Control Number: 119718

Aptivus(r) is a registered trademark used under license by Boehringer Ingelheim (Canada) Ltd.

BPI#: 0259-03

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 10 DRUG INTERACTIONS 18 DOSAGE AND ADMINISTRATION 30 OVERDOSAGE 31 ACTION AND CLINICAL PHARMACOLOGY 32 STORAGE AND STABILITY 35 DOSAGE FORMS, COMPOSITION AND PACKAGING 35

PART II: SCIENTIFIC INFORMATION 36

PHARMACEUTICAL INFORMATION 36 CLINICAL TRIALS 37 DETAILED PHARMACOLOGY 43 TOXICOLOGY 44 REFERENCES 46

PART III: CONSUMER INFORMATION. 47

PrAPTIVUS(r) (tipranavir capsules)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY OF PRODUCT INFORMATION

CONTRAINDICATIONS

APTIVUS (tipranavir) is contraindicated in patients with known hypersensitivity to the active substance or to any of the ingredients of the product. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section. In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to WARNINGS and PRECAUTIONS) the use of the product is contraindicated. APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C respectively) hepatic insufficiency. APTIVUS contains Cremophor (r) EL. Caution should be used when administering medicines containing Cremophor(r) EL (e.g. cyclosporine i.v. and paclitaxel i.v.) to patients with a prior hypersensitivity reaction to Cremephor(r) EL. Co-administration of APTIVUS with 200 mg ritonavir, with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These drugs are listed in Table 1 below.

Table 1: Drugs that are Contraindicated with APTIVUS, Co-Administered with Ritonavir

Drugs within Class that are Contraindicated with APTIVUS, Co-administered

Drug Class

with Ritonavir

Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Antihistamines Astemizole *, terfenadine *

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agent Cisapride *

HMG-CoA reductase inhibitors

Lovastatin , simvastatin

Neuroleptic Pimozide Sedatives/hypnotics Midazolam, triazolam PDE5 Inhibitors Levitra (vardenafil)

Cisapride, astemizole and terfenadine are not marketed in Canada.

Due to the need for co-administration of APTIVUS with low-dose ritonavir (RTV), please refer to ritonavir product monograph for a description of ritonavir contraindications.

WARNINGS AND PRECAUTIONS

APTIVUS co-administered with 200 mg ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage (See WARNINGS and PRECAUTIONS).

APTIVUS co-administered with 200 mg ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance including increased clinical and laboratory monitoring is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity (See Hepatic Impairment).

General

APTIVUS (tipranavir) must be administered with 200 mg ritonavir to ensure its therapeutic effect (see Dosage and Administration). 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 instructed accordingly. Please refer to ritonavir product monograph for additional information on precautionary measures. Aptivus contains up to 50.4 mg sorbitol per maximum recommended daily dose. Patients with the rare hereditary condition of fructose intolerance should not take this medicine.

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.

Effects on Platelet Aggregation and Coagulation

APTIVUS co-administered with 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 supplement 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, co-administered with ritonavir. In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see Toxicology section).

Carcinogenesis and Mutagenesis:

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 genetic toxicity in a battery of five in vitro and in vivo tests assessing mutagenicity and clastogenicity. In a study conducted in rats with tipranavir at systemic exposure levels (AUC) of 1670 uM *h, equivalent to human exposure at the adult human clinical dose, no adverse effects on mating or fertility were observed. Tipranavir did not produce teratogenic effects at maternal doses producing systemic drug exposure levels of 1310 uM *h in rats or 120 uM *h in rabbits equivalent to or below the exposure at the adult human clinical dose (APTIVUS /ritonavir 500 mg/200 mg bid), respectively. At tipranavir exposures of 1310 uM *h in rats (0.8-fold human exposure at the clinical dose), fetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post- natal development studies with tipranavir in rats, no adverse effects were noted at 340 uM *h (0.2-fold human exposure), but growth inhibition of pups was observed at maternally toxic doses of 1310 uM *h (0.8-fold human exposure). Calculated exposure in animal studies were equivalent to or below human therapeutic exposure levels. For the animal studies reported above, exposures were three to five fold lower at the end of the dosing period compared to the start of the dosing period.

Cardiovascular

QT Prolongation

There were no clinical trials conducted following current ICH guidelines to examine the effect of APTIVUS on QT prolongation; however, a definitive QT prolongation study is currently planned. The data collected from the pre clinical and clinical trials suggest that there is low potential for TPV/r to prolong the QT interval.

Endocrine and Metabolism

Diabetes Mellitus/Hypergylcemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-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 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. The causal relationship between protease inhibitor therapy and these events has not been established.

Lipid Elevation

Treatment with APTIVUS co-administered with ritonavir, and other antiretroviral agents, has resulted in increased plasma total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS therapy and during therapy. Treatment- related lipid elevations should be managed as clinically appropriate.

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.

Hematologic

Hemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia 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.

Hepatic/Biliary/Pancreatic

Hepatic Impairment

APTIVUS is contraindicated in patients with moderate or severe hepatic insufficiency (Child- Pugh Class B or C, respectively) (see CONTRAINDICATIONS). Limited data are currently available for the use of APTIVUS, co-administered with ritonavir, in patients co-infected with hepatitis B or C. Patients with chronic hepatitis B or C and treated with antiretroviral agents are at an increased risk for severe and potentially fatal hepatic adverse events. APTIVUS should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring. Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of hepatitis. Appropriate laboratory testing should be conducted prior to initiating therapy with APTIVUS and ritonavir, and frequently during treatment. Increased monitoring should be considered when APTIVUS and ritonavir are administered to patients with elevated baseline transaminase levels, or active hepatitis-B or -C, as patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. APTIVUS/ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease. APTIVUS co-administered with 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 co-administered with 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, liver tenderness or hepatomegaly. Patients with signs or symptoms of hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Tipranavir is principally metabolised by the liver. Therefore caution should be exercised when administering this drug to patients with hepatic impairment because tipranavir concentrations may be increased. For information on the multi-dose pharmacokinetics of tipranavir in hepatically impaired patients, see CLINICAL PHARMACOLOGY.

Immune

Immune Reconstitution Syndrome

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Renal

Renal Impairment

Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected in patients with renal impairment.

Sensitivity/Resistance

Sulfonamide 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 tipranavir is unknown.

Sexual Function/Reproduction

Teratogenic Effects

No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. 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 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 uM *h or 1.4 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 / AUC(0-24) levels of 30.4 uM / 340 uM *h/mL and 8.4 uM / 120 uM *h/mL. These exposure levels (AUC) are 0.4 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, but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day and above. No post-weaning functions were affected at any dose level.

Skin

Rash

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. The risk of rash increases in patients with lower CD4 cell counts.

Special Populations

Pregnant Women:

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.

Nursing Women:

APTIVUS was shown to be excreted in breast milk in rats/mice. It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk, precaution should be exercised. Consistent with the recommendation that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving APTIVUS.

Antiretroviral Pregnancy Registry:

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

Pediatrics (2 - 18 years of age).

