Rx Drugs Info

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use aptivus safely and effectively. See full prescribing information for aptivus.
aptivus (tipranavircapsule for oral use
Initial U.S. Approval: 2005

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

See full prescribing information for complete boxed warning.

  • Clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection (5.1)
  • Fatal and non-fatal intracranial hemorrhage (5.2)

RECENT MAJOR CHANGES

Indications and Usage (1)                                               10/2007

Warnings and Precautions
   Hepatic Impairment and Toxicity (5.1)                          10/2007
   Drug Interactions (5.3)                                                10/2007
   Effects on Platelet Aggregation and Coagulation (5.4)       02/2007
   Rash (5.5)                                                                10/2007


INDICATIONS AND USAGE

APTIVUS, a protease inhibitor, co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients 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)

DOSAGE AND ADMINISTRATION

  • 500 mg APTIVUS, co-administered with 200 mg ritonavir, twice daily with food (2)
  • Store unopened bottles in the refrigerator (16)


DOSAGE FORMS AND STRENGTHS

Capsules: 250 mg (3)


CONTRAINDICATIONS

  • Patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (4.1, 5.1)
  • Use with drugs highly dependent on CYP 3A for clearance or are potent CYP 3A inducers (4.2, 5.3, 7)

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 1-800-542-6257 and 1-800-459-9906 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

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hepatic Impairment

4.2 Drug Interactions

5 WARNINGS AND PRECAUTIONS

 5.1 Hepatic Impairment and Toxicity

5.2 Intracranial Hemorrhage

 5.3 Drug Interactions

 5.4 Effects on Platelet Aggregation and Coagulation

 5.5 Rash

5.6 Sulfa Allergy

5.7 Diabetes Mellitus/Hyperglycemia

5.8 Immune Reconstitution Syndrome

5.9 Fat Redistribution

5.10 Elevated Lipids

5.11 Patients with Hemophilia

5.12 Resistance/Cross Resistance

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Potential for APTIVUS/ritonavir to Affect Other Drugs

7.2 Potential for Other Drugs to Affect Tipranavir

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Hepatic Impairment and Toxicity

17.2 Intracranial Hemorrhage

17.3 Drug Interactions

17.4 Rash

17.5 Sulfa Allergy

17.6 Contraceptives

17.7 Fat Redistribution

17.8 Administration

17.9 FDA-Approved Patient Labeling


FULL PRESCRIBING INFORMATION

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

Hepatotoxicity:

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)].

1 INDICATIONS AND USAGE

APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI).

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeks duration. Both 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:

There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.

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.

3 DOSAGE FORMS AND STRENGTHS

250 mg, pink, oblong capsules imprinted with TPV 250

4 CONTRAINDICATIONS

4.1 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)].

4.2 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.
HMG CoA reductase inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis.
Neuroleptic Pimozide Potential for cardiac arrhythmias.
Sedatives/hypnotics Midazolam, triazolam Prolonged or increased sedation or respiratory depression.

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.

5 WARNINGS AND PRECAUTIONS

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

 5.1 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-naïve 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)].

5.2 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.

 5.3 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)].

 5.4 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)].

 5.5 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.

5.6 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.

5.7 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.

5.8 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.

5.9 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.

5.10 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)].

5.11 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.

5.12 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

6.1 Clinical Trials Experience

APTIVUS (tipranavir), co-administered with ritonavir, has been studied in a total of 6308 HIV-positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 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 patients and 10.8% for the comparator arm patients.

Due to the need for co-administration of APTIVUS with 200 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

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.

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.

