Aptivus^®
(tipranavir)
Capsules, 250 mg

APTIVUS^® (tipranavir) is the brand name for tipranavir (TPV), a non-peptidic protease inhibitor (PI) of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.

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.

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.

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.

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 mutations and mutational patterns on virologic outcome. Both the type and number of baseline protease inhibitor mutations as well as use of additional active agents (e.g., enfuvirtide) affected APTIVUS/ritonavir response rates in Phase 3 studies 1182.12 and 1182.48 through Week 24 of treatment.

Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 highly treatment-experienced patients in Phase 2 and 3 studies demonstrated that mutations at 16 amino acid codons in the HIV protease coding sequence were associated with reduced virologic responses at 24 weeks 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.

Analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor mutations present at baseline. Response rates were reduced if five or more protease inhibitor-associated mutations were present at baseline and subjects did not receive concomitant enfuvirtide with APTIVUS/ritonavir. See Table 1.

The median change from baseline in HIV-1 RNA at weeks 2, 4, 8, 16 and 24 was evaluated by the number of baseline primary protease inhibitor mutations (1-4 or ≥ 5) in subjects who received APTIVUS/ritonavir with or without 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 mutations (1-4 or 5+).
• Subjects with 5 or more primary protease inhibitor mutations in their HIV-1 at baseline who received APTIVUS/ritonavir without enfuvirtide (n=204) began to lose their antiviral response after Week 4.
• Early HIV-1 RNA decreases (1.5–2 log₁₀) were sustained through Week 24 in subjects with 5 or more primary protease inhibitor mutations at baseline who received enfuvirtide with APTIVUS/ritonavir (n=88).

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.

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 24 are summarized in Table 2. 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 highly protease inhibitor-experienced patients.

The median Inhibitory Quotient (IQ) determined from 301 highly treatment-experienced patients was about 75 (inter-quartile range: 29-189), from pivotal clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral IC₅₀ 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 24 and their IQ value. Among the 206 patients receiving APTIVUS/ritonavir without enfuvirtide, the response rate was 23% in those with an IQ value < 75 and 55% in those with an IQ value ≥ 75. Among the 95 patients receiving APTIVUS/ritonavir with enfuvirtide, the response rates in patients with an IQ value < 75 versus those with an IQ value ≥ 75 were 43% and 84%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints.

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 PRECAUTIONS and DOSAGE AND ADMINISTRATION). Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-glycoprotein (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 tipranavir co-administered with low-dose ritonavir (500/200 mg twice daily) compared to tipranavir 500 mg twice daily without ritonavir.

Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for the 500/200 mg tipranavir/ritonavir dose.

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 the net effect of tipranavir/ritonavir at the proposed dose regimen (500/200 mg) is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor. 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 with APTIVUS 500 mg concomitant with 200 mg ritonavir twice-daily for greater than 2 weeks and without meal restriction produced the following pharmacokinetic parameters for female and male HIV-positive patients. See Table 3.

APTIVUS capsules co-administered with ritonavir should be taken with food. Bioavailability is increased with a high fat meal. Tipranavir 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 (C_max point estimate 1.16, confidence interval 1.09-1.24).

When APTIVUS, co-administered with 200 mg ritonavir, was co-administered with 20 mL of aluminum and magnesium-based liquid antacid, tipranavir AUC_12h, C_max and C_12h were reduced by 25-29%. Consideration should be given to separating tipranavir/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

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 APTIVUS (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers (0.015% ± 0.006%) and HIV-positive patients (0.019% ± 0.076%). 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.

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 tipranavir/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.

Administration of ¹⁴C-tipranavir to subjects (n=8) that received tipranavir/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.

See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, Drug Interactions.

APTIVUS co-administered with 200 mg of ritonavir can alter plasma exposure of other drugs and other drugs may alter plasma exposure of tipranavir.

APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 24 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:

• The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response (see CLINICAL PHARMACOLOGY, Microbiology and INDICATIONS AND USAGE, Description of Clinical Studies).
• Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir (see CLINICAL PHARMACOLOGY, Microbiology). The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir (see CLINICAL PHARMACOLOGY, Microbiology).
• Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding (see WARNINGS).
• Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment (see WARNINGS).
• Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or other underlying hepatic impairment (see WARNINGS).
• The extensive drug-drug interaction potential of APTIVUS/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).
• The risk-benefit of APTIVUS/ritonavir has not been established in treatment-naïve adult patients or pediatric patients.

