Boehringer Ingelheim Limited

APTIVUS 250 mg soft capsules.

Each soft capsule contains 250 mg tipranavir.

Excipients (per capsule): 100.0 mg Ethanol, 455.0 mg Macrogolglycerol Ricinoleate and 12.6 mg Sorbitol (constituent in « Sorbitol Special-Glycerin Blend »)

For a full list of excipients, see section 6.1.

Soft capsule.

Each capsule is pink and is imprinted with “TPV 250”.

APTIVUS, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated adults and adolescents 12 years of age or older with virus resistant to multiple protease inhibitors. APTIVUS should only be used as part of an active combination antiretroviral regimen in patients with no other therapeutic options.

This indication is based on the results of two phase III studies, performed in highly pre-treated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase II study investigating pharmacokinetics, safety and efficacy of APTIVUS in mostly treatment-experienced adolescent patients aged 12 to 18 years (see section 5.1).

In deciding to initiate treatment with APTIVUS, co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of APTIVUS. Initiation of treatment should take into account the combinations of mutations which may negatively impact the virological response to APTIVUS, co-administered with low dose ritonavir (see section 5.1).

APTIVUS should be prescribed by physicians who are experienced in the treatment of HIV-1 infection.

APTIVUS soft capsules co-administered with low dose ritonavir should be taken with food (see section 5.2).

APTIVUS/ritonavir should not be used in treatment-naïve patients.

Patients should be advised of the need to take APTIVUS and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of APTIVUS and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of APTIVUS and ritonavir at the regularly scheduled time.

Adults and adolescents from 12 years of age

The recommended dose of APTIVUS is 500 mg, co-administered with 200 mg ritonavir (low dose ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).

Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy profile of the combination.

Since currently only limited efficacy and safety data are available for adolescents (see section 5.1) close monitoring of virologic response and tolerance is particularly warranted in this patient group.

Children under 12 years of age:

No data are available on the efficacy and safety of APTIVUS capsules in children under 12 years of age. Also, appropriate dose adjustments for children under 12 years cannot be achieved with APTIVUS capsules. APTIVUS oral solution is available for children between 2 and 12 years of age (please refer to the respective for further details).

APTIVUS is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy.

Elderly

Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see section 5.2).

Liver impairment

Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase of tipranavir exposure and a worsening of its safety profile. Therefore, APTIVUS should be used with caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-Pugh Class A). APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment

No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Hypersensitivity to the active substance or to any of the excipients.

Patients with moderate or severe (Child-Pugh B or C) hepatic impairment.

Combination of rifampicin with APTIVUS with concomitant low dose ritonavir is contraindicated (see section 4.5).

Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking APTIVUS due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of APTIVUS with low dose ritonavir, with active substances 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 active substances include antiarrhythmics (amiodarone, bepridil, quinidine), antihistamines (astemizole, terfenadine), ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics (orally administered midazolam and triazolam. For caution on parenterally administered midazolam see section 4.5) and HMG-CoA reductase inhibitors (simvastatin and lovastatin). In addition, co-administration of APTIVUS with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure, is contraindicated (see section 4.5).

APTIVUS must be administered with low dose ritonavir to ensure its therapeutic effect (see section 4.2). Failure to correctly co-administer tipranavir 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.

APTIVUS is not a cure for HIV-1 infection or AIDS. Patients receiving APTIVUS or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Switching from APTIVUS capsules to the oral solution: APTIVUS capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution. Also, the composition of the oral solution is different from that of the capsules, with the high vitamin E content being especially noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore patients should not be switched from APTIVUS capsules to APTIVUS oral solution (see sections 5.1 and 5.2).

Switching from APTIVUS oral solution to the capsules: APTIVUS oral solution is not interchangeable with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the same dose as capsules. However, children previously treated with APTIVUS oral solution and becoming 12 years of age should be switched to capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule formulation of APTIVUS could be associated with decreased exposure. Therefore, it is recommended that patients switching from APTIVUS oral solution to capsules at the age of 12 years are closely monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).

Elderly: 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 therapy.

Liver disease: APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic insufficiency. Limited data are currently available for the use of APTIVUS, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy 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. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination therapy and should be monitored according to standard practice. APTIVUS/ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease.

APTIVUS co-administered with low dose 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 medicinal products. Caution should be exercised when administering APTIVUS to patients with liver enzyme abnormalities or with a history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.

APTIVUS therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN, unless the potential benefit justifies the potential risk.

APTIVUS therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then rechallenge with APTIVUS may be considered when ASAT/ALAT have returned to the patient's baseline levels.