: Safety and efficacy of APTIVUS in this population has not yet been fully established. Treatment of children with APTIVUS is therefore not recommended

There are no data available in children younger than 2 years of age (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Population, Pediatric Patients).

Geriatrics (> 65 years of age)

: 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.

Monitoring and Laboratory Tests

Appropriate laboratory testing should be conducted prior to initiating therapy with APTIVUS and low-dose ritonavir, and during treatment. Increased monitoring should be considered when APTIVUS and low dose ritonavir are administered to patients with elevated AST and ALT levels, or chronic hepatitis-B or -C. Triglyceride and cholesterol testing should be performed prior to initiating tipranavir therapy and during therapy.

DRUG INTERACTIONS

Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. However, when co-administered with ritonavir at the recommended dosage, there is a net inhibition of P450 CYP3A. Co-administration of APTIVUS and ritonavir with agents primarily metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could alter their therapeutic and adverse effects. Agents that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in CONTRAINDICATIONS and in DRUG INTERACTIONS, Table 8: Drugs that Should Not Be Co-Administered with APTIVUS/Ritonavir.

Tipranavir is metabolised by CYP3A and is a Pgp substrate. Co-administration of tipranavir and agents that induce CYP3A and/or Pgp may decrease tipranavir concentrations and reduce its therapeutic effect. Co-administration of APTIVUS and medicinal products that inhibit Pgp may increase tipranavir plasma concentrations. Interaction with other drugs and other potentially significant drug interactions are discussed in greater detail in this Section.

Overview

APTIVUS co-administered with ritonavir at the recommended dose is a net inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Thus, co-administration of APTIVUS/ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life- threatening events is contraindicated (see CONTRAINDICATIONS). Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring (see DRUG INTERACTIONS). 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 slight inhibition after first dose on CYP2C19 and moderate 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 that P-gp was inhibited after the first dose of APTIVUS/ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established.

Table 7: Drugs That Should Not Be Co-Administered with APTIVUS/ritonavir

Cisapride, astemizole and terfenadine are no longer marketed in Canada

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated).

Table 8: 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 APTIVUS, co-administered with

Clinical Comment

ritonavir or Concomitant Drug

Nucleoside reverse transcriptase inhibitors:

HIV-Antiviral Agents

Abacavir

Didanosine (EC)

Zidovudine

Lamivudine and stavudine Tenofovir

|

Abacavir AUC by approximately 40%

|

Didanosine

|

Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.

No significant change in the AUC of lamivudine or stavudine

No significant change in the plasma concentrations of tenofovir.

Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.

Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS co-administered with ritonavir dosing by at least 2 hours to avoid formulation incompatibility.

Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.

No dosage adjustment of lamivudine or stavudine is recommended.

No dosage adjustment of tenofovir is recommended.

Non-nucleoside reverse transcriptase inhibitors:

Efavirenz No significant impact on the AUC and Cmin of efavirenz.

Steady-state efavirenz 600 mg qd co-administered with steady-state APTIVUS and ritonavir (500/200

mg bid) had no significant impact on tipranavir AUC and Cmax (2.9% and 8.3% decreases, respectively) and resulted in a clinically unimportant

increase in Cp12h (19.2%). Therefore

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

Clinical Comment

no dose adjustment is necessary.

Nevirapine No significant interaction with nevirapine was observed.

Therefore no dose adjustments are necessary.

Fusion Inhibitors:

Enfurvitide

No formal drug interaction data are currently available on interactions of APTIVUS, co-administered with 200 mg ritonavir, with fusion inhibitors.

The co-administration of enfurvitide with Aptivus, co-administered with ritonavir, is associated with an increase in steady-state plasma tipranavir trough concentration for the study population by approximately 45%. Similar increases also have been observed for lopinavir (23%) and saquinavir (63%) plasma trough concentrations after combination with enfuvirtide. The mechanism for this interaction is not known. Tipranavir or ritonavir dose adjustment is not recommended.

Antifungals:

Other Agents for Opportunistic Infections

Fluconazole increases TPV concentrations but dose adjustments

Fluconazole Itraconazole Ketoconazole

Voriconazole

| Tipranavir, - Fluconazole

|

Itraconazole (not studied)

|

Ketoconazole (not studied)

| Voriconazole (not studied)

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 CYP isoenzymes systems involved with voriconazole metabolism, it is difficult to predict the interaction with APTIVUS, co- administered with ritonavir.

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%.

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

Clinical Comment

• 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

Antacids | Tipranavir When APTIVUS/ritonavir, was co- administered with 20 mL of aluminum and magnesium-based liquid antacid, tipranavir AUC12h, Cmax and C12h were reduced by 27, 25, and 29%, respectively.

Consideration should be given to separating APTIVUS/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

Anticonvulsants:

Carbamazepine Phenobarbital Phenytoin

|

Tipranavir

|

Carbamazepine

Carbamazepine, phenobarbital and phenytoin should be used with caution in combination with APTIVUS/ritonavir. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.

Concomitant use of carbamazepine at a dose of 200 mg BID resulted in increased carbamazepine plasma concentrations (by approximately 23

% in geometric mean Cmin for the total of carbamazepine and carbamazepine-10,11 -epoxide; both are pharmacologically active moieties), and a decrease in tipranavir Cmin (by approximately 61% compared to historical controls), which may result in decreased effectiveness. Higher doses of carbamazepine may result in even larger decreases in tipranavir

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

Clinical Comment

plasma concentrations.

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

Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co- administration of trazodone and ritonavir. If trazodone is used with APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Calcium Channel Blockers:

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil

Combination with APTIVUS/ritonavir not studied. Cannot predict effect of APTIVUS/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp due to conflicting effect of APTIVUS/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.

Despiramine Combination with APTIVUS/ritonavir not studied

|

Despiramine

Dosage reduction and concentration monitoring of despiramine is recommended.

Disulfiram/Metronidazole Combination with APTIVUS/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:

Rosuvastatin Pravastatin

|

Tipranavir

|

Rosuvastatin

Use the lowest possible dose of rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as

Fluvastatin fluvastatin or pravastatin when in

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

Clinical Comment

concomitant use with APTIVUS, co- administered with 200 mg ritonavir.

Hypoglycemics:

Glimepiride Glyburide Pioglitazone Repaglinide Tolbutamide

Combination with APTIVUS/ritonavir not studied.

• Glimepiride (CYP 2C9)

• Glyburide (CYP 2C9)

| Pioglitazone (CYP 2C8 and CYP 3A4)

| Repaglinide (CYP 2C8 and CYP 3A4)

Tolbutamide (CYP 2C9)

The effect of APTIVUS/ritonavir on CYP 2C8 and CYP 2C9

substrates is not known.

Careful glucose monitoring is warranted.

Immunosuppressants:

Cyclosporine Sirolimus Tacrolimus

Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp.

| Cyclosporine

| Sirolimus

| Tacrolimus

The effect of co-administration of APTIVUS with ritonavir on a substrate for CYP3A4/5 showed potent inhibition at both first-dose and steady-state APTIVUS/ritonavir. When APTIVUS with ritonavir was co- administered with a substrate for P-gp moderate inhibition of P-gp occurred with first-dose APTIVUS/ritonavir, however no effect on P-gp occurred with

steady-state APTIVUS/ritonavir. It is anticipated that similar effects will be seen with these immunosuppressants.