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

The following clinical data is derived from analyses of 24-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 (tipranavir) is contraindicated in patients with known hypersensitivity to any of the ingredients of the product.

APTIVUS is contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency (see WARNINGS).

Co-administration of APTIVUS with 200 mg of ritonavir, with drugs that are highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These drugs are uled in Tables 7 below. For information regarding clinical recommendations see PRECAUTIONS, Drug Interactions, Tables 8 and 9.

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

ALERT: Find out about medicines that should NOT be taken with APTIVUS®. This statement is included on the product's bottle label.

APTIVUS (tipranavir) must be co-administered with 200 mg of ritonavir to exert its therapeutic effect (see DOSAGE AND ADMINISTRATION). Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions (effect of tipranavir and ritonavir on other drugs).

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

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.

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 ANIMAL PHARMACOLOGY AND TOXICOLOGY).

APTIVUS co-administered with 200 mg of ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. 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.

Patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Additionally, Grade 3 and 4 increases in hepatic transaminases were observed in 6% of healthy volunteers in Phase 1 studies and 6% of subjects receiving APTIVUS/ritonavir in Phase 3 studies.

Tipranavir is principally metabolized by the liver. Therefore caution should be exercised when administering APTIVUS/ritonavir to patients with hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate to severe (Child-Pugh Class B and Child-Pugh Class C) hepatic insufficiency.

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.

For information on the multi-dose pharmacokinetics of tipranavir in hepatically impaired patients see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Hepatic Impairment.

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.

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of APTIVUS/ritonavir and fluticasone propionate may produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, 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 (see PRECAUTIONS, Drug Interactions).

Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (e.g., sildefafil, tadalafil, or vardenafil) in patients receiving protease inhibitors, including APTIVUS. Co-administration of a protease inhibitor with PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS, Drug Interactions and Information for Patients, and the complete specific PDE5 inhibitor prescribing information).

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 tipranavir is unknown.

Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving APTIVUS/ritonavir. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving APTIVUS/ritonavir. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving APTIVUS/ritonavir (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).

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.

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, Table 11). 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 (see PRECAUTIONS, Drug Interactions, Table 9: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with APTIVUS/ritonavir and HMG-CoA reductase inhibitors).

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.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tipranavir. 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 jeroveci pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment.

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.

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 hepatotoxicity.

Liver function tests should be performed prior to initiating therapy with tipranavir 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 2.5-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 liver disease.

Mild to moderate rash has been reported in HIV-infected men and women receiving APTIVUS/ritonavir.

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.

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.

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

APTIVUS should be taken with food to enhance absorption.

The Patient Package Insert provides written information for the patients, and should be dispensed with each new prescription and refill.

Tipranavir administered with ritonavir can alter plasma exposure of other drugs and other drugs can alter plasma exposure of tipranavir and ritonavir.

Tipranavir co-administered with 200 mg of ritonavir at the recommended dosage 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 tipranavir/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. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring (see CONTRAINDICATIONS and PRECAUTIONS).

The mechanisms of the potential interactions are described in the CLINICAL PHARMACOLOGY, Drug Interactions section.

Drugs that are contraindicated or not recommended for co-administration with APTIVUS are included in Table 8 below. 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.

Clinically significant drug-drug interactions of APTIVUS co-administered with 200 mg of ritonavir are summarized in Table 9 below.

Long term animal carcinogenicity bioassays with tipranavir and tipranavir/ritonavir are currently in progress. However, 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 C_max of 258 μM in females. Based on C_max 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 tipranavir/ritonavir BID.

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.

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 tipranavir, mothers should be instructed not to breastfeed if they are receiving APTIVUS.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from 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.

APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, has been studied in a total of 1854 HIV-positive adults as combination therapy in clinical studies. Of these, 1397 patients received the dose of 500/200 mg BID. Seven hundred sixty one (761) adults, including 385 in the 1182.12 and 1182.48 Phase 3 pivotal studies, have been treated for at least 24 weeks.

In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent AEs were diarrhea, nausea, fatigue, headache and vomiting. Adverse events leading to discontinuation were reported by 7.8% of the tipranavir-treated patients and 4.9% of 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.

The most frequent clinical treatment-emergent adverse events reported in Phase 3 clinical studies (1182.12 and 1182.48) in adults are summarized in Table 10 below. Events of moderate to severe intensity (Grades 2-4) reported in at least 2% of highly treatment-experienced subjects in either treatment group are included.

