have been reported [see Warnings and Precautions (5.2)].

DOSAGE AND ADMINISTRATION

The recommended dose of APTIVUS (tipranavir) capsules is 500 mg (two 250 mg capsules), co-administered with 200 mg of ritonavir, twice daily. APTIVUS capsules, co-administered with 200 mg of ritonavir should be taken with food. Bioavailability is increased with a high fat meal. APTIVUS must be co-administered with 200 mg of 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.

DOSAGE FORMS AND STRENGTHS

250 mg, pink, oblong capsules imprinted with TPV 250

CONTRAINDICATIONS

Hepatic Impairment

APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1)].

Drug Interactions

Co-administration of APTIVUS with 200 mg of ritonavir with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers are contraindicated (See Table 1). These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. For information regarding clinical recommendations see Drug Interactions (7.2).

Table 1 Drugs that are Contraindicated with APTIVUS Co-Administered with 200 mg of Ritonavir

Drug Class

Drugs within Class that are Contraindicated with APTIVUS

Co-administered with 200 mg of Ritonavir Clinical Comments:

Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.

Antimycobacterials

Rifampin May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors or other co-

administered antiretroviral agents.

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI

motility agent Cisapride Potential for cardiac arrhythmias.

Herbal

Products St. John's Wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to

APTIVUS or to the class of protease inhibitors.

Due to the need for co-administration of APTIVUS with 200 mg of ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications.

WARNINGS AND PRECAUTIONS

Please refer to the ritonavir prescribing information for additional information on precautionary measures.

Hepatic Impairment and Toxicity

Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS co-administered with 200 mg of ritonavir. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment. If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. If asymptomatic elevations in AST or ALT between 5 - 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced patients, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48. In a study of treatment-naive patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir 500 mg/200 mg through week 48. Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased [see Clinical Pharmacology (12.3)].

Intracranial Hemorrhage

APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.

Drug Interactions

See Table 1 for a listing of contraindicated drugs with APTIVUS due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity [see Contraindications (4.2)].

Effects on Platelet Aggregation and Coagulation

APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E. In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir. In rats, co-administration with vitamin E increased the bleeding effects of tipranavir [see Nonclinical Toxicology (13.2)].

Rash

Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in subjects receiving APTIVUS/ritonavir. In some cases rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavir through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. Discontinue and initiate appropriate treatment if severe skin rash develops.

Sulfa Allergy

APTIVUS (tipranavir) should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross- sensitivity between drugs in the sulfonamide class and APTIVUS is unknown.

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Elevated Lipids

Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6)]. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions [see Drug Interactions (7.2)].

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.

Resistance/Cross Resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in APTIVUS/ritonavir treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.

DRUG INTERACTIONS

See also Contraindications (4.2), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3).

Potential for APTIVUS/ritonavir to Affect Other Drugs

APTIVUS co-administered with 200 mg of ritonavir at the recommended dose is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of APTIVUS/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated [see Contraindications (4.2)]. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring [see Drug Interactions (7)]. Clinically significant drug-drug interactions of APTIVUS co-administered with 200 mg of 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 administration on the activity of hepatic CYP 1A2 (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 CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co- administered drugs for CYP 3A 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.

Potential for Other Drugs to Affect Tipranavir

Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP 3A 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 CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady- state administration of APTIVUS/ritonavir 500/200 mg twice daily. Clinically significant drug-drug interactions of APTIVUS co-administered with 200 mg of ritonavir are summarized in Table 4 below.

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

HIV-Antiviral Agents

Nucleoside reverse transcriptase inhibitors:

Abacavir Didanosine (EC) Zidovudine

Protease inhibitors (co-administered with 200 mg of ritonavir):

Fosamprenavir Lopinavir Saquinavir

Protease inhibitors (co-administered with 100 mg of ritonavir):

Atazanavir | Abacavir AUC by approximately 40% | Didanosine | Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. | Amprenavir, | Lopinavir, | Saquinavir | Atazanavir, | Tipranavir Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time. Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours. Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time. Combining a protease inhibitor with APTIVUS/ritonavir is not recommended. Agents for Opportunistic Infections

Antifungals:

Fluconazole Itraconazole Ketoconazole Voriconazole

Antimycobacterials:

| Tipranavir, - Fluconazole | Itraconazole (not studied) | Ketoconazole (not studied) | Voriconazole (not studied) Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses > 200 mg/day are not recommended. Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction. Clarithromycin | Tipranavir, | Clarithromycin, | 14-hydroxy-clarithromycin metabolite No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.