More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilized.

Loperamide A pharmacodynamic interaction study in healthy volunteers demonstrated that administration of loperamide and APTIVUS, co-

The clinical relevance of these changes is unknown.

administered with low-dose

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

ritonavir, does not cause any clinically relevant change in the respiratory response to carbon dioxide.

The pharmacokinetic analysis showed that the AUC and Cmax of loperamide are reduced by 51% and 61%, respectively, and the Cmin of tipranavir by 26%.

Clinical Comment

Narcotic analgesics:

Meperidine

Methadone

Combinations with APTIVUS/ritonavir not studied

| Meperidine, | Normeperidine

| Methadone AUC and Cmax by 50%

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).

Because APTIVUS/ritonavir decreases methadone AUC and Cmax patients should be monitored for opiate withdrawal syndrome. Dosage of methadone may need to be increased when co-administered with tipranavir 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 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 rash.

PDE5 inhibitors:

Sildenafil Tadalafil Vardenafil

Only the combination of tadalafil with APTIVUS/ritonavir has been studied

|

Sildenafil (not studied)

|

Tadalafil with first dose APTIVUS/ritonavir

Tadalafil at APTIVUS/ritonavir steady-state

Concomitant use of APTIVUS, co- administered with 200 mg ritonavir, and tadalafil resulted in a 2.3-fold increase in tadalafil exposure with first-dose APTIVUS/ritonavir and no change in tadalafil exposure with steady-state tipranavir/ritonavir.

If tadalafil is used within the first days of APTIVUS/ritonavir treatment, then the lowest dose

should be administered. However,

Concomitant Drug Class: Drug name

Effect on Concentration of APTIVUS, co-administered with ritonavir or Concomitant Drug

Clinical Comment

after 7-10 days of APTIVUS/ritonavir dosing, steady- state for tipranavir and ritonavir is achieved and the dose of tadalafil may be increased, as clinically necessary.

Concomitant use of PDE5 inhibitors with APTIVUS and ritonavir should be used with caution and in no case should the starting dose of:

sildenafil exceed 25 mg within 48 hours

tadalafil exceed 10 mg every 72 hours

vardenafil is contraindicated

Selective Serotonin-Reuptake Inhibitors:

Fluoxetine Paroxetine Sertraline

Combination with APTIVUS/ritonavir not studied

|

Fluoxetine

|

Paroxetine

|

Sertraline

Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.

Theophylline APTIVUS, co-administered with low-dose ritonavir, is expected to decrease theophylline concentrations.

Increased dosage of theophylline may be required and therapeutic monitoring should be considered.

Warfarin and other oral anticoagulants

- S-Warfarin Clinical and biological (INR measurement) monitoring is recommended when these medicinal products are combined.

Drug-Food Interactions

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. Food 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). APTIVUS may be safely taken with standard or high-fat meals. APTIVUS capsules, co- administered with ritonavir, should be taken with food.

Drug-Herb Interactions

Co-administration of protease inhibitors, including APTIVUS, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of tipranavir and lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors. Concomitant use of APTIVUS and St. John's wort (Hypericum perforatum), or products containing St. John's wort, is not recommended.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Driving and Using Machines

: There are no specific studies about the ability to drive vehicles and use machinery.

Other Medications

The following medications were discouraged in the pivotal trials: amitriptyline, benazepril, buspirone, carbamazepine, cimetidine, clonazepam, desiryl, encainide erythromycin, fentanyl, loratadine, milk thistle, mirtazapine, nortriptyline, phenobarbital, phenytoin, quetiapine fumarate, risperidone, sublimaze, sulfinpyrazone, systemic cytotoxic chemotherapy, temazepam, troleandomycin, venlafaxine, verapamil, zaleplon, and zolpidem tartrate. Clinicians should monitor patients taking any of these medications concomitantly with APTIVUS/r.

Table 9: Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs

*steady state comparison to historical data (n)

Table 10: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug

in the Presence of APTIVUS/ritonavir

Ratio (90% Confidence Interval) of Co-administered

0.82)

Co-administered Drug

Co- administered Drug Dose

APTIVUS/ritonavir Drug Dose

n PK

Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without APTIVUS/ritonavir;

No Effect = 1.00

0.92)

a

HIV+ patients

b

HIV+ patients (APTIVUS/ritonavir 250 mg/200 mg, 750 mg/200 mg and 1250 mg/100 mg) and healthy volunteers (APTIVUS/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

DOSAGE AND ADMINISTRATION

Dosing Considerations

APTIVUS must be administered with 200 mg ritonavir to ensure its therapeutic effect. Patients should be instructed accordingly. Please also refer to the ritonavir product monograph for contraindications, warnings, precautions, side effects and potential drug interactions. Triglyceride and cholesterol testing should be performed prior to initiating tipranavir therapy and during therapy.

Dosage for Elderly Patients

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. See ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS sections.

Dosage for Pediatric Patients

The safety and efficacy of APTIVUS in this population has not been established. Treatment of children with APTIVUS is therefore not recommended. See ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS, Special Populations, ADVERSE REACTIONS sections.

Dosage for Hepatically Impaired Patients

APTIVUS is contraindicated in patients with moderate or severe hepatic insufficiency (Child- Pugh Class B or C, respectively) (See CONTRAINDICATIONS). APTIVUS co-administered with 200 mg ritonavir should be used with caution in patients with mild hepatic insufficiency (Child-Pugh Class A); these patients should be monitored closely.

Recommended Dose and Dosage Adjustment

The recommended dose of APTIVUS (tipranavir) Capsules is 500 mg (two 250 mg capsules), co-administered with 200 mg ritonavir (low-dose ritonavir), twice daily. APTIVUS co-administered with 200 mg ritonavir should be administered with food. APTIVUS, co-administered with 200 mg ritonavir, should be taken with at least two additional antiretroviral agents. The manufacturers' product monograph of the antiretroviral agents should be followed. APTIVUS, co-administered with 200 mg ritonavir, causes a reduction in the AUC of didanosine. Dosing of enteric-coated didanosine and tipranavir, co-administered with 200 mg ritonavir, should be separated by at least 2 hours to avoid formulation incompatibility.

Missed Dose:

If a dose of APTIVUS is missed by less than or equal to 5 hours, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is missed by more than 5 hours, patients should skip that dose and return to the normal schedule without doubling the next dose.

OVERDOSAGE

For management of a suspected drug overdose, please contact your regional Poison Control Centre. 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. 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.

ACTION AND CLINICAL PHARMACOLOGY

Microbiology

Mechanism of action:

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Pharmacokinetics:

In order to achieve effective tipranavir plasma concentrations and a bid dosing regimen, co- administration of APTIVUS with 200 mg ritonavir twice daily is essential (see DOSAGE AND ADMINISTRATION). Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (Pgp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0-12h, Cmax and Cmin and decreases the clearance of tipranavir. APTIVUS co-administered with ritonavir (500 mg/200 mg twice daily) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to APTIVUS 500 mg twice daily without ritonavir. 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 11.

