Boehringer Ingelheim Limited

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.

Section 10
Date of revision amended to 02 March 2009

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.

Section 10
Date of revision has been amended

Section 4.4

Addition of the following paragraph:

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

and amendment of paragraph:

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.

Section 5.3

Amendment of paragraph:

The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The effects were reversible with termination of treatment. Additional changes included bleeding in rats at high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

Section 10

Amended Date of Revision

Addition of the following paragraph in section 4.4:

Omeprazole: APTIVUS co-administered with low dose ritonavir decreases the plasma concentrations of omeprazole and esomeprazole (see section 4.5).  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.

Addition of the following paragraph in section 4.5:

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.

Rewording of following paragraph in section 4.5:

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.

Updating of bolded information in following paragraph in section 4.8:

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.

24 week data changed to 48 week data in following sentence of Section 5.1:

Clinical pharmacodynamic data: The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts.

Section 10

Date of revision amended.

Section 5.3: 3rd paragraph new.

Change to date of revision

 In addition, the pre-existing wording on bleeding risk in general, contained within section 4.8 of the original SPC, has also been added to section 4.4, directly preceding the above wording on ICH risk.