Clinically meaningful adverse reactions in < 2% of adult patients (n=1397) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 trials uled below by body system:

Blood and Lymphatic System Disorders: anemia, neutropenia, thrombocytopenia

Gastrointestinal Disorders: abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis

General Disorders: influenza like illness, malaise, pyrexia

Hepatobiliary Disorders: hepatitis, hepatic failure

Immune System Disorders: hypersensitivity

Infections and infestations: reactivation of herpes simplex and varicella zoster

Investigations: hepatic enzymes increased, liver function test abnormal, lipase increased, weight decreased

Metabolism and Nutrition Disorders: anorexia, decreased appetite, dehydration, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia

Musculoskeletal and Connective Tissue Disorders: muscle cramp, myalgia

Nervous System Disorders: dizziness, intracranial hemorrhage, neuropathy peripheral, somnolence

Psychiatric Disorders: insomnia, sleep disorder

Renal and Urinary Disorders: renal insufficiency

Respiratory, Thoracic and Mediastinal Disorders: dyspnea

Skin and Subcutaneous System Disorders: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus

Treatment emergent clinical laboratory abnormalities reported at 24 weeks in Phase 3 clinical studies (1182.12 and 1182.48) in adults are summarized in Table 11 below.

In clinical trials extending up to 48 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased to 24.4% with APTIVUS/ritonavir and to 12.8% with CPI/ritonavir.

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. The mechanism for these effects is unknown.

In preclinical studies of tipranavir in dogs, an effect on coagualation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

There is no known antidote for tipranavir 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 be beneficial in significant removal of this medicine.

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 (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)

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.

Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or
(800) 459-9906 TTY.

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

OT2000D

10003515/US/4
10003515/04

Revised: February 5, 2007

Aptivus^® (ap’· ti · vəs)
(tipranavir)
Capsules, 250 mg

ALERT: Find out about medicines that should not be taken with APTIVUS®. Please also read the section “Who Should Not Take APTIVUS?”.

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 doctor about your medical condition or treatment. You should stay under a doctor'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 bleeding in the brain that can cause death.

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

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/ritonavir treatment and call your doctor 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 doctor should check your blood tests more often because you have an increased chance of developing liver problems.

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 infection.

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 doctor 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:

• are allergic to tipranavir or any of the other ingredients in APTIVUS. See the end of this leaflet for a ul of major ingredients.
• are allergic to ritonavir (NORVIR^®)
• have moderate to severe liver problems
• take any of the following types of medicines because you could have serious side effects:
  • Migraine headache medicines called “ergot alkaloids”. If you take migraine headache medicines, ask your doctor or pharmacist if any of them are “ergot alkaloids”.
  • Halcion^® (triazolam)
  • Hismanal^® (astemizole)
  • Orap^® (pimozide)
  • Propulsid^® (cisapride)
  • Seldane^® (terfenadine)
  • Versed^® (midazolam)
  • Pacenone^® (amiodarone)
  • Vascor^® (bepridil)
  • Tambocor^® (flecainide)
  • Rythmol^® (propafenone)
  • Quinaglute dura^® (quinidine)

What should I tell my doctor before I take APTIVUS?

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

• have hemophilia or another medical condition that increases your chance of bleeding, or are taking medicines which increase your chance of bleeding. These patients may have an increased chance of bleeding.
• have liver problems or are infected with hepatitis B or hepatitis C. These patients may have worsening of their liver disease.
• are allergic to sulfa medicines.
• have diabetes. APTIVUS may worsen your diabetes or high blood sugar levels.
• are pregnant or planning to become pregnant. It is not known if APTIVUS can harm your unborn baby. You and your doctor will need to decide if APTIVUS is right for you. If you take APTIVUS while you are pregnant, talk to your doctor about how you can be in the Antiretroviral Pregnancy Registry.
• are breast-feeding. Do not breast-feed if you are taking APTIVUS. You should not breast-feed if you have HIV because of the chance of passing the HIV virus to your baby. Talk with your doctor about the best way to feed your baby.
• are using estrogens for birth control or hormone replacement. Women who use estrogens for birth control or hormone replacement have an increased chance of developing a skin rash while taking APTIVUS. If a rash occurs, it is usually mild to moderate, but you should talk to your doctor as you may need to temporarily stop taking either APTIVUS or the other medicine that contains estrogen or female hormones.