Table 11: Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV+ Patients by Gender

a

Population pharmacokinetic parameters reported as mean +- standard deviation

A trial of HIV infected patients assessed the pharmacokinetics and safety of APTIVUS/ritonavir 500/200 mg administered with and without lopinavir, amprenavir, or saquinavir compared to ritonavir 100 mg administered with lopinavir, amprenavir, or saquinavir. 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. 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. Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic and transporter enzyme induction. Steady state is attained in most subjects after 7 days of dosing. APTIVUS, co-administered with 200 mg ritonavir, exhibits linear pharmacokinetics at steady-state. Dosing with APTIVUS 500 mg concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) of 94.8 +- 22.8 uM for female patients (n=14) and 77.6 +- 16.6 uM for male patients (n=106), occurring approximately 3 hours after administration. The mean steady-state trough concentration prior to the morning dose was 41.6 +- 24.3 uM for female patients and 35.6 +- 16.7 uM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 +- 309 uM *h (CL=1.15 l/h) for female patients and 710 +- 207 uM *h (CL=1.27 l/h) for male patients. The mean half-life was 5.5 (females) or 6.0 hours (males). Effects of food on oral absorption: APTIVUS may be safely taken with standard or high-fat meals. APTIVUS capsules, co-administered with 200 mg ritonavir, should be taken with food. 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. Food 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). When APTIVUS, co-administered with 200 mg ritonavir, was co-administered with 20 ml of aluminium and magnesium-based liquid antacid, tipranavir AUC12h, Cmax and C12h were reduced by 25-29 %. Consideration should be given to separating APTIVUS/ritonavir dosing from anatacid administration to prevent reduced absorption of tipranavir. Distribution: Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy volunteers and HIV-positive subjects who received APTIVUS without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% +- 0.006%; HIV positive subjects 0.019% +- 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 mM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range. No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Metabolism: In vitro

metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform 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 low-dose ritonavir is minimal. In a 14C-tipranavir human study (14C-tipranavir/ritonavir, 500 mg/200 mg bid), unchanged tipranavir was predominant and 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. Excretion: Administration of 14C-tipranavir to subjects (n = 8) that received APTIVUS/ritonavir 500 mg/200 mg bid dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56.3 %) 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 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg bid daily with a light meal.

Special Populations and Conditions

Geriatric Patients

: Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies 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, but the trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.

Gender: Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS /ritonavir 500 mg/200 mg bid., the median plasma trough concentration of tipranavir was 43.9 mM for females and 31.1 mM for males. This 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 RESIST-1 and RESIST-2 studies 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. Females of either race generally had higher trough tipranavir concentrations than males.

Renal Insufficiency

: Tipranavir 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 Insufficiency: In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose pharmacokinetic profiles of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in the clinical studies. No dosing adjustment is required in patients with mild hepatic impairment; however, patients should be closely monitored. The influence of moderate hepatic impairment (Child Pugh B) on the multiple-dose pharmacokinetics of either tipranavir or ritonavir has not been evaluated. APTIVUS is contraindicated in patients with moderate or severe hepatic impairment.

STORAGE AND STABILITY

APTIVUS capsules should be stored under refrigeration (2oC to 8oC). Once opened, the bottle can be stored at 25oC, excursions permitted to 15 to 30oC for up to 60 days.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

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.

Composition:

Each APTIVUS (tipranavir) capsule contains 250 mg of tipranavir. Inactive ingredients include Cremophor(r) EL, ethanol, mono/diglycerides of caprylic/capric acid, propyl gallate, propylene glycol, purified water, and trometamol. Capsule shell: gelatin, iron oxide red, propylene glycol, purified water, 'sorbitol special glycerin blend' (d-sorbitol, 1,4-sorbitan, mannitol and glycerin) and titanium dioxide. Black printing ink: ammonium hydroxide, ethylacetate, iron oxide black, isopropyl alcohol, Macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and SDA 35 alcohol.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Tipranavir Chemical name: 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) Molecular formula and molecular mass: C H F N O S; 602.7

31 33 3 2 5

Structural formula:

CH3

H N

SO2

O O N

CF3 Single Stereoisomer 1R, 6R Tipranavir (free acid form) Physicochemical properties: Description: Tipranavir is a white to off-white to slightly yellow solid. Melting point: Tipranavir melts at approximately 90oC. The DSC data show an onset of melt at 88oC and a peak temperature of 97oC when heated at 10oC per minute. Crystallinity/Polymorphism: Tipranavir is partially crystalline substance. No polymorphs have been observed in the drug substance manufactured by the A1, B, B1, and B2 synthesis routes. Solubility: 0.11 mg/mL at pH 2 aqueous buffer, 13 mg/mL at pH 7.4 aqueous buffer, and 385 mg/mL at pH 8.6 aqueous buffer. Soluble in organic solvents such as ethanol (>1 g/mL), propylene glycol (>500 mg/mL), and PEG 400 (>600 mg/mL).

CLINICAL TRIALS

Description of clinical studies: Treatment Experienced Patients

Studies RESIST-1 and RESIST-2: APTIVUS/Ritonavir 500/200 mg bid + optimized background regimen (OBR) vs. Comparator PI/Ritonavir bid + OBR The following clinical data is derived from analyses of 24-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV-1 RNA levels and CD4 cell counts. These studies are currently continuing and longer term data will be supplied when available. At present there are no results from controlled trials evaluating the effect of APTIVUS on clinical progression of HIV.

Table 12: Study Demographic and Trial Design

RESIST-1 and RESIST-2 are ongoing, randomized, open-label, multicenter studies in HIV- positive, triple-class experienced patients, evaluating treatment with APTIVUS, co-administered with 200 mg ritonavir (APTIVUS/ritonavir), plus an OBR individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir-boosted PI (CPI/r; also individually defined) plus an OBR. The ritonavir-boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir. All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based regimen at the time of study entry. 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 on codons 33, 82, 84 or 90. After week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to APTIVUS/ritonavir in a separate roll-over study. The 1159 patients included in the primary interim analysis had a median age of 43.0 years (range 17-80), were 88 % male, 73 % white, 14 % black and 1 % Asian. In the APTIVUS/ritonavir and CPI/ritonavir groups median baseline CD4 cell counts were 155 and 158 cells/mm3, respectively, (ranges 1-1893 and 1-1184 cells/mm3); median baseline plasma HIV-1 RNA was 4.83 and 4.82 log10 copies/ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log10 copies/ml).

Study Results

Treatment response and outcomes of randomised treatment at week 24 are presented for the two RESIST studies as well as combined studies as shown in the table 13 below.

