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Procedural steps taken and scientific information after the authorisation

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The DDPS has been updated to version 5.2 to reflect the change of the Qualified Person for Pharmacovigilance (QPPV) as well as to notify other changes to the DDPS performed since the last approved version. Consequently, Annex II has been updated using the standard text including the new version number of the agreed DDPS. Please note that this assessment report will be published after deletion of Extension of indication to include the treatment of HIV-1 infection in highly pre-treated adolescents 12 years of age or older with virus resistant to multiple protease inhibitors. Study 1182.85 assessed the effect of steady-state tipranavir/ritonavir (TPV/r) twice daily on the steady-state pharmacokinetics of buprenorphine/naloxone. The active metabolite norbuprenorphine Update of section 4.5 of the SPC to include presented decreased pharmacokinetic parameters (about -80%) when co- information on the interaction between TPV administered with TPV/r. This may result in decreased clinical efficacy of buprenorphine. Therefore, patients should be monitored for opiate buprenorphine/naloxone from results of the 1 Major changes e.g. Type II variations, Annex II applications, Renewals and Annual Reassessments 2 SPC (Summary of Product Characteristics), Annex II, Labelling, PL (Package Leaflet) European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged. Commission Product
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During the review of PSUR 3 a potential interaction between tipranavir and enfuvirtide was suspected from 13 case reports which involved a hepatic event whilst the patients were on a tipranavir/ritonavir/enfuvirtide Update of section 4.5 of the SPC to include (TPV/r/ENF) combination. In 2006, Requena et al also described this interaction where co-administration of TPV/r with ENF resulted in an levels associated with co-administration of increase in TPV and RTV plasma trough concentrations of approximately 50%. At last, in the RESIST trials, higher TPV trough plasma levels were observed in patients receiving TPV/r with ENF compared to patients not receiving ENF (45% higher). The increase in plasma concentrations occurred within the first two weeks of combination. These findings cannot be explained by the metabolic profile of the medicinal products. No information was available for AUC and Cmax parameters. 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. The results of the study 1182.95 showed that co-administration of tipranavir/ritonavir with bupropion resulted in potentially clinically significant reductions in Ctrough, Cmax and AUC of bupropion (60%, Update of section 4.5 of the SPC to include 44% and 49%, respectively) without significant changes in Tmax and T1/2. Co-administration of tipranavir/ritonavir with bupropion also tipranavir/ritonavir and bupropion. Section 2 resulted in 24-25% decreases in the Ctrough, Cmax and AUC for the active metabolite hydroxybupropion. The half-life of hydroxybupropion addition the MAH took the opportunity to was substantially reduced by approximately 58%. This reduction is likely update the contact details of the Austrian due to induction of CYP2B6 and UGT activity by ritonavir, and possibly due to induction of CYP3A4 by tipranavir/ritonavir. As the maximum recommended dose of bupropion (300 mg / day) should not be increased to compensate for this induction effect, the combination should be avoided. However, if the co-administration with bupropion is considered unavoidable, close clinical monitoring for bupropion efficacy is necessary. In 2005 an interaction study on saquinavir boosted with ritonavir together with rifampicin in healthy volunteers had to be prematurely discontinued due to an increased risk of hepatotoxicity associated with this co- Update of section 4.3 and section 4.5 of the administration. The mechanism for this interaction is not fully elucidated. SPC to implement the class labelling text It has been hypothesised that the predominant effect between the inducer effect of rifampicin and the inhibitor effect of the boosted protease Commission Product
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combination of rifampicin with tipranavir inhibitors might depend on the boosted protease inhibitor involved. given with concomitant low-dose ritonavir. Lacking the results of specific interaction studies, the CHMP concluded as a conservative measure to reinforce the contraindication with rifampicin in section 4.4 and improve the guidance provided to physicians regarding the interaction of boosted protease inhibitors with rifampicin in section 4.5. Following reports of intracranial hemorrhage during clinical trials, studies were conducted in male rats to explore the effects of tipranavir (TPV) on coagulation. Bleeding events were observed, associated with prolonged Update of sections 4.4 and 5.3 of the SPC to prothrombin time (PT), activated partial thromboplastin time (aPTT) and a include results from non-clinical studies for decrease in some vitamin K dependent factors. Co-administration of tipranavir-related effects on coagulation tipranavir with vitamin E-TPGS, an esterified derivative of vitamin E, parameters and to advise caution for the co- resulted in an exacerbation of the anti-coagulant effects of TPV in male administration of high doses of vitamin