Tell your doctor 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?”).

• Some medicines cannot be taken at all with APTIVUS.
• Some medicines will require a change in dosage if taken with APTIVUS.
• Some medicines will require close monitoring if taken with APTIVUS.

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 ul of them with you. Show this ul to all your doctors 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 doctor or pharmacist. You can ask your doctor or pharmacist for a ul of medicines that can interact with APTIVUS.

How should I take APTIVUS?

• Take APTIVUS exactly as your doctor has prescribed. You should check with your doctor or pharmacist if you are not sure. You must take APTIVUS at the same time as NORVIR^®(ritonavir). The usual dose is 500 mg (two 250 mg capsules) of APTIVUS, together with 200 mg (two 100 mg capsules or 2.5 mL of solution) of NORVIR, twice per day. APTIVUS with NORVIR must be used together with other anti-HIV medicines.

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

• Always take APTIVUS with food.
• Do not change your dose or stop taking APTIVUS without first talking with your doctor.
• If you take too much APTIVUS, call your doctor or poison control center right away.
• If you forget to take APTIVUS, take the next dose of APTIVUS, together with NORVIR^® (ritonavir), as soon as possible. Do not take a double dose to make up for a missed dose.
• It is very important to take all your anti-HIV medicines as prescribed and at the right times of day. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV (drug resistance).
• When your APTIVUS® supply starts to run low, get more from your doctor or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short period of time. The HIV virus may develop resistance to APTIVUS and become harder to treat. You should NEVER stop taking APTIVUS or your other HIV medicines without talking with your doctor.

What are the possible side effects of APTIVUS?

APTIVUS may cause serious side effects, including:

• bleeding in the brain. This has occurred in patients treated with APTIVUS in clinical trials and can lead to permanent disability or death. Many of the patients experiencing bleeding in the brain had other medical conditions or were receiving other medications that may have caused or added to bleeding in the brain. Patients with hemophilia or another medical condition that increases the chance of bleeding, or patients taking medicines that may cause bleeding may have an increased chance of bleeding in the brain.
• liver problems, including liver failure and death. Your doctor should do blood tests to monitor your liver function during treatment with APTIVUS. Patients with liver diseases such as hepatitis B and hepatitis C may have worsening of their liver disease with APTIVUS and should have more frequent monitoring blood tests.
• rash. Mild to moderate 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 joint pain or stiffness, throat tightness, or generalized itching.
• increased bleeding in patients with hemophilia. This can happen in patients taking APTIVUS or other protease inhibitor medicines.
• diabetes and high blood sugar (hyperglycemia). This can happen in patients taking APTIVUS or other protease inhibitor medicines. Some patients have diabetes before starting treatment with APTIVUS which gets worse. Some patients get diabetes during treatment with APTIVUS. Some patients will need changes in their diabetes medicine. Some patients will need new diabetes medicine.
• increased blood fat (lipid) levels. Your doctor should do blood tests to monitor your blood fat (triglycerides and cholesterol) during treatment with APTIVUS. Some patients taking APTIVUS have large increases in triglycerides and cholesterol. The long-term chance of having a heart attack or stroke due to increases in blood fats caused by APTIVUS is not known at this time.
• changes in body fat. These changes have happened in patients taking APTIVUS and other anti-HIV medicines. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known.

The most common side effects include diarrhea, nausea, vomiting, stomach pain, tiredness and headache. Women taking birth control pills may get a skin rash.

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 doctor about any changes in your health. You should report any new or continuing symptoms to your doctor right away. Your doctor may be able to help you manage these side effects.

The ul of side effects is not complete. Ask your doctor or pharmacist for more information.

How should I store APTIVUS?

• Store APTIVUS capsules in a refrigerator at approximately 36ºF to 46ºF (2ºC to 8ºC). Once the bottle is opened, the spans must be used within 60 days. Patients may take the bottle with them for use away from home so long as the bottle remains at a temperature of approximately 59ºF to 86ºF (15ºC to 30ºC). You can write the date of opening the bottle on the label. Do not use after the expiration date written on the bottle.
• Keep APTIVUS and all medicines out of the reach of children.

General advice about APTIVUS

Medicines are sometimes prescribed for purposes other than those uled 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 doctor. You can ask your pharmacist or doctor 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. You may also request information through the company website at http://us.boehringer-ingelheim.com.

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

OT2000D

10003515/US/4
10003515/04

Revised: February 5, 2007