Table 13: Outcomes of Randomised Treatment at Week 24 (Pooled Studies RESIST-1 and

RESIST-2 in Treatment Experienced Patients)

• Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure

* * Lost to follow-up, nonadherence to protocol, consent withdrawn, or other reasons

* * * Comparator PI/RTV: LPV/r 400/100 mg bid (n=290), IDV/r 800/100 mg bid (n=20), SQV/r 1000/100 mg bid or 800/200 mg bid (n=118), APV/r 600/100 mg bid (n=149)

RESIST data also demonstrate that APTIVUS co-administered with low dose ritonavir exhibits a better treatment response at 24 weeks when the OBR contains genotypically available antiretroviral agents (eg enfuvirtide). 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 PI mutations (1-4 or > 5) in subjects who received APTIVUS, co-administered with low dose ritonavir, with or without enfuvirtide. The following observations were made:

• Approximately 1.5 log10 decrease in HIV-1 RNA occurs at early time points (week 2) regardless of the number of baseline primary PI mutations (1-4 or 5+)

• Subjects with 5 or more primary PI mutations in their HIV-1 at baseline who received APTIVUS/ritonavir without enfuvirtide began to lose antiviral activity between Weeks 4 and 8

• Sustained HIV-1 RNA decreases (1.5 - 2 log10) through Week 24 were observed in subjects with 5 or more primary PI mutations at baseline who received APTIVUS/ritonavir and enfuvirtide

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

Table 14: Outcomes of Randomised Treatment at Week 24 (Individual Studies RESIST-1 and RESIST-2 in Treatment Experienced Patients)

FAS = full analysis set; NCF = non completers considered failures; PPS = per protocol set; DC = discontinuation;

AE = adverse event; BLQ = below the level of quantification

* statistical testing not performed due to the relatively small number of patients involved

Data from the RESIST trials were combined to analyze treatment response within each pre- selected PI stratum (Table 15). The APTIVUS/r group had significantly higher treatment responses than LPV/r, SQV/r, or APV/r groups. The IDV stratum had too few patients to make definitive statements. After adjustment for PI and ENF stratum, being randomized to the APTIVUS group increased the odds of a treatment response at Week 24 by nearly three fold (p<0.0001).

Table 15: Treatment response at Week 24 by PI strata - RESIST trials (FAS)

n = Number of responders; N = Number of evaluable patients

a Treatment difference and confidence interval weighted for the size of ENF strata and PI strata.

b Weighted difference and confidence interval not presented for the IDV stratum due to small sample size.

Genotypic analyses of tipranavir resistance in treatment-experienced patients

The virologic response to APTIVUS co-administered with low-dose ritonavir has been evaluated with respect to baseline viral genotype in treatment-experienced patients participating in studies RESIST-1 and RESIST-2. In these studies, the patients had baseline HIV-1 isolates with an average of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. In addition the majority of participants evaluated had mutations associated with both NRTI and NNRTI resistance. The use of genotypic resistance testing and the clinical interpretation of genotypic mutations is a complex and evolving field. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data. Several analyses were conducted to evaluate the impact of specific mutations and mutational patterns on virology outcome. The HIV-1 RNA response at Week 24 in studies RESIST-1 and RESIST-2 by number of protease gene mutations is shown in Table 16 below.

Table 16: Change in Viral load at Week 24 by Number of Protease Gene Mutations in

Studies RESIST-1 and RESIST-2 * *

* Change in Viral load was the change in HIV RNA from baseline through week 24 in log10 copies/mL (LOCF).

* * Protease gene mutations include any deviation from Los Alamos database consensus sequence for subtype B

Virologic response to APTIVUS/ritonavir therapy has been evaluated with respect to baseline genotype and phenotype in treatment experienced patients participating in four studies (RESIST- 1, RESIST-2, 1182.52, 1182.51), which provided the greatest spectrum of patients with highly mutated virus. A correlation between key protease mutations (at amino acids 33, 82, 84 and 90), baseline phenotypic susceptibility to tipranavir and response to APTIVUS/ritonavir therapy at weeks 2 and 24 has been established and is summarized in Table 17. Data on comparator protease inhibitor/ritonavir arm is not shown in Table 17 because the 1182.51 and 1182.52 trials did not include a comparator arm.

Table 17: HIV RNA Response at Weeks 2 and 24 by Baseline Key Mutations and Tipranavir Phenotypic Susceptibility in RESIST-1 and RESIST-2 and Studies 1182.52 and 1182.51 *

* All trials tipranavir/ritonavir 500 mg/200 mg bid dose; Trials 1182.52 and 1182.51 had patient population infected with highly mutated virus. All patients included from 1182.51 received APTIVUS/ritonavir 500 mg/200 mg bid, without additional PI therapy

* * Fold change in susceptibility from wild-type determined by recombinant phenotypic AntivirogramTM assay.

Phenotypic analyses of tipranavir resistance in treatment-experienced patients

Virologic response to APTIVUS/ritonavir therapy has been evaluated with respect to baseline genotype in treatment experienced patients participating in trials RESIST-1 and RESIST-2. A score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced 24-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation between the tipranavir susceptibility score and response to APTIVUS/ritonavir therapy at weeks 2 and 24 has been established and is summarized in Table 18.

Table 18: HIV Response: Change in Viral load at Weeks 2 and 24 by Baseline Tipranavir Susceptibility Score * * in Studies RESIST-1, and RESIST-2

Change in Viral load was the change in HIV RNA from baseline through weeks 2 and 24 in log10 copies/mL (LOCF).

* * Count of altered bases at 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T,

83D and 84V in baseline HIV-1 sequence

The virologic response to APTIVUS, co-administered with low-dose ritonavir, therapy has been evaluated with respect to baseline tipranavir phenotypic susceptibility (N=454) in treatment- experienced patients participating in trials RESIST-1 and RESIST-2. In these studies, the patients had baseline HIV isolates with an average decrease in susceptibility of 12-fold wild-type (WT) for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-fold WT for nelfinavir, 195-fold WT for ritonavir, 20-fold WT for saquinavir, and 2-fold WT for tipranavir. Phenotypic analysis of baseline isolates from these studies demonstrated a correlation between baseline susceptibility to tipranavir and response to tipranavir, co-administered with low-dose ritonavir, therapy. Table 19 below summarizes the HIV RNA response by tipranavir susceptibility.

Table 19: HIV Response at Weeks 2 and 24 by Baseline Tipranavir Susceptibility in

Studies RESIST-1, RESIST-2

* Change in Viral load was the change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log10 copies/mL.

DETAILED PHARMACOLOGY

Microbiology

Mechanism of action:

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 uM (18-42 ng/ml). Tipranavir demonstrates antiviral activity in vitro 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 vitro to tipranavir with EC50 values ranging from 0.164-1 uM and 0.233-0.522 uM, respectively. Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present. When used with other antiretroviral agents in vitro, 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). APTIVUS was synergistic with the HIV fusion inhibitor enfuvirtide. There was no antagonism of the in vitro combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis. Resistance: The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing >= 3-fold resistance to tipranavir grow at less than 1 % of the rate detected for wild type HIV-1 in the same conditions. Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or reduced 24-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a >=10-fold decrease in tipranavir susceptibility harboured eight or more tipranavir-associated mutations. In Phase II and III clinical trials, 276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations with APTIVUS treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross resistance:

Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 clinical isolates showing post-treatment decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir.