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 Groupa (48 week Analyses)
  Percentage of patients (rate per 100 patient-exposure years)
  APTIVUS/ritonavir (500/200 mg
BID) + OBRc
(n=749; 757.4 patient-exposure years)
Comparator PI/ritonavirb + 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 patients (n=1474) treated with APTIVUS/ritonavir 500/200 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 x 103/μL 5.4% (5.6) 4.8% (7.7)
   Grade 4 < 1.0 x 103/μL 0.3% (0.3) 1.1% (1.7)
Chemistry
   Amylase
   Grade 3
> 2.5 x ULN 5.7% (5.9) 6.4% (10.4)
   Grade 4 > 5 x ULN 0.3% (0.3) 0.7% (1.1)
 
   ALT
   Grade 2
> 2.5-5 x ULN 14.9% (16.5) 7.5% (12.4)
   Grade 3 > 5-10 x ULN 5.6% (5.7) 1.7% (2.6)
   Grade 4 > 10 x ULN 4.1% (4.1) 0.4% (0.7)
 
   AST
   Grade 2
> 2.5-5 x ULN 9.9% (10.5) 8.0% (13.3)
   Grade 3 > 5-10 x ULN 4.5% (4.6) 1.4% (2.2)
   Grade 4 > 10 x ULN 1.6% (1.6) 0.4% (0.6)
 
   ALT and/or AST
   Grade 2-4
> 2.5 x 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 patients 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.

7 DRUG INTERACTIONS

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

7.1 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.

7.2 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
↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict
HIV-Antiviral Agents
Nucleoside reverse transcriptase inhibitors:  
Abacavir ↓ Abacavir AUC by approximately 40% Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
Didanosine (EC) ↓ Didanosine 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.
Zidovudine ↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease inhibitors (co-administered with 200 mg of ritonavir):  
Fosamprenavir
Lopinavir
Saquinavir
↓ Amprenavir,
↓ Lopinavir,
↓ Saquinavir
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.
Protease inhibitors (co-administered with 100 mg of ritonavir):  
Atazanavir ↓ Atazanavir,
↑ Tipranavir
 
Agents for Opportunistic Infections  
Antifungals:
Fluconazole
Itraconazole
Ketoconazole
Voriconazole

↑ 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.
Antimycobacterials:  
Clarithromycin ↑ Tipranavir, ↑ Clarithromycin,
↓ 14-hydroxy-clarithromycin metabolite
No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.
  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
↓ Tipranavir 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.
 
Valproic Acid ↓ Valproic Acid 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.
Antidepressants:

Trazodone


↑ Trazodone


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.

 
Desipramine Combination with APTIVUS/ritonavir not studied
↑ Desipramine
Dosage reduction and concentration monitoring of desipramine is recommended.
Selective Serotonin-Reuptake Inhibitors: Combination with APTIVUS/ritonavir not studied Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine
Paroxetine
Sertraline
↑ Fluoxetine
↑ Paroxetine
↑ Sertraline
 
Calcium Channel Blockers:

Diltiazem
Felodipine
Nicardipine
Nisoldipine
Verapamil
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 clear whether it is a P-gp substrate)
↕ Verapamil
Caution is warranted and clinical monitoring of patients is recommended.
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

↑ Atorvastatin
↓ Hydroxy-atorvastatin metabolites
↑ Tipranavir
↑ Rosuvastatin
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.
Hypoglycemics: Combination with APTIVUS/ritonavir not studied. Careful glucose monitoring is warranted.
 
Glimepiride
Glipizide
Glyburide
Pioglitazone

Repaglinide
↔ Glimepiride (CYP 2C9)
↔ Glipizide (CYP 2C9)
↔ Glyburide (CYP 2C9)
↕ Pioglitazone (CYP 2C8 and CYP 3A4)
↕ Repaglinide (CYP 2C8 and CYP 3A4)
↔ Tolbutamide (CYP 2C9)
 
 
Tolbutamide The effect of TPV/ritonavir on CYP 2C8 substrate is not known.  
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
↑ 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.
Narcotic analgesics:  
Meperidine Combinations with APTIVUS/ritonavir not studied
↓ Meperidine, ↑ Normeperidine
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).
 