E. rats, specifically causing increases in PT, aPTT, and Thrombotest levels and decreases in vitamin K dependent factors. Co-administration of tipranavir with vitamin E should be used with caution and at doses not higher than 1200 IU vitamin E per day. In view of the submitted efficacy and safety data, the CHMP concluded that the benefit risk balance of ritonavir-boosted tipranavir in the treatment of adult patients with virus resistant to multiple protease inhibitors remains positive. As all remaining Specific Obligations were fulfilled, the CHMP agreed that exceptional circumstances should be lifted. In contrast to observations with other Protease Inhibitors, no clinically significant effect on tipranavir plasma concentrations after co- administration with omeprazole was seen. Based on this information no Update of section 4.4 and 4.5 of the SPC dose adjustment of tipranavir/ritonavir in case of co-administration would with information on the interaction between be required. However, a clinically important effect on omeprazole tipranavir/ritonavir and omeprazole. Section concentrations was observed. Omeprazole exposure was decreased by 2 of the PL has been updated accordingly. about 70% in the presence of steady-state tipranavir/ritonavir. Due to the uncertainty of the effectiveness of such lowered concentrations of omeprazole in patients, this combination is therefore not recommended. Nevertheless, for those patients in need of proton-pump-inhibitor therapy and without reasonable alternatives, omeprazole might be used. This will Commission Product
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necessitate appropriate omeprazole dose increases and clinical evaluation of the patient's response to therapy and, if necessary, further dose-alteration, depending on response. Tipranavir was found to inhibit platelet aggregation when testing human platelets and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving Aptivus/ritonavir. Update of section 5.3 of the SPC based on The clinical implications of these findings are not known. The currently the CHMP's assessment in June 2007 of in known effects of Aptivus/ritonavir on bleeding are already reflected in vitro studies showing effects of tipranavir on thromboxane synthase, thromboxane A2, thrombin and PAF binding. Based on two in vitro studies, investigating the antiretroviral activity of tipranavir against HIV-1 group M and O clades as well as HIV-2 isolates section 5.1 of the SPC was updated to reflect the fact that tipranavir shows Update of section 5.1 subsection "Antiviral antiretroviral activity in vitro against all of the tested sub-types. However, activity in vitro" of the Aptivus SPC to add interpretation of results in the HIV-1 group O and HIV-2 isolates were the results of recently performed studies complicated by the lack of a suitably validated assay for the determination measuring the in vitro activity of tipranavir of the inhibitor concentration leading to 50% inhibition of viral replication Furthermore, additional information on in vitro results on the interaction of tipranavir with other antiretroviral medicinal products was removed from this section of the SPC in light of the clinical data already reflected elsewhere in the SPC. The submitted study showed that the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) efavirenz, co-administered with tipranavir/ritonavir at the currently recommended and approved dosages, did not significantly alter the pharmacokinetics of tipranavir and/or Update of section 4.5 of the SPC based on a ritonavir. Moreover, it was confirmed that efavirenz plasma concentration pharmacokinetic drug-drug interaction study was not modified by tipranavir/ritonavir. between efavirenz and tipranavir/ritonavir. Due to the absence of significant interaction between efavirenz and Furthermore, the MAH clarified the wording tipranavir/ritonavir observed in the submitted study, and taking into on interaction with nevirapine. In addition, account previous data provided by the MAH on the nevirapine- the MAH took this opportunity to update the tipranavir/ritonavir interaction, a significant drug-drug interaction between nevirapine and tipranavir/ritonavir seems unlikely to occur. Commission Product
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The information in section 4.5 of the SPC on the interaction of tipranavir/ritonavir and both NNRTIs efavirenz and nevirapine was updated accordingly. Based on the results of in vitro studies, tipranavir seems to be a substrate P-glycoprotein (P-gp). Consequently, it is possible that interactions Update of section 4.5 of the SPC based on in vitro mechanistic studies assessing P-gp and P-gp could affect the absorption, distribution and excretion of other drugs PXR induction as requested by the CHMP in that interact with P-gp when administered concomitantly with November 2006 following the assessment of tipranavir/ritonavir (TPV/r). At this time, the most reliable method to study the ability for a drug to induce Cytochrome P (CYP) is to quantify the enzyme activity of primary hepatocyte cultures. It has been shown in vitro that tipranavir is a CYP3A4 inducer but only mildly induces P-gp, MRP2 (Multidrug resistance Protein 2) and UGT1A1 (Uridine glucuronosyltransferase 1A1). Based on these results, the data related to P-gp induction by tipranavir in the current section 4.5 of Aptivus SPC was updated. In comparing the pharmacokinetic profile of tadalafil prior to tipranavir/ritonavir and with