Protease Inhibitors

Tipranavir

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 »)

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.

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.

Adults:

The recommended dose of APTIVUS is 500 mg, co-administered with 200 mg ritonavir (low dose ritonavir), twice daily.

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

Paediatrics:

APTIVUS is not recommended for use in children due to insufficient data on safety and efficacy.

General:

APTIVUS soft capsules co-administered with low dose ritonavir should be taken with food.

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 should not be used in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C)

Renal impairment:

No dosage adjustment is required in patients with renal impairment.

Safety and efficacy of APTIVUS in this population has not yet been established.

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

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, with 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.

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

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.

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 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 patients, APTIVUS/ritonavir 500/200 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. Haemaophiliac 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 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.

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.

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 adults 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 drug related factors 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.

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.

Osteonecrosis: Although the etiology 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.

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 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. 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.

Atorvastatin: APTIVUS, 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, careful monitoring is necessary.

Omeprazole: APTIVUS co-administered with low dose ritonavir decreases the plasma concentrations of omeprazole and esomeprazole. Therefore, the combined use of APTIVUS/ritonavir with either omeprazole or esomeprazole is not recommended. If unavoidable, upward dose adjustments for either omeprazole or esomeprazole may be considered based on clinical response to therapy. Recommendations for maximal doses of omeprazole or esomeprazole are found in the corresponding product information.

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 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 adverse effects (see list and details of considered agents, below).

A cocktail study was conducted in 16 healthy volunteers with twice-daily APTIVUS/ritonavir 500/200 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 drugs 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.

Nucleoside reverse transcriptase inhibitors:Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no dosage adjustment of APTIVUS is required when co-administered with these agents.

Abacavir and Zidovudine: APTIVUS, co-administered with low dose ritonavir, decreases the AUC of abacavir by approximately 40% and the AUC of zidovudine by approximately 35%. There is no impact on glucuronidated-ZDV levels. The clinical relevance of these reductions has not been established, but may decrease the efficacy of these antiretroviral agents. Therefore the concomitant use of tipranavir, co-administered with low dose ritonavir, with either abacavir or zidovudine is not recommended unless there are no other available NRTIs suitable for patient management. In such cases no dosage adjustment of abacavir or zidovudine can be recommended.

Didanosine: APTIVUS, co-administered with low dose ritonavir, causes a reduction in the AUC of didanosine. The clinical relevance of the reduction in didanosine levels has not been established. Dosing of enteric-coated didanosine and APTIVUS soft capsules, co-administered with low dose ritonavir, should be separated by at least 2 hours to avoid formulation incompatibility.

Lamivudine and stavudine:APTIVUS, co-administered with low dose ritonavir, does not cause a significant change in the AUC of lamivudine or stavudine. No dosage adjustment of lamivudine or stavudine is recommended.

Nucleotide reverse transcriptase inhibitors:

Tenofovir: APTIVUS, co-administered with low dose ritonavir, did not cause a significant change in the plasma concentrations of tenofovir. No dosage adjustment of tenofovir is recommended.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Efavirenz: Steady-state efavirenz 600 mg qd co-administered with steady-state APTIVUS and low-dose ritonavir (500/200 mg bid) did not significantly alter tipranavir AUC and C_max and increased C_p12h by 19.2% which is not considered as clinically relevant. APTIVUS, co-administered with low-dose ritonavir, had no significant impact on the C_min of efavirenz.

Nevirapine: No specific drug-drug interaction study has been performed between APTIVUS and low-dose ritonavir (500/200 mg bid) with nevirapine. However, the limited data available from a phase IIa study in HIV-infected patients suggest that no significant interaction is expected between nevirapine and APTIVUS co-administered with low dose ritonavir. Moreover a study with APTIVUS and low dose ritonavir and another NNRTI (efavirenz) did not show any clinically relevant interaction (see above). Therefore no dose adjustments are necessary.

Protease Inhibitors:

Amprenavir, lopinavir, saquinavir: In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults, APTIVUS, co-administered with low dose ritonavir, caused a 55%, 70% and 78% reduction in the C_min of amprenavir, lopinavir and saquinavir, respectively. Therefore the concomitant administration of APTIVUS, co-administered with low dose ritonavir, with amprenavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, is not recommended, as the clinical relevance of the reduction in their levels has not been established. If the combination is nevertheless considered necessary, a monitoring of the plasma levels of these protease inhibitors is strongly encouraged.