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

For patients with renal impairment the following dosage adjustments should be considered:

• For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.

• For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

Rifabutin Tipranavir not changed, |Rifabutin | Desacetyl-rifabutin Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage

reduction may be necessary.

Other Agents Commonly Used

Anticonvulsants:

Carbamazepine Phenobarbital Phenytoin Valproic Acid

Antidepressants:

Trazodone Desipramine Selective Serotonin-Reuptake Inhibitors: Fluoxetine Paroxetine Sertraline

Calcium Channel Blockers:

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil | Tipranavir | Valproic Acid | Trazodone Combination with APTIVUS/ritonavir not studied | Desipramine Combination with APTIVUS/ritonavir not studied | Fluoxetine | Paroxetine | Sertraline Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. | Diltiazem | Felodipine (CYP 3A substrate but not P- gp substrate) | Nicardipine | Nisoldipine (CYP 3A substrate but not Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly. Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly. Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co- administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. Dosage reduction and concentration monitoring of desipramine is recommended. Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy. Caution is warranted and clinical monitoring of patients is recommended.

clear whether it is a P-gp substrate)

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

| Verapamil

Clinical Comment

Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co- administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

HMG-CoA reductase inhibitors:

Atorvastatin Rosuvastatin

Hypoglycemics:

Glimepiride Glipizide Glyburide Pioglitazone Repaglinide Tolbutamide | Atorvastatin | Hydroxy-atorvastatin metabolites | Tipranavir | Rosuvastatin Combination with APTIVUS/ritonavir not studied. Glimepiride (CYP 2C9) Glipizide (CYP 2C9) Glyburide (CYP 2C9) | Pioglitazone (CYP 2C8 and CYP 3A4) | Repaglinide (CYP 2C8 and CYP 3A4) Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known. Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin when in concomitant use of APTIVUS, co- administered with 200 mg of ritonavir. Careful glucose monitoring is warranted.

Immunosuppressants:

Cyclosporine Sirolimus Tacrolimus Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. | Cyclosporine | Sirolimus | Tacrolimus Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.

Inhaled /nasal steroids:

Fluticasone

Narcotic analgesics:

| Fluticasone Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Meperidine Methadone Combinations with APTIVUS/ritonavir not studied | Meperidine, | Normeperidine | Methadone | S-Methadone >| R-Methadone Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.

Oral contraceptives/Estrogens:

Ethinyl estradiol | Ethinyl estradiol concentrations by 50% Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an

increased risk of non serious rash.

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

Proton Pump Inhibitors:

Omeprazole | omeprazole - tipranavir Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.

PDE-5 inhibitors:

Sildenafil Tadalafil Vardenafil Only the combination of tadalafil with APTIVUS/ritonavir has been studied. | Sildenafil (not studied) | Tadalafil with first dose APTIVUS/ritonavir -- Tadalafil at APTIVUS/ritonavir steady- state | Vardenafil (not studied) Concomitant use of PDE-5 inhibitors with APTIVUS and ritonavir should be used with caution and in no case should the starting dose of:

• sildenafil exceed 25 mg within 48 hours

• tadalafil exceed 10 mg every 72 hours

• vardenafil exceed 2.5 mg every 72 hours

Warfarin - S-Warfarin Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy. | increase, | decrease, - no change, unable to predict

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects, Pregnancy Category C.

Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats. No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 uM *h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 uM/340 uM *h and 8.4 uM/120 uM *h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to APTIVUS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breastfeed if they are receiving APTIVUS.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of APTIVUS/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild (Child-Pugh Class A) hepatic impairment because tipranavir concentrations may be increased [see Clinical Pharmacology (12.3)]. APTIVUS/ritonavir is contraindicated in patients with moderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepatic impairment [see Contraindications (4.1)].

OVERDOSAGE

There is no known antidote for APTIVUS overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since tipranavir is highly protein bound, dialysis is unlikely to provide significant removal of the drug.