the first dose of tipranavir/ritonavir, there was a clinically important increase in tadalafil exposure. However, for Update of section 4.5 of the SPC based on a tipranavir/ritonavir administration at steady-state, there was essentially no clinical study report assessing the effects of change in tadalafil except for the Cmax that was decreased. Although there were no important safety findings observed in the clinical trial, the increase in the tadalafil exposure seen with the first dose of tipranavir/ritonavir administration suggests that the increase in tadalafil exposure might alter the tadalafil safety profile. Therefore, the use of tadalafil should be avoided during the first 7-10 days of tipranavir/ritonavir dosing. After steady-state is achieved with tipranavir/ritonavir, tadalafil can be administered without dose modification. This study demonstrated that the co-administration of tipranavir/ritonavir (TPV/RTV) with carbamazepine (CBZ) 200 mg twice daily led to an increased exposure of CBZ and of its active metabolite by about 20 %, Update of sections 4.4 and 4.5 of the SPC however no significant effect was observed with CBZ 100 mg twice daily. based on a study assessing the steady state It could also be extrapolated that higher doses of CBZ may result in larger Commission Product
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pharmacokinetics of carbamazepine (200mg decreases in TPV plasma concentrations, which may further lead to reduced antiviral efficacy. Therefore, the CHMP considered that caution is required when co-administering TPV/RTV with high doses of CBZ. combination with tipranavir/ritonavir after a single dose and at steady state. The Package Additionally, the statement in section 4.5 of the SPC includes phenobarbital and phenytoin, as they are, like CBZ, also inducers of CYP3A4. The PL is updated accordingly. The presented "Cocktail study" uses a methodology which is a tool to test the drug interaction profile of a substance. It is a phenotyping tool for screening potential drug-drug interactions when an active compound has Update of sections 4.3, 4.4 and 4.5 of the got an effect on several metabolism-involved enzymes and transporters. To SPC to include information on interactions this end, a "Cocktail" of either isozyme or transporter specific biomarkers of tipranavir/ritonavir with transporters and is administered in healthy human volunteers who are given the active CYP isoenzymes based on the results of a under investigation (here tipranavir/r) as well. human pharmacokinetic study as requested The results of this study are summarised as such: Over the first few doses of TPV/r moderate inhibition of CYP1A2 and CYP2C9 occurred, moderate inhibition of p-glycoprotein occurred and potent inhibition of CYP2D6 and hepatic and intestinal CYP3A occurred. Intestinal P-glycoprotein and CYP3A activity were more profoundly affected than hepatic P-glycoprotein and CYP3A activity. Prolonged TPV/r exposure induced the activity of CYP1A2, CYP2C9, hepatic and intestinal P- glycoprotein, and hepatic and intestinal CYP3A, whereas prolonged exposure further inhibited CYP2D6 activity. At steady-state, modest net induction of CYP1A2 and CYP2C9 occurred, and potent inhibition of CYP2D6 and hepatic and intestinal CYP3A occurred. The net effect on P-glycoprotein, as measured by digoxin, was decreased compared to baseline conditions. The analysis of resistance data from RESIST-1 and -2 trials showed that treatment and virological response at week 48 was superior in the tipranavir/ritonavir arm than in the comparator arm in both pivotal clinical Update of sections 4.1 and 5.1, subsection trials. However, the analysis also showed clearly that the magnitude of "Analyses of tipranavir resistance in response was to a very high degree dependant on the use of enfuvirtide for treatment experienced patients" of the SPC the first time in the optimised background regimen. Additionally, the based on the data on the impact of mutations analysis showed that mutations on the protease gene that also occur with the use of other, more widely used protease inhibitors may lead to loss of Commission Product
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tipranavir/ritonavir observed at 48 weeks in virological response during tipranavir treatment. Therefore, a sentence was the two pivotal clinical trials. This follows a added in section 4.1 to draw special attention to the need for careful evaluation of a patient's genotype prior to initialisation of further to the assessment of the submitted clinical trial data and their corresponding A regression analysis was performed to determine which mutation score was most predictive of virological and therapeutic response in patients participating in the RESIST-1 and -2 trials. As this analysis proved the so called tipranavir mutation score to be the most relevant, it is now reflected in the SPC to allow treating physicians to make the most informed choice on starting tipranavir treatment based on genotyping of their patients. In view of the submitted efficacy and safety data, the CHMP concluded that the benefit risk balance of ritonavir-boosted tipranavir in the treatment of adult patients with virus resistant to multiple protease inhibitors remains positive. As there are still remaining Specific Obligations, the CHMP agreed that the Marketing Authorisation should remain under exceptional circumstances. The studies showed that tipranavir is a rat and mouse carcinogen with the