Co-administration of Tipranavir/ritonavir and Atazanavir/ritonavir:

In a study performed in healthy volunteers co-administration of atazanavir 300 mg with TPV/r 500/100 mg bid resulted on one hand in a marked increase of Tipranavir exposure (notably Cp12h ratio of 1.75 with 90% CI [1.39-2.20]) and ritonavir exposure (AUC ratio of 1.51 with 90% CI [1.24-1.83] and C_max ratio of 1.38 with 90% CI [1.13-1.67]) associated with a risk of over-toxicity and on the other hand on a marked decrease of atazanavir exposure associated with a risk of loss of efficacy (AUC_0-24h ratio of 0.32 with 90% CI [0.29-0.36], C_max ratio of 0.43 with 90% CI [0.38-0.50] and Cp24h ratio of 0.19 with 90% CI [0.15-0.24]).

Consequently, this co-administration is not recommended. If the co-administration is nevertheless considered necessary, a close monitoring of the safety of tipranavir and a monitoring of plasma concentrations of atazanavir are strongly encouraged.

No data are currently available on interactions of APTIVUS, co-administered with low dose ritonavir, with protease inhibitors other than those listed above. Hence their combination with tipranavir co-administered with low dose ritonavir, is not recommended.

Fusion inhibitors:

In studies where tipranavir co-administered with low-dose ritonavir was used with or without enfuvirtide, it has been observed that the steady-state plasma tipranavir trough concentration of patients receiving enfuvirtide were 45% higher as compared to patients not receiving enfuvirtide. No information is available for the parameters AUC and C_max. A pharmacokinetic interaction is mechanistically unexpected and the interaction has not been confirmed in a controlled interaction study. The clinical impact of the observed data, especially regarding the tipranavir/ritonavir safety profile, remains unknown. Nevertheless, the clinical data available from the RESIST trials did not suggest any significant alteration of the tipranavir/ritonavir safety profile when combined with enfuvirtide as compared to patients treated with tipranavir/ritonavir without enfuvirtide.

Anticonvulsants:

Carbamazepine, phenobarbital, and phenytoin induce CYP3A4 and should be used with caution in combination with APTIVUS/ritonavir. Concomitant use of carbamazepine at a dose of 200mg BID resulted in decreased concentrations of tipranavir (C_min decreased by 61% compared to historical controls), which may result in decreased effectiveness. Higher doses of carbamazepine may result in even larger decreases in tipranavir plasma concentrations. The total C_min of carbamazepine and its active metabolite C_min is increased by 23% which is not expected to have clinical consequences.

Antifungals:

Fluconazole: APTIVUS, co-administered with low dose ritonavir, does not substantially affect the steady-state pharmacokinetics of fluconazole. Fluconazole increases the AUC and C_min of tipranavir by 56% and 104%, respectively, when compared to historical data. No dosage adjustments are recommended. Fluconazole doses >200 mg/day are not recommended.

Itraconazole/ketoconazole: Based on theoretical considerations APTIVUS, co-administered with low dose ritonavir, is expected to increase itraconazole or ketoconazole concentrations. Itraconazole or ketoconazole should be used with caution (doses >200 mg/day are not recommended).

Voriconazole: Due to multiple enzyme systems being involved in voriconazole metabolism, it is difficult to predict the interaction.

HMG CoA reductase inhibitors:

Simvastatin and lovastatin: The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of APTIVUS co-administered with low dose ritonavir, with simvastatin or lovastatin are contra-indicated due to an increased risk of myopathy, including rhabdomyolysis.

Atorvastatin: APTIVUS, co-administered with low dose ritonavir, increases the plasma concentrations of single dose atorvastatin by approximately 8-10 fold and reduces the AUCs of its metabolites by approximately 85 %. Atorvastatin does not significantly change the AUC, C_max or C_min of tipranavir. 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, careful monitoring is necessary.

CYP isoenzyme inducers:

Rifampicin: Rifampicin is a strong CYP3A4 inducer and has been shown to cause profound decreases in concentrations of other protease inhibitors which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with ritonavir, a high frequency of liver reactions was seen. The combination of rifampicin with APTIVUS with concomitant low-dose ritonavir is contraindicated.

Rifabutin: APTIVUS, co-administered with low dose ritonavir, increases plasma concentrations of rifabutin by up to 3 fold, and its active metabolite by up to 20 fold. Rifabutin increases the C_min of tipranavir by 16 %. Dosage reductions of rifabutin by at least 75% of the usual 300 mg/day are recommended (ie 150 mg on alternate days, or three times per week). Patients receiving rifabutin with APTIVUS/ritonavir should be closely monitored for emergence of adverse events associated with rifabutin therapy. Further dosage reduction may be necessary.

