Leitlinien & Arzneimittelsicherheit

HOS-287589 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most serious adverse reaction was immune reconstitution inflammatory syndrome (see section 4.4). The most commonly seen adverse reactions were diarrhoea (24%), headache (17%), nausea (15%), rash (12%), abdominal pain (12%), and vomiting (11%). Tabulated list of adverse reactions The adverse reactions identified in clinical trials are listed in Table 2 by body system, organ class and frequency. Frequencies are defined as 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), very rare (<1/10,000). 10 Table 2: Tabulated list of adverse reactions System Organ Class Frequency1 Adverse Reactions Immune system Common Immune reconstitution inflammatory syndrome2 (see disorders section 4.4) Psychiatric disorders Common Insomnia Nervous system Very Headache disorders common Common Dizziness, somnolence, dysgeusia Cardiac disorders Common Electrocardiogram QT prolonged (see section 4.4) Gastrointestinal Very Diarrhoea, nausea, abdominal pain3, vomiting disorders common Common Dyspepsia, flatulence Hepatobiliary Common Transaminases increased4 disorders Skin and Very Rash5 subcutaneous tissue common disorders Common Pruritus6 Musculoskeletal and Common Myalgia connective tissue disorders General disorders Common Fatigue and administration site conditions Investigations Common Blood creatinine increased, blood creatine phosphokinase increased 1 Calculated based on safety data from 570 subjects (n=370 from phase III [BRIGHTE] study at 144 weeks, and n=200 from phase IIb study with mean duration 174 weeks). 2 Includes central nervous system immune reconstitution inflammatory response and immune reconstitution inflammatory syndrome. 3 Includes abdominal discomfort, abdominal pain and abdominal pain upper. 4 Includes increases in ALT, AST, hepatic enzymes and transaminases. 5 Includes rash, rash erythematous, rash generalised, rash macu

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HOS-287585 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with strong CYP3A inducers including, but not limited to: carbamazepine, phenytoin, mitotane, enzalutamide, rifampicin and St John’s wort (see section 4.5).

HOS-287584 · has-indication-information · PDF-Seite 2

Rukobia, in combination with other antiretrovirals, is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen (see sections 4.4 and 5.1).

HOS-287587 · has-interaction-information · PDF-Seite 4

Effect of other medical products on the pharmacokinetics of temsavir Temsavir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not of organic anion transporters OATP1B1 or OATP1B3. Its biotransformation to two circulating metabolites, BMS-646915 and BMS-930644, is mediated by unidentified esterases (36.1%) and by cytochrome P450 (CYP)3A4 enzyme (21.2%), respectively. When fostemsavir was co-administered with the strong CYP3A inducer rifampicin, a significant reduction in temsavir plasma concentrations was observed. Significant decreases in temsavir plasma concentrations may also occur when fostemsavir is co-administered with other strong CYP3A inducers, and may result in loss of virologic response (see section 4.3). 4 Fostemsavir may be co-administered with strong CYP3A4, BCRP and/or P-gp inhibitors (e.g., clarithromycin, itraconazole, posaconazole, and voriconazole) without dose adjustment based on the results of clinical drug interaction studies with cobicistat and ritonavir. Effect of temsavir on the pharmacokinetics of other medicinal products In vitro, temsavir inhibited OATP1B1 and OATP1B3 (IC50 = 32 and 16 µM, respectively). Additionally, temsavir and its two metabolites (BMS-646915 and BMS-930644) inhibited BCRP (IC50 = 12, 35, and 3.5 to 6.3 µM, respectively). Based on these data, temsavir is expected to affect the pharmacokinetics of active substances that are substrates of OATP1B1/3 or BCRP (e.g. rosuvastatin, atorvastatin, simvastatin, pitavastatin and fluvastatin). Therefore, dose modifications and/or careful titration of dose is recommended for certain statins. Interaction table Selected drug interactions are presented in Table 1. Recommendations are based on either drug interaction studies or predicted interactions based on the expected magnitude of the interaction and potential for serious adverse events or loss of efficacy. (Abbreviations:  = Increase;  =decrease;  = no significant change; AUC=area under the concentration versus time curve; Cmax=maximum observed concentration, C=concentration at the end of dosing interval; *= Using cross-study comparisons to historical pharmacokinetic data). Table 1: Interactions Concomitant medicinal Effect on concentration of Recommendation concerning co- product by therapeutic temsavir or concomitant

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HOS-287588 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of fostemsavir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposure levels of temsavir in the range of the recommended human dose (RHD) (see section 5.3). In pregnant rats fostemsavir and/or its metabolites cross the placenta and are distributed to all foetal tissues. As a precautionary measure, it is preferable to avoid the use of Rukobia during pregnancy. Breast-feeding It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. It is unknown whether fostemsavir/temsavir are excreted in human milk. Available toxicokinetic data in lactating rats have shown excretion of fostemsavir/temsavir in milk (see section 5.3). Fertility 9 There are no data on the effects of fostemsavir on human male or female fertility. Animal studies indicate no effects of fostemsavir on male or female fertility at clinically relevant doses (see section 5.3).

HOS-287586 · has-warning-information · PDF-Seite 3

Immune reconstitution inflammatory syndrome In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (formerly P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves’ disease, autoimmune hepatitis, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation. QTc prolongation A supratherapeutic dose (at a Cmax approximately 4.2-fold the therapeutic dose) of fostemsavir has been shown to significantly prolong the QTc interval of the electrocardiogram (see section 5.1). Fostemsavir should be used with caution in patients with a history of QT interval prolongation, when co-administered with a medicine with a known risk of Torsade de Pointes (e.g. amiodarone, disopyramide, ibutilide, procainamide, quinidine, or sotalol) or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Patients with hepatitis B or C virus co-infection Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products. Opportunistic infections Patients should be advised that fostemsavir or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

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