augmentation of liver and thyroid tumours. These tumours are likely due to the fact that tipranavir is an enzyme inducer leading to liver hyperplasia Update of section 5.3 of the SPC with results and augmentation of the clearance of thyroid hormones. Such mechanisms of two-year carcinogenicity studies in rats of liver and thyroid tumours observed in rodents have been observed with several chemicals and it is unlikely that this effect would occur in humans. The in vitro assays performed in human and rat plasma showed that tipranavir inhibits platelet aggregation. This indicates that there may be a weak anti-platelet effect at concentrations achieved in clinical practice. Update of section 4.4 of the SPC to reflect This study only tested the in vitro ability of tipranavir to inhibit platelet the results of an in vitro platelet aggregation aggregation. It is unknown whether this effect also would occur in vivo and if this effect is reversible or not. This will be undergoing further investigations. Commission Product
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The data presented from a clinical trial in antiretroviral naïve patients showed that tipranavir/ritonavir should not be used in this patient population. This conclusion was based on the fact that in the treatment arm Update of sections 4.2 and 4.4 of SPC based where tipranavir was given together with 200mg ritonavir twice daily as on the analysis of resistance data from a 48 currently approved for experienced patients, the safety profile was unfavourable as compared to the comparator arm (lopinavir/ritonavir) patients. A warning not to use Aptivus in the without having additional benefits. Therefore, this arm was closed treatment of antiretroviral naïve patients was prematurely. In the second tipranavir arm where ritonavir was given at 100mg twice daily, the safety profile was more favourable. However, non- inferiority could not be shown to the comparator. Consequently, this arm was stopped as well. Tipranavir/ritonavir should not be used in antiretroviral naïve patients, as the benefit risk balance in this population was found to be negative. Hepatotoxicity is one of the major concerns as regards the safety profile of tipranavir/ritonavir used at the indicated dose of 500/200 mg twice daily. To minimise this risk in clinical practice, the liver function test monitoring Update of section 4.4 of the SPC to amend was reviewed. In consequence, the frequency of liver function testing was the liver function test (LFT) monitoring increased, specifically during the initiation period of treatment. schedules and the criteria for rechallenge, as Additionally, a recommendation to discontinue tipranavir/ritonavir as soon as any sings of liver damage appear was added. "Hyperbilirubinemia" with three reports and "blood bilirubin increased" with another two reports were unlisted hepatic terms that had been reported more than once within the first quarterly safety review covering To update section 4.8 of the SPC and section the period 1 January to 31 March 2006. Both hyperbilirubinaemia and increased levels of blood bilirubin had not been reported more than once in the reference data set of 1397 patients; therefore, it was assigned to the assessment of the first quarterly report of Cases of osteonecrosis (death of the bone tissue resulting from an insufficient blood supply) have been reported in HIV-infected patients since the end of the 80's. Although the cause of this disease could be due Update of sections 4.4 and 4.8 of the SPC to multiple factors (including the use of corticosteroids, alcohol and section 2 of the PL to implement the consumption, severe immunosuppression, higher body mass index) it has class labelling text on osteonecrosis, agreed occurred specially in patients with HIV advanced disease and/or in patients Commission Product
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with long term use of combination antiretroviral therapy (CART). Further to the review of all available data the CHMP agreed that this information Section 6 of the PL was updated with the should now be included in the SPC and PL of all antiretroviral medicinal products. Patients should be warned to seek medical advice in case they experience joint stiffness, aches and pain especially of the hip, knee and shoulder or if they experienced any difficulty in movement. In a pharmacokinetic study performed in 10 healthy volunteers, the concomitant use of ritonavir (at a lower dose of 200mg) with one dose of trazodone led to an increase in the blood plasma levels of trazodone. Three Update of section 4.5 of the Aptivus SPC patients experienced adverse events, such as dizziness, nausea, with information on the potential interaction hypotension, bradycardia, pallor and syncope. It is unknown whether between tipranavir/ritonavir and trazodone tipranavir/ritonavir may cause an even larger increase in the levels of trazodone. Therefore, the combination of these medicinal products should pharmacokinetic study between ritonavir and be used with caution, including a possible need for dose adjustments. This information was included in the interaction section of the SPC and Relevant sections of the PL are amended in Further to preclinical data where rats exposed to tipranavir experienced bleedings and based on a cumulative review provided by the MAH, the CHMP concluded that there is a signal for increased rates of intracranial haemorrhage (ICH) in tipranavir/ritonavir-exposed patients. The rate