Liver monitoring

Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when APTIVUS and low dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic impairment, chronic hepatitis B or C, or other underlying liver disease.

Treatment-naïve patients

In a study performed in antiretroviral naïve adult patients, APTIVUS/ritonavir 500 mg/200 mg twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend towards a lower efficacy). Therefore, this study was prematurely stopped after 60 weeks.

Renal impairment

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

Haemophilia

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 has been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Bleeding

RESIST participants receiving APTIVUS/ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further studied.

Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving APTIVUS, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of APTIVUS cannot be excluded. No pattern of abnormal haematological or 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.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the APTIVUS clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3 Preclinical safety data).

APTIVUS, co-administered with low dose 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 medicinal products known to increase the risk of bleeding such as antiplatelet agents and anticoagulants or who are taking supplemental vitamin E. Based on the limits of exposure available from observation in clinical trials, it is recommended not to co-administer to patients more than 1200 IU vitamin E per day.

Diabetes mellitus/hyperglycaemia

New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

Lipid elevations

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

Fat redistribution

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors, has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with factors related to the active substance such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with APTIVUS, co-administered with low dose ritonavir.

APTIVUS contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.

APTIVUS soft capsules contain small amounts of alcohol (7% ethanol, ie 100 mg per capsule or 200 mg per dose).

Rash

Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been reported in subjects receiving APTIVUS, co-administered with low dose ritonavir. At 48-weeks in Phase III trials, rash of various types was observed in 15.5% males and 20.5% females receiving APTIVUS co-administered with low dose ritonavir. Additionally, in one interaction trial, in healthy female volunteers administered a single dose of ethinyl oestradiol followed by APTIVUS co-administered with low dose 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 co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Interactions

The interaction profile of APTIVUS, co-administered with low dose ritonavir, is complex. For a description of the mechanisms and potential mechanisms contributing to the interaction profile of APTIVUS, see section 4.5.

Abacavir and zidovudine: The concomitant use of APTIVUS, co-administered with low dose ritonavir, with zidovudine or abacavir, results in a significant decrease in plasma concentration of these nucleoside reverse transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or abacavir with APTIVUS, co-administered with low dose ritonavir, is not-recommended unless there are no other available NRTIs suitable for patient management (see section 4.5).

Protease inhibitors: Concomitant use of APTIVUS, co-administered with low dose ritonavir, with the protease inhibitors amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir) in a dual-boosted regimen, results in significant decreases in plasma concentrations of these protease inhibitors. A significant decrease in plasma concentrations of atazanavir and a marked increase of tipranavir and ritonavir concentrations was observed when APTIVUS, associated with low dose ritonavir, was co-administered with atazanavir (see section 4.5). No data are currently available on interactions of APTIVUS, co-administered with low dose ritonavir, with protease inhibitors other than those listed above. Therefore, the co-administration of APTIVUS, co-administered with low dose ritonavir, with protease inhibitors is not recommended.

Oral contraceptives and oestrogens: Since levels of ethinyl oestradiol are decreased, the co-administration of APTIVUS co-administered with low dose ritonavir is not recommended. Alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-administered with APTIVUS co-administered with low dose ritonavir (see section 4.5). Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency. Women using oestrogens may have an increased risk of non serious rash.

Anticonvulsants: Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations in patients taking these agents concomitantly.

Halofantrine, Lumefantrine: Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of halofantrine and lumefantrine with APTIVUS co-administered with low dose ritonavir, is not recommended.

Disulfiram/metronidazole: APTIVUS soft capsules contain alcohol (7% ethanol, ie 100 mg per capsule or up to 200 mg per dose) which can produce disulfiram-like reactions when co-administered with disulfiram or other medicinal products which produce this reaction (eg metronidazole).

Fluticasone: Concomitant use of APTIVUS, co-administered with low dose ritonavir, and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Atorvastatin: APTIVUS, co-administered with low dose ritonavir, increases the plasma concentrations of atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5). However, if atorvastatin is specifically required for patient management, it should be started with the lowest dose and careful monitoring is necessary.

Omeprazole and other proton pump inhibitors: The combined use of APTIVUS/ritonavir with either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended (see section 4.5).

Due to APTIVUS containing small amounts of sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.

Interaction studies have only been performed in adults.

Metabolic profile of tipranavir:

Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co-administered with ritonavir at the recommended dosage (see section 4.2) there is a net inhibition of P450 CYP3A. Co-administration of APTIVUS and low dose 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 undesirable effects (see list and details of considered agents, below). Agents that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse reactions are detailed in this section, and listed in section 4.3.