DESCRIPTION

APTIVUS is a protease inhibitor of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides. The chemical name of tipranavir is 2-Pyridinesulfonamide, N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3- yl]propyl]phenyl]-5-(trifluoromethyl). It has a molecular formula of C31H33F3N2O5S and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration.

OH

H N

SO2

O O N

CF3 Tipranavir is a white to off-white to slightly yellow solid. It is freely soluble in dehydrated alcohol and propylene glycol, and insoluble in aqueous buffer at pH 7.5. APTIVUS soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tipranavir is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacodynamics

Anitviral Activity

The median Inhibitory Quotient (IQ) determined from 264 treatment-experienced patients was about 80 (inter-quartile range: 31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral EC50 value, corrected for protein binding. There was a relationship between the proportion of patients with a >= 1 log10 reduction of viral load from baseline at week 48 and their IQ value. Among the 198 patients receiving APTIVUS/ritonavir with no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of enfuvirtide for the first time), the response rate was 23% in those with an IQ value < 80 and 59% in those with an IQ value >= 80. Among the 66 patients receiving APTIVUS/ritonavir with new enfuvirtide, the response rates in patients with an IQ value < 80 versus those with an IQ value >= 80 were 55% and 71%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints.

Pharmacokinetics

In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with 200 mg of ritonavir is essential [see Dosage and Administration (2)]. Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-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 (500/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. The mean systemic ritonavir concentration when 200 mg of ritonavir was given with 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-infected patients dosed with 500/200 mg tipranavir/ritonavir for 14 days.

Figure 1 Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200 mg BID)

Tipranavir mean

95% Confidence Interval

Ritonavir mean

Tipranavir Cp (mM) and Ritonavir Cp (mg/mL)

Tipranavir

Ritonavir

0 2 4 6 8 10 12

Time (h)

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 500/200 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 twice-daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic parameters for male and female HIV-positive patients presented in Table 5.

Table 5 Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV+ Patients by Gender

a

Population pharmacokinetic parameters reported as mean +- standard deviation

Effects of Food on Oral Absorption

APTIVUS capsules co-administered with ritonavir should be taken with food. Bioavailability is increased with a high fat meal. APTIVUS capsules, administered under high fat meal conditions or with a light snack of toast and skimmed milk, were tested in a multiple dose study. High-fat meals (868 kcal, 53% derived from fat, 31% derived from carbohydrates) enhanced the extent of bioavailability (AUC point estimate 1.31, confidence interval 1.23-1.39), but had minimal effect on peak tipranavir concentrations (Cmax point estimate 1.16, confidence interval 1.09-1.24).

Distribution

Tipranavir is extensively bound to plasma proteins (> 99.9%). It binds to both human serum albumin and a-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 mM. 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 CYP 3A4 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 14C-tipranavir to subjects that received APTIVUS/ritonavir 500/200 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 14C-tipranavir to subjects (n=8) that received APTIVUS/ritonavir 500/200 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-infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal.

Special Populations

Renal Impairment

APTIVUS pharmacokinetics have 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-negative patients with mild (Child-Pugh Class A) hepatic impairment to 9 HIV-negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in patients 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 (4.1), and Warnings and Precautions (5.1)].

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 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 mM for females and 31.1 mM 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

The pharmacokinetic profile of tipranavir in pediatric patients has not been established.

Drug Interactions

Drug interaction studies were performed with APTIVUS co-administered with 200 mg of 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, Cmax, and Cmin 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

Ratio (90% Confidence Interval) of Tipranavir

Co-administered Drug

Co-

administered Drug Dose

tipranavir/ ritonavir Drug Dose

n PK

Pharmacokinetic Parameters with/without Co-administered Drug;

No Effect = 1.00

(23 doses)

*

steady state comparison to historical data (n)

| increase, | decrease, - no change, unable to predict

Table 7 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of APTIVUS/Ritonavir

(42 doses)

Table 7 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of APTIVUS/Ritonavir

25-O-desacetyl- rifabutin (1 dose) (15 doses)

-

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

(23 doses)

a

HIV+ patients

b

HIV+ patients (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)

c

Normalized sum of parent drug (rifabutin) and active metabolite (25-O-desacetyl-rifabutin)

d

Intensive PK analysis

e

Drug levels obtained at 8-16 hrs post-dose

| increase, | decrease, - no change, unable to predict

Microbiology

Mechanism of Action

Tipranavir (TPV) is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Antiviral Activity