St John's wort (Hypericum perforatum): Plasma levels of tipranavir can be reduced by concomitant use of the herbal preparation St John's wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should not be used concomitantly with APTIVUS. If a patient is already taking St John's wort, stop St John's wort, check viral levels and if possible tipranavir levels. Tipranavir levels may increase on stopping St John's wort, and the dose of APTIVUS may need adjusting. The inducing effect of St John's wort may persist for at least 2 weeks after cessation of treatment.

CYP isoenzyme inhibitors:

Clarithromycin: APTIVUS, co-administered with low dose ritonavir, increases the AUC and C_min of clarithromycin by 19% and 68%, respectively, and decreases the AUC of the 14-hydroxy active metabolite by over 95%. Whilst the changes in clarithromycin parameters are not considered clinically relevant, the reduction in the 14-OH metabolite AUC should be considered for the treatment of infections caused by Haemophilus influenzae in which the 14-OH metabolite is most active. Clarithromycin increases the C_min of tipranavir by more than 100%. This large increase in C_min may be clinically relevant. Patients using clarithromycin at doses higher than 500 mg twice daily should be carefully monitored for signs of toxicity. For patients with renal impairment the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 ml/min the dose of clarithromycin should be reduced by 50 %. For patients with CL_CR < 30 ml/min the dose of clarithromycin should be decreased by 75 %. No dosage adjustments for patients with normal renal function are necessary.

Other agents:

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), gastointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole) and sedatives/hypnotics (triazolam).

In addition, co-administration of APTIVUS with low dose ritonavir, with drugs that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure, is contraindicated.

Some anti-infectives are not recommended (halofantrine, lumefantrine) as well as miscellaneous agents (tolterodine).

Oral contraceptives/oestrogens:

APTIVUS, co-administered with low dose ritonavir, decreases the AUC and C_max of ethinyl-oestradiol by 50 %, but does not significantly alter the pharmacokinetic behaviour of norethindrone. The concomitant administration with 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 and low dose ritonavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

Phosphodiesterase 5 (PDE5) inhibitors

Sildenafil and vardenafil: Particular caution should be used when prescribing the phosphodiesterase (PDE5) inhibitors sildenafil or vardenafil in patients receiving APTIVUS co-administered with low dose ritonavir. Co-administration of APTIVUS and low dose ritonavir with PDE5 inhibitors is expected to substantially increase PDE5 concentrations and may result in an increase in PDE5 inhibitor-associated adverse events including hypotension, visual changes and priapism.

Tadalafil: In a pharmacokinetic study performed in healthy male volunteers, co-administration of APTIVUS and low dose ritonavir with single dose tadalafil increased tadalafil exposure (AUC increased by 2.3 fold) at the first dose and did not change tadalafil exposure at steady-state. Therefore it is recommended to prescribe tadalafil after at least 7 days of APTIVUS/ritonavir dosing.

Narcotic analgesics (Methadone/Meperidine): Co-administration of APTIVUS and low dose ritonavir with single dose methadone was demonstrated to decrease methadone pharmacokinetic parameters (AUC_0-24h ratio of 0.47 with 90% CI [0.44; 0.51] and C_max ratio of 0.45 with 90% CI [0.41; 0.49]), in a study conducted in fasted healthy subjects. Therefore in such cases, patients should be monitored for opiate withdrawal syndrome. Dosage of methadone may need to be increased.

APTIVUS, co-administered with low dose ritonavir, is expected to decrease meperidine concentrations and increase normeperidine metabolite concentrations. Dosage increase and long-term use of meperidine with APTIVUS co-administered with low dose ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (eg seizures).

Immunosuppressants (cyclosporin, tacrolimus, sirolimus): Concentrations of cyclosporin, tacrolimus, or sirolimus cannot be predicted when co-administered with APTIVUS co-administered with low dose ritonavir, due to conflicting effect of APTIVUS, co-administered with low dose ritonavir, on CYP 3A and Pgp. More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilised.

Warfarin and other oral anticoagulants: Co-administration of APTIVUS with low dose ritonavir and warfarin may alter the metabolism of S-warfarin (initial inhibition and after 10 days a net induction was observed). Consequently, APTIVUS co-administered with low dose ritonavir, may be associated with changes in INR (International Normalised Ratio) values, and may affect anticoagulation (thrombogenic effect) or increase the risk of bleeding. Close clinical and biological (INR measurement) monitoring is recommended when these medicinal products are combined.

Antacids: When APTIVUS, co-administered with low dose ritonavir, was co-administered with 20 ml of aluminium- and magnesium-based liquid antacid, tipranavir AUC_12h, C_max and C_min were reduced by 25-29 %. Dosing of APTIVUS, co-administered with low dose ritonavir, with antacids should be separated by at least a two hours time interval.