A cocktail study was conducted in 16 healthy volunteers with twice-daily APTIVUS/ritonavir 500 mg/200 mg capsule administration for 10 days to assess the net effect on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4 (midazolam) and P-glycoprotein (Pgp) (digoxin). At steady state, there was a significant induction of CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4 activities were observed. Pgp activity is significantly inhibited after the first dose, but there was a slight induction at steady state. Practical recommendations deriving from this study are displayed below.

Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir/ritonavir on CYP 2D6 is inhibition, because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir/ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of APTIVUS/ritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of treatment. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases.

In vitro studies show that tipranavir is a substrate and also an inhibitor of Pgp.

It is difficult to predict the net effect of APTIVUS co-administered with low dose ritonavir on oral bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and Pgp. The net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and Pgp, and the extent of intestinal first-pass metabolism/efflux.

Co-administration of APTIVUS and agents that induce CYP3A and/or Pgp may decrease tipranavir concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co-administration of APTIVUS and medicinal products that inhibit Pgp may increase tipranavir plasma concentrations.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below.

Interaction table

Interactions between APTIVUS and co-administered medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “”, no change as “↔”,once daily as “QD”, twice daily as “BID”).

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of APTIVUS/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with this recommended dosage. Nevertheless, the results of many of these interaction studies can be extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100mg, TPV/r 750/200mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the recommended dosage of APTIVUS/r.

There are no adequate data from the use of APTIVUS in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

APTIVUS adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment.

Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving APTIVUS.

No studies on the effects on the ability to drive and use machines have been performed.

Patients should be informed that APTIVUS soft capsules contain small amounts of alcohol (7% ethanol, ie 100 mg per capsule or 200 mg per dose).

Adults

Tipranavir (as soft capsules), co-administered with low dose ritonavir has been studied in a total of 6308 HIV-positive adults as combination therapy in clinical studies, including compassionate use studies. Of these 5219 patients received the dose of 500 mg/200 mg twice daily. 909 adults in clinical trials, including 541 in the RESIST-1 and RESIST-2 Phase III pivotal trials, have been treated with 500 mg/200 mg twice daily for at least 48 weeks.

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among APTIVUS/ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with APTIVUS/ritonavir administration. The clinical significance of these observations has not been fully explored.

Hepatotoxicity: After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was higher in APTIVUS/ritonavir patients compared with comparator arm patients (10 % and 3.4 %, respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with APTIVUS/ritonavir.

Hyperlipidaemia: Grade 3 or 4 elevations of triglycerides occurred more frequently in the APTIVUS/ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2 % of patients in the APTIVUS/ritonavir arm and 15.6 % in the comparator arm.

Bleeding: RESIST participants receiving APTIVUS/ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further studied.

Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving APTIVUS, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of APTIVUS cannot be excluded. No pattern of abnormal haematological or 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.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the APTIVUS clinical trials.

Rash: An interaction study in women between APTIVUS, co-administered with low dose ritonavir, and ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST trials, the risk of rash was similar between APTIVUS/ritonavir and comparator arms (16.3 % vs. 12.5 %, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of APTIVUS.

The most frequent adverse reactions of any intensity (Grades 1-4) reported in the Phase III clinical studies in the APTIVUS/ritonavir arms (n=749) are listed below by system organ class and frequency according to the following categories:

Very common ( 1/10), common ( 1/100 to <1/10)

Metabolism and nutrition disorders:

Common: hypertriglyceridaemia, hyperlipidaemia, anorexia.

Nervous system disorders:

Common: headache.

Gastrointestinal disorders:

Very common: diarrhoea, nausea.

Common: vomiting, flatulence, abdominal distension, abdominal pain, loose stools, dyspepsia.

Skin and subcutaneous tissue disorders:

Common: rash, pruritus.

General disorders and administration site conditions:

Common: fatigue.

Clinically meaningful adverse reactions of moderate to severe intensity occurring in less than 1% (<1/100) of adult patients in all Phase II and III trials treated with the 500 mg/200 mg tipranavir/ritonavir dose (n=1397) are listed below by system organ class and frequency according to the following categories:

Uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000)

Blood and lymphatic system disorders:

Uncommon: anaemia, neutropenia, thrombocytopenia.

Immune system disorders:

Uncommon: hypersensitivity.

Metabolism and nutrition disorders:

Uncommon: decreased appetite, diabetes mellitus, hyperamylasaemia, hypercholesterolaemia.

Rare: dehydration, facial wasting, hyperglycaemia.

Psychiatric disorders:

Uncommon: insomnia, sleep disorder.

Nervous system disorders:

Uncommon: dizziness, neuropathy peripheral, somnolence.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea.

