Givlaari · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098711 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile The most frequently occurring adverse reactions reported in patients treated with givosiran are injection site reactions (ISRs) (36%), nausea (32.4%) and fatigue (22.5%). The adverse reactions resulting in discontinuation of treatment were elevated transaminases (0.9%) and anaphylactic reaction (0.9%). Tabulated list of adverse reactions The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organ class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed according to the following categories: • Very common (≥ 1/10) • Common (≥ 1/100 to < 1/10) • Uncommon (≥ 1/1 000 to < 1/100) 5 Table 1: Adverse reactions System organ class Adverse reaction Frequency Hypersensitivity Common Immune system disorders Anaphylactic reaction Uncommon Nausea Very common Gastrointestinal disorders Pancreatitis Common Hepatobiliary disorders Transaminase elevations Very common Skin and subcutaneous tissue Rasha Very common disorders Glomerular filtration rate (GFR) Renal and urinary disorders Very common decreasedb General disorders and administration Injection site reactions Very common site conditions Fatigue Very common c Investigations Blood homocysteine increased Common a Includes pruritus, eczema, erythema, rash, rash pruritic, urticaria. b Includes blood creatinine increased, GFR decreased, chronic kidney disease (estimated GFR (eGFR) decrease

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098707 · has-contraindication-information · PDF-Seite 3

Severe hypersensitivity (e.g. anaphylaxis) to the active substance or to any excipients listed in section 6.1.

HOS-098706 · has-indication-information · PDF-Seite 2

Givlaari is indicated for the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 12 years and older.

HOS-098709 · has-interaction-information · PDF-Seite 4

In a clinical drug-drug interaction study, givosiran resulted in a weak to moderate reduction in activity of certain CYP450 enzymes in the liver thereby increasing plasma exposures: • CYP1A2: 1.3-fold increase in Cmax and 3.1-fold increase in AUC0–∞ of caffeine • CYP2D6: 2.0-fold increase in Cmax and 2.4-fold increase in AUC0–∞ of dextromethorphan • CYP2C19: 1.1-fold increase in Cmax and 1.6-fold increase in AUC0–∞ of omeprazole 4 • CYP3A4: 1.2-fold increase in Cmax and 1.5-fold increase in AUC0–∞ of midazolam • CYP2C9: no effect on the exposure of losartan Caution is recommended during the use of medicinal products that are substrates of CYP1A2 or CYP2D6 while on treatment with Givlaari as this medicinal product may increase or prolong their therapeutic effect or alter their adverse event profiles. Consider decreasing the CYP1A2 or CYP2D6 substrate dose in accordance with the approved product information.

HOS-098710 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are no or limited amount of data from the use of givosiran in pregnant women. Studies in animals have shown reproductive toxicity in the presence of maternal toxicity (see section 5.3). The use of this medicinal product could be considered during pregnancy taking into account the expected health benefit for the woman and potential risks to the foetus. Breast-feeding It is unknown whether givosiran/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of givosiran/metabolites in milk (for details see section 5.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Givlaari therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of givosiran on human fertility. No impact on male or female fertility was detected in animal studies (see section 5.3).

HOS-098708 · has-warning-information · PDF-Seite 3

Patients with AHP subtypes other than acute intermittent porphyria (AIP) The efficacy and safety data in patients with AHP subtypes other than AIP (hereditary coproporphyria (HCP), variegate porphyria (VP) and ALA dehydratase-deficient porphyria (ADP)) are limited (see section 5.1). This should be taken into consideration when assessing the individual benefit-risk in these rare AHP subtypes. 3 Anaphylactic reaction In clinical studies, anaphylaxis occurred in one patient who had a history of allergic asthma and atopy (see section 4.8). Signs and symptoms of anaphylaxis should be monitored. If anaphylaxis occurs, administration of this medicinal product should be immediately discontinued, and appropriate medical treatment should be instituted. Transaminase elevations Transaminase elevations have been observed in patients treated with givosiran. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment (see section 4.8). Liver function tests should be performed prior to initiating treatment. These tests should be repeated monthly during the first 6 months of treatment, and as clinically indicated thereafter. Interrupting or discontinuing treatment should be considered for clinically relevant transaminase elevations. In case of subsequent improvement in transaminase levels, resumption of treatment at a 1.25 mg/kg dose after interruption could be considered (see section 4.2). There are limited data on efficacy and safety of the lower dose, particularly in patients who previously experienced transaminase elevations. There are no data on sequentially increasing the 1.25 mg/kg dose to the 2.5 mg/kg dose after dose interruption for transaminase elevations (see section 4.8). Blood homocysteine increased Blood homocysteine levels may be increased in patients with AHP, vitamin deficiencies, or chronic kidney disease. During treatment with givosiran, increases in blood homocysteine levels have been observed compared to levels before treatment (see section 4.8). The clinical relevance of the elevations in blood homocysteine during treatment with givosiran is unknown. However, homocysteine elevations have been previously associated with an increased risk of thromboembolic events. Measurement of blood homocysteine levels prior to initiating treatment and monitoring for changes during treatment with givosiran is recommended. In patients with elevated homocysteine levels

Auszug; vollständigen Abschnitt im Original lesen.