Greater than 10-fold resistance to tipranavir is uncommon (< 2.5 % of tested isolates) in viruses obtained from treatment experienced patients who have received multiple peptidic protease inhibitors. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.

TOXICOLOGY

Animal toxicology studies have been conducted with tipranavir alone and co-administered with ritonavir (3.75:1 w/w ratio) in various species. Studies with co-administration of tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those seen in the tipranavir single agent toxicological studies. The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). In animals, this effect was observed at exposure levels of 290 - 450 uM *h, dependent on duration of treatment. The effects were reversible with termination of treatment. 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 majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or below the human exposure levels at the recommended clinical dose. Bleeding in rats was observed at exposure levels of 300 - 1100 uM *h (rodent specific). The co-administration of tipranavir with vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) 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 coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs. 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 genetic toxicity in a battery of five in vitro and in vivo tests assessing mutagenicity and clastogenicity. In a study conducted in rats with tipranavir at systemic exposure levels (AUC) of 1670 uM *h, equivalent to human exposure at the adult human clinical dose, no adverse effects on mating or fertility were observed. Tipranavir did not produce teratogenic effects at maternal doses producing systemic drug exposure levels of 1310 uM *h in rats or 120 uM *h in rabbits equivalent to or below the exposure at the adult human clinical dose (APTIVUS /ritonavir 500 mg/200 mg bid), respectively. At tipranavir exposures of 1310 uM *h in rats (0.8-fold human exposure at the clinical dose), fetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post- natal development studies with tipranavir in rats, no adverse effects were noted at 340 uM *h (0.2-fold human exposure), but growth inhibition of pups was observed at maternally toxic doses of 1310 uM *h (0.8-fold human exposure). Calculated exposure in animal studies were equivalent to or below human therapeutic exposure levels. For the animal studies reported above, exposures were three to five fold lower at the end of the dosing period compared to the start of the dosing period.

REFERENCES

1. Chong KT and Pagano PJ. In vitro combination of HIV-1 protease inhibitor PNU-140690 with ritonavir against ritonavir sensitive and resistant clinical isolates. Antimicrob Agents Chemother 1997, 41: 2367-73 (P00-12500)

2. Larder BA, Hertogs K, Bloor S, Eyne C van den, DeCian W, Yenyun, W, Freimuth WW, Tarpley G. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 2000; 14: 1943-48. (P00-03066)

3. Pope SM, Slade DE, Chong KT, Hinshaw RR, Pagano PJ, Markowitz M, Ho DD, Mo H, Gorman RR, Dueweke TJ, Thaisrivongs S, Tarpley WG. Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic Human Immunodeficiency Virus protease inhibitor. Antimicrobiol Agents Chemother 1997; 41: 1058-1063. (P00-12499)

4. S Rusconi, S La Seta Catamancio, P Citterio, S Kurtagic, M Violin, C Balotta, M Moroni, M Galli, A D'Arminio-Monforte. Susceptibility to PNU-140690 (tipranavir) of Human Immunodeficiency Virus Type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrobiol Agents Chemother 2000; 44: 1328-1332. (P00- 14859)

5. Back NKT, van Wijk A, Remmerswaal D, van Monfort M, Nijhuis M, Schuurman R, Boucher CAB. In vitro-tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors. AIDS 2000; 14: 101-102. (P00-11747)

6. Molla A, Mo H, Vasavanonda S, Han L, Lin CT, Hsu A, Kempf DJ. In vitro antiviral interaction of lopinavir with other protease inhibitors. Antimicrobiol Agents Chemother 2002; 46: 2249-2253. (P02-06079)

7. Bulgheroni E, Citterio P, Croce F, Lo Cicero M, Vigano O, Soster F, Chou TC, Galli M, Rusconi S. Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against Human Immunodeficiency Virus Type 1 wild-type and drug-resistant isolates. J Antimicrob Chemother 2004; 53: 464-468. (P04-02030)

8. Sulkowski MS; Thomas DL; Hepatitis C in the HIV-infected person. Ann Intern Med 138 (3), 197-207 (2003). (P03-01836)

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrAptivus(r)

(Tipranavir) Capsules

This leaflet is part III of a three-part "Product Monograph" published when APTIVUS was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about APTIVUS. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

Read this information carefully before you start taking APTIVUS. Read it again each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor. You and your doctor should discuss APTIVUS when you start taking your medicine and at regular checkups. You should stay under a doctor's care when using APTIVUS. Do not change treatment or stop treatment without first talking to your doctor. Ask your doctor if you have any questions about APTIVUS.

Before taking your medicine, make sure you have received the correct medicine. Compare the name of the product stated above with the name of the product on your bottle and the appearance of your medicine with the description provided below. Contact your pharmacist immediately if you believe you have been given the wrong medication.

In addition, since APTIVUS must be taken together with Norvir(r) (ritonavir), please read the Patient Information for Norvir(r) (ritonavir).

What the medication is used for:

APTIVUS is a medicine to treat adults with Human

Immunodeficiency Virus (HIV), the virus that causes AIDS (Acquired Immune Deficiency Syndrome). APTIVUS must always be taken with Norvir(r) (ritonavir) and with other anti-HIV medicines to treat people with HIV infection.

What it does:

HIV infection destroys CD4 (T) cells, which are important to the immune system. After a large number of T cells are destroyed,

acquired immune deficiency syndrome (AIDS) develops.

APTIVUS blocks HIV protease, an enzyme which is needed for HIV to multiply (make more virus). APTIVUS reduces the amount of HIV in your blood and increases the number of T cells. Reducing the amount of HIV in the blood reduces the risk of death or infections that happen when your immune system is weak (opportunistic infections).

When it should not be used:

Do not take APTIVUS:

• If you are hypersensitive (allergic) to tipranavir, ritonavir, or any of the other ingredients of APTIVUS or ritonavir

(Norvir(r)) (see What the important nonmedicinal ingredients are and ritonavir product monograph);

If you have moderate to severe liver problems;

If you are currently taking any of the following medications:

• dihydroergotamine, ergonovine, ergotamine and methylergonovine

• triazolam

• astemizole *

• pimozide

• cisapride *

• terfenadine *

• midazolam

• amiodarone

• bepridil

• flecainide

• propafenone

• quinidine

• vardenafil

• lovastatin

• simvastatin

Do not take APTIVUS if you have a rare hereditary condition of fructose intolerance as this product contains 50.4 mg sorbitol per maximum recommended daily dose.

What the medicinal ingredient is:

APTIVUS capsules contain the active ingredient called tipranavir.

What the important nonmedicinal ingredients are: Inactive ingredients include Cremophor(r) EL, ethanol, mono/diglycerides of caprylic/capric acid, propyl gallate, propylene glycol, purified water, and trometamol.

Capsule shell: gelatin, iron oxide red, propylene glycol, purified water, 'sorbitol special glycerin blend' (d-sorbitol, 1,4-sorbitan, mannitol and glycerin) and titanium dioxide.

Black printing ink: ammonium hydroxide, ethylacetate, iron oxide black, isopropyl alcohol, Macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and SDA 35 alcohol.