Gastrointestinal disorders:

Uncommon: gastrooesophageal reflux disease, pancreatitis.

Hepatobiliary disorders:

Uncommon: cytolytic hepatitis, hepatic steatosis, hepatitis, toxic hepatitis.

Rare: hepatic failure (including fatal outcome), hyperbilirubinaemia.

Skin and subcutaneous tissue disorders:

Uncommon: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle cramp, myalgia.

Renal and urinary disorders:

Uncommon: renal insufficiency.

General disorders and administration site conditions:

Uncommon: influenza like illness, malaise, pyrexia.

Investigations:

Uncommon: hepatic enzymes increased (ALAT, ASAT), lipase increased, liver function test abnormal (ALAT, ASAT), weight decreased.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2 % of patients in the APTIVUS/ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-2) after 48-weeks were increased ASAT (6.1 %), increased ALAT (9.7 %), increased amylase (6.0 %), increased cholesterol (4.2 %), increased triglycerides (24.9 %), and decreased white blood cell count (5.7 %).

Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated with redistribution of body fat in some patients, including loss of peripheral subcutaneous fat, increased intra-abdominal fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance and hyperglycaemia.

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4). Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Paediatrics

In an open-label, dose-finding study of APTIVUS plus ritonavir (Trial 1182.14), 28 children who were 12 years of age or above received APTIVUS capsules. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients aged 12 to 18 years who took Aptivus capsules (reported in 2 or more children, Trial 1182.14, week 48 analyses, Full Analysis Set).

1. Includes abdominal pain (N=1) and dyspepsia (N=1).

2. Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruritic, and urticaria

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

Pharmacotherapeutic group: protease inhibitor, ATC code: J05AE09

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.

Antiviral activity in vitro

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% and 90% effective concentrations (EC₅₀ and EC₉₀) ranging from 0.03 to 0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. 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 µM and 0.233-0.522 µM, 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.

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. 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.

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 48-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 8 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 highly treatment experienced patients who have received multiple peptidic protease inhibitors.

Clinical pharmacodynamic data

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with APTIVUS co-administered with low dose ritonavir (500 mg/200 mg twice daily) plus an optimised background regimen (OBR) individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir-boosted PI (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 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 86 % male, 75 % white, 13 % black and 1 % Asian. In the APTIVUS and comparator arms median baseline CD4 cell counts were 158 and 166 cells/mm³, respectively, (ranges 1-1893 and 1-1184 cells/mm³); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log₁₀ copies/ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log₁₀ copies/ml).

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a median 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. With respect to mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 and 90 and 53% had at least one key mutation at codon 90. One patient in the APTIVUS arm had four mutations. In addition the majority of participants had mutations associated with both NRTI and NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples. There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold 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, and 20-fold WT for saquinavir.

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% in the APTIVUS/ritonavir arm and 15% in the comparator arm. Treatment response is presented for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of patients with genotypically resistant strains in the Table below.

Treatment response* at week 48 (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

** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 600 mg/100 mg twice daily (n=194)

ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv

Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the APTIVUS/ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all randomised and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log₁₀ copies/ml in patients receiving APTIVUS/ritonavir versus -0.22 log₁₀ copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm³ in patients receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm³ in the comparator PI/ritonavir (N=727) arm.

The superiority of APTIVUS co-administered with low dose ritonavir over the comparator protease inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that APTIVUS is superior to these boosted comparator protease inhibitors in patients harbouring strains susceptible to these protease inhibitors. RESIST data also demonstrate that APTIVUS co-administered with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (eg enfuvirtide).

At present there are no results from controlled trials evaluating the effect of APTIVUS on clinical progression of HIV.

Paediatric patients

HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, multicenter study (trial 1182.14). Patients were required to have a baseline HIV1 RNA concentration of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m²/150 mg/m² dose, compared to the 290 mg/m²/115 mg/m² dose, plus background therapy of at least two non-protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500 mg/200 mg twice daily could change to APTIVUS capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic and immunologic responses through 48 weeks.

No data are available on the efficacy and safety of APTIVUS capsules in children less than 12 years of age. Since APTIVUS capsules and oral solution are not bioequivalent, results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2). In patients with a body surface area of less than 1.33 m² appropriate dose adjustments cannot be achieved with the capsule formulation.

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients receiving APTIVUS capsules are displayed in the tables below. Data on the 29 patients who switched to capsules during the first 48 weeks are presented. Due to limitations in the study design (e.g. non-randomized switch allowed according to patient/clinician decision), any comparisons between patients taking capsules and oral solution are not meaningful.

