Each ml of oral solution contains 100 mg tipranavir.

Oral solution. Clear yellow viscous liquid.

APTIVUS 100 mg/ml oral solution, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated children from 2 to 12 years of age 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 one phase II study investigating pharmacokinetics, safety and efficacy of APTIVUS oral solution in mostly treatment-experienced children aged 2 to 12 years.

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.

APTIVUS must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with APTIVUS (especially as regards the contraindications, warnings and undesirable effects sections).

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

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

Posology

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 tipranavir 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 tipranavir and ritonavir at the regularly scheduled time.

Paediatric population

The recommended dose for children (age 2 to 12 years) is 375 mg/m² APTIVUS co-administered with 150 mg/m² ritonavir, twice daily. The paediatric dose should not exceed the 500 mg/200 mg dose.

Doses of ritonavir lower than 150 mg/m² twice daily, should not be used as they might alter the efficacy profile of the combination.

The safety and efficacy of APTIVUS in children under 2 years of age has not been established. No data are available.

APTIVUS is available as soft capsules for adults and adolescents from 12 years of age (please refer to the respective SPC for further details). Patients treated with APTIVUS and reaching the age of 12 years should be switched to the capsule formulation.

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.

Renal impairment

No dosage adjustment is required in patients with renal impairment.

Method of administration

APTIVUS oral solution co-administered with low dose oral solution ritonavir should be taken with food.

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.

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.

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) 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.

APTIVUS must be administered with low dose ritonavir to ensure its therapeutic effect. 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.

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.

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 reaction. 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 with 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, tipranavir 500 mg with ritonavir 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). The study was prematurely stopped after 60 weeks.

Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients.

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 with 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 with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir.

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. Patients taking APTIVUS oral solution should be advised not to take any supplemental vitamin E.

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.

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.

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 tipranavir, co-administered with low dose ritonavir, is complex. For a description of the mechanisms and potential mechanisms contributing to the interaction profile of tipranavir.

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.

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. No data are currently available on interactions of tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than those listed above. Therefore, the co-administration of tipranavir, 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. 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.

Fluticasone: Concomitant use of tipranavir, 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.

Atorvastatin: Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations of atorvastatin. The combination is not recommended. Other HMG-CoA reductase inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin 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 with ritonavir with either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended.

The interaction profile of APTIVUS, co-administered with low dose ritonavir, is complex and requires special attention in particular in combination with other antiretroviral agents.

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  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).

A cocktail study was conducted in 16 healthy volunteers with twice-daily tipranavir 500 mg with ritonavir 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. This study was also conducted with APTIVUS oral solution 500 mg with ritonavir 200 mg and showed the same CYP P450 and Pgp interactions as the APTIVUS capsule 500 mg with ritonavir 200 mg. Based on the results from this study, APTIVUS oral solution might be expected to have a similar interaction profile as the capsules.

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 with ritonavir on CYP 2D6 is inhibition, because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of tipranavir withritonavir 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 500/100 mg, TPV/r 750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the recommended dosage of APTIVUS/r. 

APTIVUS co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is therefore needed in patients treated with APTIVUS, co-administered with low dose ritonavir.

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. APTIVUS should therefore be used with caution in patients co-infected with hepatitis B or C. APTIVUS should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Adults:

Tipranavir (as soft capsules), co-administered with low dose ritonavir has been studied in a total of 6,308 HIV-positive adults as combination therapy in clinical studies, including compassionate use studies. Of these 5,219 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.

Clinically meaningful adverse reactions of any intensity (Grades 1-4) of adult patients in all Phase II and III trials treated with the 500 mg tipranavir with 200 mg ritonavir dose (n=1397) are listed below by system organ class and frequency according to the following categories:

Very common ( 1/10), common ( 1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000)

Blood and lymphatic system disorders:

Uncommon: neutropenia, anaemia, thrombocytopenia.

Immune system disorders:

Uncommon: hypersensitivity.

Metabolism and nutrition disorders:

Common: hypertriglyceridaemia, hyperlipidaemia.

Uncommon: anorexia, decreased appetite, weight decreased, hyperamylasaemia, hypercholesterolaemia, diabetes mellitus, hyperglycaemia.

Rare: dehydration, facial wasting.

Psychiatric disorders:

Uncommon: insomnia, sleep disorder.

Nervous system disorders:

Common: headache.

Uncommon: intracranial haemorrhage*, dizziness, neuropathy peripheral, somnolence.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea.

Gastrointestinal disorders:

Very common: diarrhoea, nausea.

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

Uncommon: gastrooesophageal reflux disease, pancreatitis.

Rare: lipase increased.

Hepatobiliary disorders:

Uncommon: hepatic enzymes increased (ALAT, ASAT), cytolytic hepatitis, liver function test abnormal (ALAT, ASAT), toxic hepatitis.

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

Skin and subcutaneous tissue disorders:

Common: rash.

Uncommon: pruritus, lipohypertrophy, exanthem, lipoatrophy, lipodystrophy acquired.

Musculoskeletal and connective tissue disorders:

Uncommon: myalgia, muscle cramp.

Renal and urinary disorders:

Uncommon: renal insufficiency.

General disorders and administration site conditions:

Common: fatigue.

Uncommon: pyrexia, influenza like illness, malaise.

* This undesirable effect was not observed as an at least possibly related adverse event in the respective studies. The frequency estimate is based on the upper limit of its 95% confidence interval, calculated from the totality of treated patients in accordance with the EU SPC guideline (3/1397 which relates to “uncommon”).

Description of selected adverse reactions

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with 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 tipranavir with 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 tipranavir with ritonavir.

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

Bleeding: RESIST participants receiving tipranavir with 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 tipranavir, 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 tipranavir 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 tipranavir, 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 tipranavir with ritonavir and comparator arms (16.3% vs. 12.5%, respectively). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the tipranavir with 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. 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.

Paediatric population

In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 62 children aged 2 to 12 years received APTIVUS oral solution. 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 age 2 to < 12 years (reported in 2 or more children, Trial 1182.14, 48 weeks analyses, Full Analysis Set).

¹ Includes abdominal pain (N=1), dysphagia (N=1) and epigastric discomfort (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.

Boehringer Ingelheim Limited

POM – Prescription Only Medicine

27 October 2010