Proton pump inhibitors :

Omeprazole: In clinical pharmacokinetic studies of tipranavir/ritonavir in combination with omeprazole (40 mg qd), no clinically important changes in tipranavir/ritonavir plasma concentrations were observed and thus no tipranavir/ritonavir dose adjustment is required. Tipranavir/ritonavir at steady state resulted in decreases in omeprazole AUC and Cmax by 71% and 73%, respectively. Similar effects were observed for the S-enantiomer, esomeprazole. Therefore, the combined use of tipranavir/ritonavir with either omeprazole or esomeprazole is not recommended (see section 4.4). If unavoidable, upward dose adjustments for either omeprazole or esomeprazole may be considered based on clinical response to therapy. There are no data available indicating that omeprazole or esomeprazole dose adjustments will overcome the observed pharmacokinetic interaction. Recommendations for maximal doses of omeprazole or esomeprazole are found in the corresponding product information.

H2-receptor antagonists: No data are available for H2-receptor antagonists in combination with tipranavir and low dose ritonavir. An increase in gastric pH that may result from H2-receptor antagonist therapy is not expected to have an impact on tipranavir plasma concentrations. Caution should be exercised when such drugs are combined with tipranavir and low dose ritonavir.

Theophylline: Based on data from the cocktail study where caffeine (CYP1A2 substrate) AUC was reduced by 43%, APTIVUS/ritonavir is expected to decrease theophylline concentrations. Theophylline plasma concentrations should be monitored during the first two weeks of co-administration with APTIVUS/ritonavir and the theophylline dose should be increased as needed.

Desipramine: APTIVUS, co-administered with low dose ritonavir, is expected to increase desipramine concentrations. Dosage reduction and concentration monitoring of desipramine is recommended.

Midazolam: Concomitant use of APTIVUS/ritonavir and oral midazolam is contra-indicated. Ritonavir is a potent inhibitor of CYP3A4 and therefore will affect drugs metabolised by this enzyme. When co-administered with APTIVUS/ritonavir at steady-state concentrations of intravenously administered single dose midazolam were increased 2.8 fold (AUC_0-24h) and concentrations of orally administered midazolam were increased 10 fold. If APTIVUS/ritonavir is administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be instituted and dosage adjustment should be considered.

Digoxin:APTIVUS, co-administered with low dose ritonavir, may double the exposure of orally administered digoxin at first dose,while the net effect at steady state may rather consist in a slight decrease in digoxin exposure. Monitoring of digoxin serum concentrations is recommended until steady state has been obtained.

Trazodone: In a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increased plasma concentration of trazodone (AUC increased by 2.4 fold). Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir in this study. However, it is unknown whether the combination of tipranavir/ritonavir might cause a larger increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered.

Bupropion: APTIVUS co-administered with low-dose ritonavir at steady-state resulted in approximately a 50% decrease in bupropion Cmax and AUC0-12h. This effect may be due to induction of bupropion metabolism. There was no relevant change in TPV Cmin. If the co-administration with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.

Loperamide: A pharmacodynamic interaction study in healthy volunteers demonstrated that administration of loperamide and APTIVUS, co-administered with low dose ritonavir does not cause any clinically relevant change in the respiratory response to carbon dioxide. The pharmacokinetic analysis showed that the AUC and C_max of loperamide are reduced by 51% and 61%, respectively, and the C_min of tipranavir by 26%. The clinical relevance of these changes is unknown.

Fluticasone propionate (interaction with ritonavir): In a clinical study where ritonavir 100 mg capsules bid were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82-89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway eg budesonide. Consequently, concomitant administration of tipranavir, co-administered with low dose ritonavir, and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels are as yet unknown.

Tipranavir, 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. 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)

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.

Metabolism and nutrition disorders:

Common: hypertriglyceridaemia, hyperlipidaemia, anorexia.

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)

Investigations:

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

Blood and lymphatic system disorders:

Uncommon: anaemia, neutropenia, thrombocytopenia.

Nervous system disorders:

Uncommon: dizziness, neuropathy peripheral, somnolence.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea.

Gastrointestinal disorders:

Uncommon: gastrooesophageal reflux disease, pancreatitis.

Renal and urinary disorders:

Uncommon: renal insufficiency.

Skin and subcutaneous tissue disorders:

Uncommon: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle cramp, myalgia.

Metabolism and nutrition disorders:

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

Rare: dehydration, facial wasting, hyperglycaemia.

General disorders and administration site conditions:

Uncommon: influenza like illness, malaise, pyrexia.

Immune system disorders:

Uncommon: hypersensitivity.

Hepatobiliary disorders:

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

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

Psychiatric disorders:

Uncommon: insomnia, sleep disorder.

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. 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.

Boehringer Ingelheim Limited

(POM)

27 October 2010