of ICH in tipranavir-exposed patients appears to be higher than the ones seen in the nevirapine and enfuvirtide clinical development programs but in the range of the rate reported in the literature from clinical cohorts of HIV- observed in Aptivus clinical trials. This infected persons. In many of the tipranavir/ritonavir-exposed patients, a plausible alternative explanation for the ICH was noted on review of the individual case reports. However, in the six remaining cases of the case- haemorrhage events, especially intracranial by-case analysis, the role of tipranavir/ritonavir in the ICH event could not be excluded. Due to the serious nature of these ICH events with an expected mortality rate of approximately 50% these findings require further evaluation. The added wording to the SPC and PL reflects the current state of knowledge and is well accompanied by the Dear Doctor Letter to inform prescribers about this safety signal. The benefit risk balance for tipranavir Commission Product
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remains favourable, although all bleeding adverse events must be carefully monitored and all findings should be cumulatively presented in future PSURs. Although, the combination of tipranavir/ritonavir (500/100 mg twice daily) with atazanavir (300 mg once daily) appeared to be at least as tolerable as atazanavir/ritonavir alone in this healthy volunteer population, coadministration of tipranavir/ritonavir (500/100 mg twice daily) with atazanavir (300 mg once daily) is not recommended. This is due to the PK interaction of the combination leading to a significant reduction in protease inhibitor atazanavir into sections atazanavir levels, as well as substantial increase of tipranavir and ritonavir 4.4 and 4.5 of the Aptivus SPC, as requested exposure. Therefore, the co-administration of atazanavir and tipranavir should be strictly discouraged. It cannot be excluded that the effects of the the assessment of the report for a clinical medicinal products on each other would be more pronounced if they were study, assessing the PK interaction between to be administered at both their recommended dosages (tipranavir/ritonavir steady-state tipranavir/ritonavir at single 500/200 mg twice daily & atazanavir/ritonavir 300/100 mg once daily). Therefore, further studies to explore dose adjustments would be very Consequently, Section 2 of the PL is also difficult to handle and are not recommended. Co-administration of single-dose methadone with tipranavir/ritonavir resulted in a decrease in methadone exposure in fasted healthy volunteers. The pharmacokinetics data in the study suggest that patients treated with methadone co-administered with tipranavir/ritonavir require monitoring effects of methadone within the paragraph for clinical symptoms of withdrawal from methadone and may require an increased dose of methadone. The steady-state tipranavir exposure (Methadone/Meperidine) in section 4.5 of decreased as well when methadone was co-administered with steady-state Characteristics as requested by the CHMP on 3 May 06 further to the assessment of the report of a clinical study assessing the PK interaction between tipranavir/ritonavir at steady state and methadone. Commission Product
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The proposed additions to the PL harmonise the information on uncommon and rare adverse reactions with that of section 4.8 in the SPC. Update of section 4 of the PL to include the The potential risks of tipranavir therapy are thereby better and more list of uncommon and rare adverse reactions accurately described and accessible by the patients. The liver toxicity is a major concern with tipranavir. Therefore the CHMP agreed in his opinion on the granting of a marketing authorisation for Aptivus under exceptional cirmcumstances during September 2005 CHMP information on the occurrence of hepatitis on introducing strong warnings and stringent monitoring of liver tests prior and hepatic failure (hepatotoxicity) in line and during treatment as specified in the Summary of Product Characteristics. The proposed wording in the PL corresponds to the information already included within section 4.8 "Undesirable Effects" of the SPC, in which hepatitis and hepatic failure (including fatal outcome) are listed as expected adverse reactions, under the frequency category 'uncommon' and 'rare', respectively. Furthermore, the advice to be observant for signs and symptoms of hepatitis reflects the advice already given in section 4.4 "Special Warnings and Precautions for Use" of the SPC. Addition of this information to the PL clearly highlights and more accurately informs the patient of the potential risk of hepatitis and hepatic failure. The potential risk to all patients, not just those higher risk patients with baseline prognostic factors, is thereby better and more accurately described.
MINOR CHANGES3

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Minor change in labelling or package leaflet not connected with the SPC (Art. 61.3 Notification) 05_Change in the name and/or address of a manufacturer of the finished product 17_a_Change in re-test period of the active substance 22_a_Submission of TSE Ph. Eur. certificate for exc. - Approved/new manufacturer 3 Minor changes e.g. Type I variations and Notifications 4 Date of entry into force of the change

Source: http://antiretroviraux.free.fr/ARV-RCP/Aptivus-091026-PostAMM.pdf

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