What dosage forms it comes in:

APTIVUS capsules are available in 250 mg strength.

WARNINGS AND PRECAUTIONS

Patients taking APTIVUS, together with 200 mg of Norvir(r) (ritonavir) may develop bleeding in the brain that can cause death. You should report any unusual or unexplained bleeding to your doctor.

Patients taking APTIVUS, together with 200 mg Norvir(r) (ritonavir), may develop severe liver disease that can cause death. If you have chronic hepatitis B or C infection you have an increased chance of developing liver problems (See Side Effects and What to do About Them).

*

no longer marketed in Canada

IMPORTANT: PLEASE READ

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). Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection, which may necessitate further evaluation and treatment. Therefore, it is very important that you stay under the care of your doctor.

APTIVUS does not reduce the risk of passing HIV to others through sexual contact or blood contamination. Continue to practice safe sex and 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.

APTIVUS can cause dangerous and life-threatening interactions if taken with certain other medicines. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements (see INTERACTIONS WITH THIS MEDICATION).

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

Do not take APTIVUS with rifampin, as it may lower the amount of APTIVUS in your blood and make it less effective.

Do not take APTIVUS/ritonavir with fluticasone propionate (Flonase(r), Flovent(r), Advair(r)) unless your doctor believes the benefits outweigh the risks.

The use of APTIVUS/ritonavir with Desyrel(r) (trazodone) should be used with caution as it may increase the level of trazodone in the blood. The doctor may consider a lower dose of trazodone.

Do not take APTIVUS with St. John's wort (hypericum perforatum), a herbal product sold as a dietary supplement, or products containing St. John's wort. Talk with your doctor if you are taking or planning to take St. John's wort. Taking St. John's wort may decrease APTIVUS levels and lead to an increase in HIV and possible resistance to APTIVUS or resistance to other anti- HIV medications.

Do not take Aptivus/ritonavir with omeprazole or esomeprazole unless your doctor believes the benefits outweigh the risks.

BEFORE you use APTIVUS talk to your doctor or pharmacist:

If you are pregnant or planning to become pregnant:

The effects of APTIVUS on pregnant women or their unborn babies are not known. If you are pregnant, APTIVUS should only be taken after careful discussion with your doctor. Tell your doctor immediately if you become pregnant.

If you are breast-feeding:

Do not breast-feed if you are taking APTIVUS. You should not breast-feed if you have HIV. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby. You should be

aware that if your baby does not already have HIV infection, there is a chance that HIV can be transmitted through breast- feeding.

If you 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.

If you have liver problems:

If you have liver problems or are infected with Hepatitis B or Hepatitis C, you should tell your doctor before taking APTIVUS.

If you have diabetes:

Some people taking protease inhibitors develop new or more serious diabetes or high blood sugar. Tell your doctor if you have diabetes or an increase in thirst or frequent urination while taking APTIVUS.

If you have hemophilia:

Patients taking protease inhibitors may have increased bleeding.

If you are taking antiplatelet or anticoagulant drugs, or vitamin E supplements:

you may have increased bleeding.

If you have had or will have surgery or other medical conditions which make you prone to bleeding.

INTERACTIONS WITH THIS MEDICATION

APTIVUS may interact with other medicines, including those you take without a prescription. You must tell your doctor about all the medicines you are taking or planning to take before you take APTIVUS (See "When it should not be used").

Not all medicines can be safely taken with APTIVUS

Some medicines will require a change in dosage if taken with APTIVUS

Some medicines will require close monitoring if taken with APTIVUS

Know all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Keep a list of the medicines you take. Show this list to all your doctors and pharmacists anytime you get a new medicine. 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 list of medicines that can interact with APTIVUS. Tell your doctor if you are taking antiplatelet or anticoagulant medications, such as acetylsalicylic acid (ASA).

Medicines that require dosage adjustments:

It is possible that your doctor may need to increase or decrease the dose of other medicines when you are also taking APTIVUS.

The blood levels of the HIV protease inhibitors Invirase(r) or Fortovase(r) (saquinavir), Agenerase(r) (amprenavir), Reyataz(r) (atazanavir), and Kaletra(r) (lopinavir) are decreased when IMPORTANT: PLEASE READ

combined with APTIVUS taken together with Norvir(r) (ritonavir). The use of these protease inhibitors in combination with APTIVUS is not recommended. Your doctor needs to carefully consider whether to treat you with combinations of APTIVUS and these protease inhibitors.

Fluconazole (e.g. Diflucan(r)) increases the blood levels of APTIVUS. Consequently, fluconazole doses greater than 200mg/day are not recommended if taken together with

APTIVUS.

Ketoconazole (e.g. Nizoral(r)) and itraconazole (e.g.

Sporanox(r)) should be used with caution. Doses of these medicines greater than 200mg/day are not recommended if taken together with APTIVUS.

If you have kidney disease and you are taking both clarithromycin (e.g. Biaxin(r)) and APTIVUS, your doctor should reduce the dose of clarithromycin based on the extent of your kidney disease.

APTIVUS may interact with medicines used to treat erectile dysfunction and lead to dangerous side effects or serious problems. These medicines are: sildenafil (Viagra(r)) and tadalafil (Cialis(r)). Vardenafil (Levitra(r)) should not be used with APTIVUS. Before you take any of these medicines with APTIVUS talk to your doctor.

If you are taking selective serotonin reuptake inhibitors (SSRIs - medications for depression), the dose may have to be adjusted by your doctor.

If you are taking methadone and APTIVUS, the dose of methadone may need to be increased. Ask your doctor.

• If you are taking meperidine (e.g. Demerol(r)) and APTIVUS, a dose increase and long-term use of meperidine are not recommended. Discuss this with your doctor.

• APTIVUS taken together with ritonavir (Norvir(r)) can reduce the effectiveness of oral contraceptives and may be associated with a rash. If you are taking oral contraceptives ("the pill")

to prevent pregnancy, you should use an additional or different

type of contraceptive (e.g. condoms) if you are taking APTIVUS. If you are using estrogen for hormone replacement therapy, you should be clinically monitored for estrogen deficiency.

If you are taking desipiramine and APTIVUS, the dose of desipiramine may have to be decreased by your doctor.

If you are taking theophylline and APTIVUS, the dose of theophylline may have to be increased by your doctor.

Although atorvastatin (Lipitor(r)) is not recommended for use with APTIVUS, your doctor may recommend atorvastatin at

the lowest dose, or may switch you to another cholesterol-

lowering medication.

If you are taking the cholesterol-lowering medication rosuvastatin (Crestor(r)) and APTIVUS, your doctor may decrease the dosage of rosuvastatin or may switch you to another cholesterol-lowering medication.

If you are taking the antibiotic rifabutin (Mycobutin(r)) and APTIVUS, your dose of rifabutin will be reduced by your doctor.

If you are taking both Videx(r) (didanosine) and APTIVUS, Videx (r) should be taken at least two hours after taking

APTIVUS.

If you are taking antacids and APTIVUS, consideration should be given to separating the dosing of these two drugs by 2 hours.