Methadone ↓ Methadone
↓ S-Methadone >↓ R-Methadone
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.
Proton Pump Inhibitors:  
Omeprazole ↓ omeprazole ↔ tipranavir Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.
PDE-5 inhibitors: Only the combination of tadalafil with APTIVUS/ritonavir has been 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
Tadalafil
Vardenafil
↑ Sildenafil (not studied)
↑ Tadalafil with first dose APTIVUS/ritonavir
↔ Tadalafil at APTIVUS/ritonavir steady-state
↑ Vardenafil (not studied)
  • 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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 μM•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 μM/340 μM•h and 8.4 μM/120 μM•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.

8.3 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

8.6 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)].

10 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.

11 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.

Image from Drug Label Content

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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 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.

12.3 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)

Image from Drug Label Content

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
  Females
(n = 14)
Males
(n = 106)
a Population pharmacokinetic parameters reported as mean ± standard deviation
Cptrough (μM) 41.6 ± 24.3 35.6 ± 16.7
Cmax(μM) 94.8 ± 22.8 77.6 ± 16.6
Tmax(h) 2.9 3.0
AUC0-12h(μM•h) 851 ± 309 710 ± 207
CL (L/h) 1.15 1.27
V (L) 7.7 10.2
t1/2(h) 5.5 6.0

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 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-positive patients. 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 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 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
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
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
Cmax AUC Cmin
*steady state comparison to historical data (n)
↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict
Antacids (Maalox®) 20 mL
(1 dose)
500/200 mg
(1 dose)
23 0.75 (0.63, 0.88) 0.73 (0.64, 0.84) -
Atazanavir/ritonavir 300/100 mg QD
(9 doses)
500/100 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)
500/200 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)
500/200 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)
500/100 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)
500/100 mg BID*

750/200 mg BID*
21 (89)

25 (100)


0.79 (0.69, 0.89)

0.97 (0.85, 1.09)
0.69 (0.57, 0.83)

1.01 (0.85, 1.18)
0.58 (0.36, 0.86)

0.97 (0.69, 1.28)
Ethinyl estradiol
/Norethindrone
0.035/1.0 mg
(1 dose)
500/100 mg BID
(21 doses)
21 1.10 (0.98, 1.24) 0.98 (0.88, 1.11) 0.73 (0.59, 0.90)
    750/200 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)
500/200 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)
750/200 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)
500/200 mg BID
(15 doses)
21 0.99 (0.93, 1.07) 1.00 (0.96, 1.04) 1.16 (1.07, 1.27)
Tadalafil 10 mg
(1 dose)
500/200 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)
500/100 mg BID

750/200 mg BID (23 doses)
22

20


0.83 (0.74, 0.94)

0.89 (0.84, 0.96)
0.82 (0.75, 0.91)

0.91 (0.85, 0.97)
0.79 (0.70, 0.90)

0.88 (0.78, 1.00)
Zidovudine 300 mg
(1 dose)
500/100 mg BID

750/200 mg BID (23 doses)
29

25


0.87 (0.80, 0.94)

1.02 (0.94, 1.10)
0.82 (0.76, 0.89)

1.02 (0.92, 1.13)
0.77 (0.68, 0.87)

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
  Cmax AUC Cmin
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
Amprenavir/ritonavira 600/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
16
74

0.61 (0.51, 0.73)d
-
0.56 (0.49, 0.64)d
-
0.45 (0.38, 0.53)d
0.44 (0.39, 0.49)e
Abacavira 300 mg BID
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 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)
-
-
-
Atazanavir/ritonavir 300/100 mg QD
(9 doses)
500/100 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)
500/200 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   21, 12, 17 0.02 (0.02, 0.03) 0.11 (0.08, 0.17) 0.07 (0.06, 0.08)
   Parahydroxy-atorvastatin   13, 22, 1 1.04 (0.87, 1.25) 0.18 (0.14, 0.24) 0.33 (NA)
Carbamazepine 100 mg BID
(29 doses)
500/200 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)
500/200 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)
500/200 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)
Didanosineb 200 mg BID, ≥ 60 kg
125 mg BID, < 60 kg
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 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)
500/100 mg BID
(27 doses)
5 0.80 (0.63, 1.02) 0.90 (0.72, 1.11) 1.17 (0.62, 2.20)
Efavirenzb 600 mg QD
(15 doses)
500/100 mg BID
750/200 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)
500/100 mg BID
750/200 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)
500/200 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/ritonavira 400/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
21
69

