Hemgenix

HOS-098783 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) in clinical studies with etranacogene dezaparvovec were headache (very common; 31.6% of patients), ALT elevations (very common; 22.8% of patients), AST elevations (very common; 17.5% of patients), and influenza-like illness (very common; 14% of patients). Tabulated list of adverse reactions 11 The safety of etranacogene dezaparvovec was evaluated in clinical studies involving 57 adult patients, who received a single intravenous dose of etranacogene dezaparvovec and were followed up for a period of 5 years (see section 5.1). The Table 3 shows the overview of the ADRs from the clinical trials with etranacogene dezaparvovec. The ADRs are classified according the MedDRA System Organ Class and frequency. The ADRs are listed based on the following convention for frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing frequency. Table 3. Adverse drug reactions obtained from clinical studies with etranacogene dezaparvovec MedDRA System Organ ADR Frequency per Class (SOC) (Preferred term) patient Nervous system disorders Headache Very common Dizziness Common Gastrointestinal disorders Nausea Common General disorders and Influenza like illness Very common administration site conditions Fatigue, malaise Common Investigations Alanine aminotransferase increased, aspartate Very common aminotransferase increased, C-reactive protein increased Blood creatine phosphokinase increased, blood Common bilirubin increased Injury, poisoning and Infusion related reaction (Hypersensitivity, Very Common* procedural complications infusion site

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HOS-098779 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Active infections, either acute or uncontrolled chronic (see section 4.4). - Patients with known advanced hepatic fibrosis, or cirrhosis (see section 4.4).

HOS-098778 · has-indication-information · PDF-Seite 2

Hemgenix is indicated for the treatment of severe and moderately severe Haemophilia B (congenital Factor IX deficiency) in adult patients without a history of Factor IX inhibitors.

HOS-098781 · has-interaction-information · PDF-Seite 10

Prior to etranacogene dezaparvovec administration, the patient’s existing medicinal products should be reviewed to determine if they should be modified to prevent anticipated interactions described in this section. Patients’ concomitant medications should be monitored after etranacogene dezaparvovec administration, particularly during the first year, and the need to change concomitant medicinal products based on patient’s hepatic health status and risk should be evaluated. When a new medication is started, close monitoring of ALT and Factor IX activity levels (e.g. weekly to every 2 weeks for the first month) is recommended to assess potential effects on both levels. No in vivo interaction studies have been performed. Hepatotoxic medicinal products or substances Experience with use of this medicinal product in patients receiving hepatotoxic medications or using hepatotoxic substances is limited. Safety and efficacy of etranacogene dezaparvovec in these circumstances have not been established (see section 4.4). Before administering etranacogene dezaparvovec to patients receiving potentially hepatotoxic medicinal products or using other hepatotoxic agents (including alcohol, potentially hepatotoxic herbal products and nutritional supplements) and when deciding on the acceptability of such agents after treatment with etranacogene dezaparvovec, physicians should consider that they may reduce the efficacy of etranacogene dezaparvovec and increase the risk for more serious hepatic reactions, particularly during the first year following etranacogene dezaparvovec administration (see section 4.4). Interactions with agents that may reduce or increase plasma concentrations of corticosteroids Agents that may reduce or increase the plasma concentration of corticosteroids (e.g. agents that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects (see section 4.4). Vaccinations Prior to etranacogene dezaparvovec infusion, ensure that the patient’s vaccinations are up to date. The patient’s vaccination schedule may need to be adjusted to accommodate concomitant immunomodulatory therapy (see section 4.4). Live vaccines should not be administered to patients while on immunomodulatory therapy. 10

HOS-098782 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential No dedicated animal fertility/embryofoetal studies have been conducted to substantiate whether the use in women of childbearing potential and during pregnancy could be harmful for the newborn child (theoretical risk of viral vector integration in foetal cells through vertical transmission). No data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, Hemgenix is not recommended in women of childbearing potential. Contraception after administration in males In clinical studies, after administration of etranacogene dezaparvovec, transgene DNA was temporarily detectable in semen (see section 5.2). For 12 months after administration of etranacogene dezaparvovec treated patients of reproductive potential and their female partners of childbearing potential must prevent or postpone pregnancy using barrier contraception. Males treated with Hemgenix must not donate semen to minimise the potential risk of paternal germline transmission (see section 4.4). Pregnancy Experience regarding the use of this medicinal product during pregnancy is not available. Animal reproduction studies have not been conducted with Hemgenix. It is not known whether this medicinal product can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Hemgenix should not be used during pregnancy. Breast-feeding It is unknown whether etranacogene dezaparvovec is excreted in human milk. A risk to the newborns/infants cannot be excluded. Hemgenix should not be used during breast feeding. Fertility Effects on male fertility have been evaluated in animal studies with mice. No adverse impact on the fertility was observed (see section 5.3).

HOS-098780 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Initiation of treatment with Hemgenix Patients with pre-existing antibodies to the AAV5 vector capsid Prior to the treatment with Hemgenix patients should be assessed for the titre of preexisting neutralising anti-AAV5 antibodies. Preexisting neutralising anti-AAV5 antibodies above a titre of 1:898, based on the neutralising anti- AAV5 antibody assay with extended measuring range (equivalent to 1:678 titre based on the previous clinical study assay), may impede transgene expression at desired therapeutic levels and thus reduce the efficacy of Hemgenix therapy (see section 5.1). There is limited data in patients with neutralising anti-AAV5 antibodies above 1:898 (equivalent to the 1:678 titre based on the clinical study assay). In the clinical studies with etranacogene dezaparvovec, in 1 patient with a preexisting neutralising anti-AAV5 antibody titre of 1:3212 (tested using the clinical study assay, equivalent to 1:4417 titre based on the neutralising anti-AAV5 antibody assay with extended 4 measuring range), no Factor IX expression was observed and restarting of exogenous Factor IX prophylaxis was needed (see section 5.1). In the clinical studies with etranacogene dezaparvovec, for the patient sub-group with detectable preexisting neutralising anti-AAV5 antibodies up to a titre of 1:678 (tested using the clinical study assay, equivalent to 1:898 titre based on the neutralising anti-AAV5 antibody assay with extended measuring range), mean Factor IX activity levels were within the same range but numerically lower compared to those of the patient sub-group without detectable preexisting neutralising anti-AAV5 antibodies. However, both patient groups, with and without detectable preexisting neutralising anti-AAV5 antibodies, demonstrated an improved haemostatic protection compared to the standard of care Factor IX prophylaxis after etranacogene dezaparvovec administration (see section 5.1). Baseline hepatic function Prior to the treatment with Hemgenix, patient`s liver transaminases should be assessed and liver ultrasound and elastography performed, along with laboratory tests to evaluate for active Hepatitis B and C. This includes: • Enzyme testing (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline

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