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 uM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M non- clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 uM and 0.233-0.522 uM, respectively. When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion inhibitor enfuvirtide. There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Resistance

In cell culture:

HIV-1 isolates with a decreased susceptibility to tipranavir have been selected in cell culture and obtained from patients treated with APTIVUS/ritonavir (TPV/ritonavir). After 9 months of culture in TPV-containing media, HIV-1 isolates with 87-fold reduced susceptibility to tipranavir were selected in cell culture; these contained 10 protease substitutions that developed in the following order: L33F, I84V, K45I, I13V, V32I, V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyprotein CA/P2 cleavage site were also observed following drug selection. Experiments with site-directed mutants of HIV-1 showed that the presence of 6 substitutions in the protease coding sequence (I13V, V32I, L33F, K45I, V82L, I84V) conferred > 10-fold reduced susceptibility to tipranavir.

Clinical Studies of Treatment-Experienced Patients:

In controlled clinical trials 1182.12 and 1182.48, multiple protease inhibitor-resistant HIV-1 isolates from 59 treatment-experienced patients who received APTIVUS/ritonavir and experienced virologic rebound developed amino acid substitutions that were associated with resistance to tipranavir. The most common amino acid substitutions that developed on 500/200 mg APTIVUS/ritonavir in greater than 20% of APTIVUS/ritonavir virologic failure isolates were L33V/I/F, V82T, and I84V. Other substitutions that developed in 10 to 20% of APTIVUS/ritonavir virologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V, K55R, V82L, and L89V/M. Evolution at protease gag polyprotein cleavage sites was also observed. Tipranavir resistance was detected at virologic rebound after an average of 38 weeks of APTIVUS/ritonavir treatment with a median 14-fold decrease in tipranavir susceptibility.

Cross-resistance

Cross-resistance among protease inhibitors has been observed. Tipranavir had < 4-fold decreased susceptibility against 90% (94/105) of HIV-1 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses which emerged in cell culture from wild-type HIV-1 had decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remained sensitive to saquinavir.

Baseline Genotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining tipranavir susceptibility before initiation of APTIVUS/ritonavir therapy. Several analyses were conducted to evaluate the impact of specific substitutions and combination of substitutions on virologic outcome. Both the type and number of baseline protease inhibitor substitutions as well as use of additional active agents (e.g., enfuvirtide) affected APTIVUS/ritonavir response rates in controlled clinical trials 1182.12 and 1182.48 through Week 48 of treatment. Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 treatment-experienced patients in Phase 2 and 3 trials demonstrated that amino acid substitutions at 16 codons in the HIV protease coding sequence were associated with reduced virologic responses and/or reduced tipranavir susceptibility: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V. As-treated analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor substitutions present at baseline. Response rates were reduced if five or more protease inhibitor-associated substitutions were present at baseline and subjects did not receive concomitant new enfuvirtide with APTIVUS/ritonavir. See Table 8.

Table 8 Controlled Clinical Trials 1182.12 and 1182.48: Proportion of Responders (confirmed >= 1 log10 decrease at Week 48) by Number of Baseline Primary Protease Inhibitor (PI) Resistance Associated Substitutions

Number of Baseline

APTIVUS/ritonavir

N = 578

Comparator PI/ritonavir

N = 610

Primary PI MutationsaNo New Enfuvirtideb

Overall 38%

- 2 62%

- 4 48%

5+

26%

+ New Enfuvirtidec 69% 60%

(75/108)

(3/5) 71% (27/38) 69% (45/65)

No New Enfuvirtideb 18% 33%

(92/524)

(14/43) 23% (45/193) 11% (33/288)

+ New Enfuvirtidec 26%

(22/86) 0% (0/1) 38% (13/34) 18% (9/51)

a Primary PI mutations include any amino acid substitution at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90 b No new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide

c

New enfuvirtide is defined as initiation of enfuvirtide for the first time

The median change from baseline in plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was evaluated by the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or >= 5) in subjects who received APTIVUS/ritonavir with or without new enfuvirtide. The following observations were made:

• Approximately 1.5 log10 decrease in HIV-1 RNA at early time points (Week 2) regardless of the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or 5+).