Your doctor will use caution if you have to take concomitant non nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) because currently there are limited data on the use of these medicines with APTIVUS.

The effect of APTIVUS/ritonavir on warfarin and other blood thinners cannot be predicted. Close clinical and biological monitoring is recommended.

APTIVUS capsules contain alcohol. Talk with your doctor if you are taking or planning to take metronidazole or disulfiram. An interaction between the alcohol content of APTIVUS and either of these two medicines can lead to severe side effects.

If tadalafil is used within the first days of APTIVUS treatment, your doctor may choose the lowest tadalafil dosage and then increase the dosage after 7-10 days, if necessary.

The concomitant use of anticonvulsants such carbamazepine, phenobarbital or phenytoin may decrease tipranavir plasma concentration making APTIVUS less effective.

Your doctor may monitor concentrations of immunosuppressants (cyclosporin, tacrolimus, sirolimus) in your blood, when these medicinal products are used with APTIVUS.

The blood levels of HIV protease inhibitors Invirase(r) or Fortovase(r) (saquinavir), Agenerase(r) (amprenavir), Reyataz(r) (atazanavir) and Kaletra(r) (lopinavir) are decreased when combined with APTIVUS taken together with Norvir(r) (ritonavir). Fosamprenavir(r) is expected to act the same way. The use of these inhibitors in combination with APTIVUS is not recommended.

PROPER USE OF THIS MEDICATION

Usual adult dose:

Always take APTIVUS exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are

unsure. It is essential that you take APTIVUS together with Norvir(r) (ritonavir).

If you are taking APTIVUS capsules, the usual dose is 500 mg (two 250 mg capsules) of APTIVUS, together with 200 mg (two 100 mg capsules) of ritonavir (Norvir(r)), twice per day. The capsules should always be taken by mouth, and swallowed whole and not chewed. APTIVUS must also always be taken in combination with other antiretroviral medicines, for which you should be sure to follow the directions from your doctor or pharmacist.

Always take APTIVUS with food at all times to improve tolerability.

Do not change your dose or stop taking APTIVUS without first talking with your doctor.

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your combination

IMPORTANT: PLEASE READ

antiretroviral medicines and reduce the chances of developing antiretroviral resistance. Therefore, unless your doctor instructs you to stop treatment, it is important to keep taking APTIVUS correctly, as described.

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 virus may develop resistance to APTIVUS and become harder to treat.

Only take medicine that has been prescribed specifically for you. Do not give APTIVUS to others or take medicine prescribed for someone else.

You should stay under a doctor's care when taking APTIVUS. Do not change your treatment or stop treatment without first talking with your doctor.

You must take APTIVUS every day exactly as your doctor prescribed it. The dose of APTIVUS may be different for you than for other patients. Follow the directions from your doctor, exactly as written on the medication bottle label. Due to the need for co- administration of APTIVUS with Norvir(r) (ritonavir), please refer to the Norvir(r) Patient Information for directions on its use and precautionary measures.

Overdose:

You should IMMEDIATELY contact either your doctor, your

hospital emergency department or the nearest poison control centre.

Missed Dose:

If you forget to take APTIVUS within 5 hours of your dosing schedule, take the next dose of APTIVUS, together with Norvir(r) (ritonavir), as soon as possible. If a dose is missed by more than 5 hours do not take a double dose to make up for the forgotten individual doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

APTIVUS can have side effects. It may be difficult 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. The following list of side effects is not complete. 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 most commonly reported side effects of moderate severity that are thought to be drug-related are mostly associated with the gastrointestinal tract and include diarrhea, nausea, vomiting and abdominal pain. Other commonly reported side effects are tiredness and headache. Women taking oral contraceptives may get a mild skin rash.

Blood tests in patients taking APTIVUS may show possible liver problems. Patients with liver disease such as Hepatitis B and Hepatitis C who take APTIVUS may have worsening liver disease.

Liver problems including liver failure and death have occurred in patients taking APTIVUS. In studies, it is unclear if APTIVUS caused these liver problems because some patients had other illnesses or were taking other medicines at the time. Patients with signs or symptoms of hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. If you notice the signs or symptoms of hepatitis (fever, malaise, nausea, vomiting, abdominal pain, fatigue, jaundice) you should inform your doctor as soon as possible. Your doctor should use caution when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of hepatitis. Your doctor may consider increased liver monitoring.

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.

Some patients taking APTIVUS have large increases in triglycerides and cholesterol (fat in the blood). The long-term chance of getting complications such as heart attacks or stroke due to increases in triglycerides and cholesterol caused by protease inhibitors is not known at this time.

Diabetes and high blood sugar (hyperglycemia) can occur in patients taking protease inhibitors such as APTIVUS. Some patients had diabetes before starting protease inhibitors, others did not. Some patients need changes in their diabetes medicine while others need new diabetes medicine.

In some individuals, treatment with protease inhibitors may cause changes in body shape due to changes in fat distribution. These may include decreased fat under the skin, increased fat in the abdomen (belly), breast enlargement and fatty lumps on the back of the neck (the "buffalo hump").

Combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck ('buffalo hump'). The cause and long-term health effects of these conditions are not known at this time. Combination antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipidemia (increased fats in the blood) and resistance to insulin.

In patients with hemophilia type A and B, there have been reports of increased bleeding while taking this treatment or another protease inhibitor. People taking anticoagulant or antiplatelet medications, or those undergoing surgery may have an increased risk of bleeding while taking this treatment. Should any unusual or unexplained bleeding happen while you are taking this treatment, seek immediate advice from your doctor.

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

There have been other side effects in patients taking APTIVUS. However, these side effects may have been due to other medicines

IMPORTANT: PLEASE READ

that patients were taking or to the illness itself. Some of these side effects can be serious.

Bleeding in the brain has occurred in patients treated with APTIVUS, together with Norvir(r) (ritonavir), 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 contributed to it. Patients with hemophilia or another medical condition that increases the risk of bleeding, or patients taking medicines associated with a risk of bleeding may be at increased risk of bleeding in the brain.

This is not a complete list of side effects. For any unexpected effects while taking APTIVUS contact your doctor or pharmacist.

HOW TO STORE IT

APTIVUS capsules are pink, oblong with a black print imprint of "TPV 250". Each APTIVUS capsule contains 250 mg of the active substance tipranavir. APTIVUS is supplied in unit-of-use bottles, with a child-resistant closure, containing 120 capsules.

APTIVUS capsules should be stored at 2-8oC (refrigerated). Once the bottle is opened, refrigeration of the capsules by the patient is not required if used within 60 days and stored at controlled room temperature 15-30oC. You can write the date of opening the bottle on the label. Do not use after the expiration date stated on the bottle.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By Toll toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Health Products and Food Branch

Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.boehringer- ingelheim.ca or by contacting the sponsor, Boehringer Ingelheim (Canada) Ltd., at: 1-800-263-5103 Ext. 4633 (Medical Information). Please visit our website to see if more up-to-date information has been posted.

This leaflet was prepared by Boehringer Ingelheim (Canada) Ltd. Last revised: May 8, 2008