0.53 (0.40, 0.69)d
-
0.45 (0.32, 0.63)d
-
0.30 (0.17, 0.51)d
0.48 (0.40, 0.58)e
Loperamide 16 mg
(1 dose)
750/200 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) -
Lamivudinea 150 mg BID
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 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

R-methadone

S-methadone
5 mg
(1 dose)
500/200 mg BID
(16 doses)
14 0.45 (0.41, 0.49)

0.54 (0.50, 0.58)

0.38 (0.35, 0.43)
0.47 (0.44, 0.51)

0.52 (0.49, 0.56)

0.37 (0.34, 0.41)
0.50 (0.46, 0.54)
-
-
Nevirapinea 200 mg BID
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 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)
500/100 mg BID
750/200 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)
-
-
Rifabutin 150 mg
(1 dose)
500/200 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- rifabutinc
    20 1.86 (1.63, 2.12) 4.33 (3.86, 4.86) 2.76 (2.44, 3.12)
Saquinavir/ritonavira 600/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
20
68

0.30 (0.23, 0.40)d
-
0.24 (0.19, 0.32)d
-
0.18 (0.13, 0.26)d
0.20 (0.16, 0.25)e
Stavudinea 40 mg BID, ≥60 kg
30 mg BID, < 60 kg
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 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)
500/200 mg
(1 dose)
17 0.78 (0.72, 0.84) 2.33 (2.02, 2.69) -
  10 mg
(1 dose)
500/200 mg BID
(17 doses)
17 0.70 (0.63, 0.78) 1.01 (0.83, 1.21) -
Tenofovir 300 mg
(1 dose)
500/100 mg BID
750/200 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)
Zidovudineb 300 mg BID
300 mg BID
300 mg BID
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 mg BID
(42 doses)
48
31
23


0.54 (0.47, 0.62)
0.51 (0.44, 0.60)
0.49 (0.40, 0.59)
0.58 (0.51, 0.66)
0.64 (0.55, 0.75)
0.69 (0.49, 0.97)
-
-
-
  300 mg
(1 dose)
500/100 mg BID
750/200 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   500/100 mg BID
750/200 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)

12.4 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 μM (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 μM and 0.233-0.522 μM, 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
Primary PI Mutations
a
APTIVUS/ritonavir
N = 578
Comparator PI/ritonavir
N = 610
No New Enfuvirtideb + New Enfuvirtidec No New Enfuvirtideb + New Enfuvirtidec
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
Overall 38%
(180/470)
69%
(75/108)
18%
(92/524)
26%
(22/86)
1 - 2 62%
(24/39)
60%
(3/5)
33%
(14/43)
0%
(0/1)
3 - 4 48%
(96/202)
71%
(27/38)
23%
(45/193)
38%
(13/34)
5+ 26%
(60/229)
69%
(45/65)
11%
(33/288)
18%
(9/51)

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:

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 Change)
a
Proportion of Respondersb with
No New Enfuvirtidec Use
N=211
Proportion of Respondersb with
New Enfuvirtided Use
N=68
Tipranavir Susceptibility
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
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
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 Resistance-Associated Mutationsb Tipranavir Susceptibilityc
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
0-3 0-2 0-4 Susceptible
> 3-10 3 5-7 Decreased
Susceptibility
> 10 4 8+ Resistant

13 NONCLINICAL TOXICOLOGY

13.1 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 μM in females. Based on Cmax levels in these rats, as well as an exposure (AUC) of 1670 μM•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.

13.2 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.