• Subjects with 5 or more primary protease inhibitor resistance associated substitutions in their HIV-1 at baseline who received APTIVUS/ritonavir without new enfuvirtide (n=303) began to lose their antiviral response after Week 4.

• Early HIV-1 RNA decreases (1.5-2 log10) were sustained through Week 48 in subjects with 5 or more primary protease inhibitor resistance associated substitutions at baseline who received new enfuvirtide with APTIVUS/ritonavir (n=74).

Baseline Phenotype and Virologic Outcome Analyses

APTIVUS/ritonavir response rates were also assessed by baseline tipranavir phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, mutations at protease amino acid codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ritonavir therapy at Week 48 are summarized in Tables 9 and 10. These baseline phenotype groups are not meant to represent clinical susceptibility breakpoints for APTIVUS/ritonavir because the data are based on the select 1182.12 and 1182.48 patient population. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to APTIVUS/ritonavir in protease inhibitor-experienced patients.

Table 9 Response by Baseline Tipranavir Phenotype at 48 weeks in the Controlled Clinical Trials 1182.12 and 1182.48

Baseline Tipranavir Phenotype (Fold

Proportion of Respondersbwith

Proportion of Respondersbwith

d

Change)a

No New EnfuvirtidecUse

N=211

New Enfuvirtide

N=68

Use

Tipranavir Susceptibility

0-3 48% (73/153) 70% (33/47) Susceptible > 3-10 21% (10/48) 53% (8/15) Decreased Susceptibility > 10 10% (1/10) 50% (3/6) Resistant a Change in tipranavir EC50 value from wild-type reference b Confirmed >= 1 log10 decrease at Week 48

c

No new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide

d

New enfuvirtide is defined as initiation of enfuvirtide for the first time

Table 10 Correlation of Baseline Tipranavir Phenotype to Genotype using HIV isolates from Phase 2 and Phase 3 Clinical Trials

Baseline Tipranavir Phenotype (Fold Change)a

# of Baseline Protease Mutations at 33, 82, 84, 90

# of Baseline Tipranavir c

Resistance-Associated Mutationsb Tipranavir Susceptibility

0-3 0-2 0-4 Susceptible > 3-10 3 5-7 Decreased Susceptibility > 10 4 8+ Resistant a Change in tipranavir EC50 value from wild-type reference

b

Number of amino acid substitutions in HIV protease among L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P,

V82L/T, N83D or I84V c defined by week 48 response

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered 30, 150 or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of benign hepatocellular adenomas and combined adenomas/carcinomas were increased in females of all groups except the low dose of tipranavir. These tumors were also increased in male mice at the high-dose of tipranavir and the tipranavir/ritonavir combination group. Hepatocellular carcinoma incidence was increased in female mice given the high dose of tipranavir and both sexes receiving tipranavir/ritonavir. The combination of tipranavir and ritonavir caused an exposure-related increase in this same tumor type in both sexes. The clinical relevance of the carcinogenic findings in mice is unknown. Systemic exposures in mice (based on AUC or Cmax) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100 or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. No drug-related findings in male rats were observed. At the highest dose of tipranavir, an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans, because thyroid follicular cell adenomas are considered a rodent- specific effect secondary to enzyme induction. Tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five in vitro and in vivo tests including the Ames bacterial reverse mutation assay using

S. typhimurium and E. coli, unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation in Chinese hamster ovary cells, a chromosome aberration assay in human peripheral lymphocytes, and a micronucleus assay in mice. Tipranavir had no effect on fertility or early embryonic development in rats at dose levels up to 1000 mg/kg/day, equivalent to a Cmax of 258 uM in females. Based on Cmax levels in these rats, as well as an exposure (AUC) of 1670 uM *h in pregnant rats from another study, this exposure was approximately equivalent to the anticipated exposure in humans at the recommended dose level of 500/200 mg APTIVUS/ritonavir BID.

Animal Toxicology and/or Pharmacology

In preclinical studies in rats, tipranavir treatment induced dose-dependent changes in coagulation parameters (increased prothrombin time, increased activated partial thromboplastin time, and a decrease in some vitamin K dependent factors). In some rats, these changes led to bleeding in multiple organs and death. The co- administration of vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) with tipranavir resulted in a significant increase in effects on coagulation parameters, bleeding events, and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

CLINICAL STUDIES

The following clinical data is derived from analyses of 48-week data from ongoing studies measuring effects on plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical progression of HIV.

APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR

The two clinical trials 1182.12 and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled, open-label, multicenter studies in HIV-positive, triple antiretroviral class experienced patients. All patients were required to have previously received at least two protease inhibitor-based antiretroviral regimens and were failing a protease inhibitor-based regimen at the time of study entry with baseline HIV-1 RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations at codons 33, 82, 84 or 90. These studies evaluated treatment response at 48 weeks in a total of 1483 patients receiving either APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually defined for each patient based on genotypic resistance testing and patient history. The investigator had to declare OBR, comparator protease inhibitor, and use of new enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of new enfuvirtide. After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response or confirmed virologic failure had the option of discontinuing treatment and switching to APTIVUS/ritonavir in a separate roll-over study. Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir arm and control arm. In both studies combined, the 1483 patients had a median age of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range 2.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 162 (range 1 to 1894) cells/mm3. Overall, 38.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL, 58.6% had a baseline CD4+ cell count <= 200 cells/mm3, and 57.8% had experienced an AIDS defining Class C event at baseline. Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the HIV isolates were resistant to at least one protease inhibitor, 95% of the isolates were resistant to at least one NRTI, and > 75% of the isolates were resistant to at least one NNRTI. The individually pre-selected protease inhibitor based on genotypic testing and the patient's medical history was lopinavir in 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 21% of patients used enfuvirtide during the study of which 16.6% in the APTIVUS/ritonavir arm and 13.2% in the comparator/ritonavir arm represented first time use of enfuvirtide (new enfuvirtide). Treatment response and efficacy outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48 are shown in Table 11.

Table 11 Outcomes of Randomized Treatment Through Week 48 (Pooled Studies 1182.12 and 1182.48)

Outcome

Virologic Respondersa (confirmed at least 1

APTIVUS/ritonavir (500/200 mg BID)

+ OBR (N=746)

Comparator Protease Inhibitor/ritonavir + OBR (N=737)

*

log10 HIV-1 RNA below baseline) 33.8% 14.9% Virologic failures Initial lack of virologic response by Week 8b Rebound Never suppressed Deathc or discontinued due to adverse events 55.1% 5.9% 77.3% 57.9% 16.4% 3.0% 1.9% Death Discontinued due to adverse events 0.3% 1.6% Discontinued due to other reasonsd 5.2% 5.8%

*

Comparator protease inhibitors were lopinavir, amprenavir, saquinavir or indinavir and 85.1% of patients were possibly resistant or resistant to the chosen protease inhibitors.

a Patients achieved and maintained a confirmed >= 1 log10 HIV-1 RNA drop from baseline through Week 48 without prior evidence of treatment failure. b Patients did not achieve a 0.5 log10 HIV-1 RNA drop from baseline and did not have viral load < 100,000 copies/mL by Week 8. c Death only counted if it was the reason for treatment failure.

d

Includes patients who were lost to-follow-up, withdrawn consent, non-adherent, protocol violations, added/changed background antiretroviral drugs for reasons other than tolerability or toxicity, or discontinued while suppressed.

Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 30.3% and 13.6% respectively, and with HIV-1 RNA < 50 copies/mL was 22.7% and 10.2% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the comparator PI/ritonavir arm. Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm. Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide. Among patients with new enfuvirtide use, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 52.4 % and 19.6% respectively, and with HIV-1 RNA < 50 copies/mL was 37.3% and 14.4% respectively [see Clinical Pharmacology (12.2, 12.4)]. The median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +89 cells/mm3 in patients receiving APTIVUS/ritonavir in combination with newly introduced enfuvutide (N=124) and +18 cells/mm3 in the comparator PI/ritonavir (N=96) arm.

HOW SUPPLIED/STORAGE AND HANDLING

APTIVUS (tipranavir) capsules 250 mg are pink, oblong soft gelatin capsules imprinted in black with "TPV 250". They are packaged in HDPE unit-of-use bottles with a child resistant closure and 120 capsules. (NDC 0597-0003-02)

Storage

APTIVUS capsules should be stored in a refrigerator 2deg-8degC (36deg-46degF) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25degC (77degF); excursions permitted to 15deg-30degC (59deg-86degF) and must be used within 60 days. Store in a safe place out of the reach of children.