Baseline characteristics for patients 12 – 18 years of age who took capsule

* AIDS defining illness

Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule

Analyses of tipranavir resistance in treatment experienced patients

APTIVUS/ritonavir response rates in the RESIST studies were assessed by baseline tipranavir genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

−Primary PI mutations:

Analyses were conducted to assess virological outcome by the number of primary PI mutations (any change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. Response rates were higher in APTIVUS/ritonavir patients than comparator PI boosted with ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

−Mutations at protease codons 33, 82, 84 and 90:

A reduced virological response was observed in patients with viral strains harbouring two or more mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

−Tipranavir resistance-associated mutations:

Virological response to APTIVUS/ritonavir therapy has been evaluated using a tipranavir-associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced 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 mutation score and response to APTIVUS/ritonavir therapy at week 48 has been established.

This score has been determined from the selected RESIST patient population having specific mutation inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving APTIVUS/ ritonavir achieved a treatment response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see table below).

Proportion of patients achieving treatment response at Week 48 (confirmed 1 log₁₀ copies/ml decrease in viral load compared to baseline), according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir/ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received APTIVUS/ritonavir and new enfuvirtide. If patients did not receive APTIVUS/ritonavir with new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir/ritonavir

−Tipranavir phenotypic resistance:

Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2). 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 AUC_0-12h, C_max and C_min and decreases the clearance of tipranavir. Tipranavir co-administered with low dose 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 tipranavir 500 mg twice daily without ritonavir.

Absorption

Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is available. Tipranavir is a Pgp substrate, a weak Pgp inhibitor and appears to be a potent Pgp inducer as well. Data suggest that, although ritonavir is a Pgp inhibitor, the net effect of APTIVUS, co-administered with low dose ritonavir, at the proposed dose regimen at steady-state, is Pgp induction. 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 enzyme induction. Steady-state is attained in most subjects after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear pharmacokinetics at steady state.

Dosing with APTIVUS capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (C_max) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM 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 µM for female patients and 35.6 ± 16.7 µM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for female patients and 710 ± 207 µM•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

Food improves the tolerability of tipranavir/ritonavir. Therefore APTIVUS, co-administered with low dose ritonavir, should be given with food.

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of antacids (see section 4.5).

Distribution

Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy volunteers and HIV-1 positive subjects who received tipranavir 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 μM. The unbound fraction of tipranavir appeared to be independent of total 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 substance 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 twice daily), 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 faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination

Administration of ¹⁴C-tipranavir to subjects (n = 8) that received tipranavir/ritonavir 500 mg/200 mg twice daily 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%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n = 67) and HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500 mg/200 mg twice daily with a light meal.

Special populations

Although data available at this stage are currently limited to allow a definitive analysis, they suggest that the pharmacokinetic profile is unchanged in elderly and comparable between races. By contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir concentrations than males. After four weeks of APTIVUS/ritonavir (500 mg/200 mg twice daily) the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. This difference in concentrations does not warrant a dose adjustment.

Renal dysfunction: Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic dysfunction: In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment is required in patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 4.4).

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. APTIVUS is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).

Paediatrics:

The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. 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). The effects were reversible with termination of treatment. Additional changes included bleeding in rats at high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or even below the human exposure levels at the recommended clinical dose.

In in-vitro studies, Tipranavir was found to inhibit platelet aggregation when using human platelets (see section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving APTIVUS/ritonavir. The clinical implications of these findings are not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At maternal doses producing systemic exposure levels similar to or below those at the recommended clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of genetic toxicity in a battery of in vitro and in vivo tests.

Capsule contents:

Macrogolglycerol ricinoleate

Ethanol

Mono/diglycerides of caprylic/capric acid

Propylene glycol

Purified water

Trometamol

Propyl gallate.

Capsule shell:

Gelatin

Red iron oxide (E172)

Propylene glycol

Purified water

'Sorbitol special-glycerin blend' (d-sorbitol, 1,4 sorbitan, mannitol and glycerin)

Titanium dioxide (E171).

Black printing ink:

Propylene glycol

Black iron oxide (E172)

Polyvinyl acetate phthalate

Macrogol

Ammonium hydroxide.

Not applicable.

3 years.

In use storage: 60 days (below 25 °C), after first opening of the bottle. It is advisable that the patient writes the date of opening the bottle on the label and/or carton.

Store in a refrigerator (2 - 8°C).

High density polyethylene (HDPE) bottle with two-piece child-resistant closure (outer shell HDPE, inner shell polypropylene, with a pulpboard/aluminium liner). Each bottle contains 120 soft capsules.

No special requirements.

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

EU/1/05/315/001

25 October 2005

23 November 2009

POM

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/