14 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 APTIVUS/ritonavir (500/200 mg BID)
+ OBR
(N=746)
Comparator Protease
Inhibitor*/ritonavir + OBR
(N=737)
* 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.
Virologic Respondersa
(confirmed at least 1 log10 HIV-1
RNA below baseline)
33.8% 14.9%
Virologic failures
      Initial lack of virologic
      response by Week 8b
      Rebound
      Never suppressed
55.1%

      33.0%
      18.9%
     3.2%
77.3%

      57.9%
      16.4%
     3.0%
Deathc or discontinued due to adverse events
      Death
      Discontinued due to adverse events
5.9%
      0.5%
      5.4%
1.9%
      0.3%
      1.6%
Discontinued due to other reasonsd 5.2% 5.8%

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.

16 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 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days.

Store in a safe place out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (17.9)

17.1 Hepatic Impairment and Toxicity

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir, has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of developing hepatotoxicity.

Liver function tests should be performed prior to initiating therapy with APTIVUS and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe hepatic impairment.

17.2 Intracranial Hemorrhage

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage. Patients should report any unusual or unexplained bleeding to their physician.

17.3 Drug Interactions

APTIVUS may interact with some drugs; therefore, patients should be advised to report to their health care provider the use of any other prescription or non-prescription medications or herbal products, particularly St. John’s wort.

17.4 Rash

Rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving APTIVUS. Some patients who developed rash also had one or more of the following symptoms: joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin. Women taking birth control pills may get a skin rash. Patients should be told to discontinue use of APTIVUS and call their physician right away if any of these symptoms develop.

17.5 Sulfa Allergy

Patients should be told to report any history of sulfonamide allergy to the physician.

17.6 Contraceptives

Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives.

17.7 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

17.8 Administration

Patients should be informed that APTIVUS must be co-administered with 200 mg ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect.

Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using APTIVUS. Patients should be advised to take APTIVUS and other concomitant antiretroviral therapy every day as prescribed. APTIVUS, co-administered with ritonavir, must be given in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare professional. If a dose of APTIVUS is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

Patients should be informed that APTIVUS is not a cure for HIV-1 infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of APTIVUS are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with APTIVUS can reduce the risk of transmitting HIV to others through sexual contact.

APTIVUS should be taken with food to enhance absorption.

17.9 FDA-Approved Patient Labeling

Read the Patient Information that comes with APTIVUS before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare professional about your medical condition or treatment. You should stay under a healthcare professional’s care while taking APTIVUS.

What is the most important information I should know about APTIVUS?

Patients taking APTIVUS, together with 200 mg NORVIR® (ritonavir), may develop severe liver disease that can cause death. If you develop any of the following symptoms of liver problems, you should stop taking APTIVUS and NORVIR® (ritonavir) and call your healthcare professional right away: tiredness, general ill feeling or "flu-like" symptoms, loss of appetite, nausea (feeling sick to your stomach), yellowing of your skin or whites of your eyes, dark (tea-colored) urine, pale stools (bowel movements), or pain, ache, or sensitivity on your right side below your ribs. If you have chronic hepatitis B or C infection, your healthcare professional should check your blood tests more often because you have an increased chance of developing liver problems.

Patients taking APTIVUS together with 200 mg NORVIR® (ritonavir) may develop bleeding in the brain that can cause death.

You should report any unusual or unexplained bleeding to your healthcare professional if you are taking APTIVUS together with 200 mg of NORVIR® (ritonavir).

What is APTIVUS?

APTIVUS is a medicine called a "protease inhibitor" that is used to treat adults with Human Immunodeficiency Virus (HIV). APTIVUS blocks HIV protease, an enzyme which is needed for HIV to make more virus. When used with other anti-HIV medicines, APTIVUS may reduce the amount of HIV in your blood and increase the number of CD4+ cells. Reducing the amount of HIV in the blood may keep your immune system healthy, so it can help fight infections.

APTIVUS is always taken with NORVIR® (ritonavir) and at the same time as NORVIR. When you take APTIVUS with NORVIR, you must always use at least 2 other anti-HIV medicines.

Does APTIVUS cure HIV or AIDS?

APTIVUS does not cure HIV infection or AIDS. The long-term effects of APTIVUS are not known at this time. People taking APTIVUS may still get infections or other conditions common in people with HIV (opportunistic infections). It is very important that you stay under the care of your doctor during treatment with APTIVUS.

Does APTIVUS lower the chance of passing HIV to other people?

APTIVUS does not reduce the chance of passing HIV to others through sexual contact, sharing needles, or being exposed to your blood. Continue to practice safer sex. Use a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Never use or share dirty needles.

Ask your healthcare professional if you have any questions about safer sex or how to prevent passing HIV to other people.

Who should not take APTIVUS?

Do not take APTIVUS if you:

What should I tell my healthcare professional before I take APTIVUS?

Tell your healthcare professional about all of your medical conditions, including if you:

Tell your healthcare professional about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. APTIVUS and many other medicines can interact. Sometimes serious side effects will happen if APTIVUS is taken with certain other medicines (see “Who should not take APTIVUS?”).

Do not take Flonase®, Viagra®, Cialis®, or Levitra® with Aptivus/ritonavir without first speaking with your healthcare professional.

Women taking birth control pills need to use another birth control method. APTIVUS makes birth control pills work less well.

Know all the medicines you take and keep a list of them with you. Show this list to all your healthcare professionals and pharmacists anytime you get a new medicine you take. They will tell you if you can take these other medicines with APTIVUS. Do not start any new medicines while you are taking APTIVUS without first talking with your healthcare professional or pharmacist. You can ask your healthcare professional or pharmacist for a list of medicines that can interact with APTIVUS.

How should I take APTIVUS?

APTIVUS comes in a capsule form and you should swallow APTIVUS capsules whole. Do not chew the capsules.

What are the possible side effects of APTIVUS?

APTIVUS may cause serious side effects, including:

The most common side effects of APTIVUS include diarrhea, nausea, headache, fever, vomiting, tiredness, and stomach pain.

It may be hard to tell the difference between side effects caused by APTIVUS, by the other medicines you are also taking, or by the complications of HIV infection. For this reason it is very important that you tell your healthcare professional about any changes in your health. You should report any new or continuing symptoms to your healthcare professional right away. Your healthcare professional may be able to help you manage these side effects.

The list of side effects is not complete. Ask your healthcare professional or pharmacist for more information.

How should I store APTIVUS?

General advice about APTIVUS

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use APTIVUS for a condition for which it was not prescribed. Do not give APTIVUS to other people, even if they have the same condition you have. It may harm them.

This leaflet summarizes the most important information about APTIVUS. If you would like more information, talk with your healthcare professional. You can ask your pharmacist or healthcare professional for information about APTIVUS that is written for health professionals.

For additional information, you may also call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in APTIVUS?

Active Ingredient: tipranavir

Major Inactive Ingredients: dehydrated alcohol, polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin.

Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

APTIVUS® is a registered trademark used under license from Boehringer Ingelheim International GmbH

©Copyright Boehringer Ingelheim International GmbH, 2007 ALL RIGHTS RESERVED

APTIVUS capsules are covered by U.S. Patents 5,852,195; 6,147,095; 6,169,181 and 6,231,887

OT2000FJ0307
10003515/US/5
10003515/05


Aptivus (tipranavir)
PRODUCT INFO
Product Code 0597-0003 Dosage Form CAPSULE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
tipranavir (tipranavir) Active 250 MILLIGRAM  In 1 CAPSULE
dehydrated alcohol Inactive 0.1 GRAM  In 1 CAPSULE
polyoxyl 35 castor oil Inactive  
propylene glycol Inactive  
mono/diglycerides of caprylic/capric acid Inactive  
gelatin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color PINK (pink) Score 1
Shape OVAL (oval) Symbol false
Imprint Code TPV;250 Coating false
Size 22mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0597-0003-02 120 CAPSULE In 1 BOTTLE None

Revised: 10/2007Boehringer Ingelheim Pharmaceuticals, Inc.

Data are from FDA and U.S. National Library of Medicine.