Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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) 
Table 1: Adverse reactions
System organ class                               Adverse reaction                         Frequency Anaphylactic reaction                      Uncommon
Immune system disorders
Hypersensitivity                         Common
Nausea                          Very common
Gastrointestinal disorders
Pancreatitis                       Common
Hepatobiliary disorders                           Transaminase elevations                     Very common Skin and subcutaneous tissue
Rasha                          Very common disorders
Renal and urinary disorders                Glomerular filtration rate decreasedb              Very common General disorders and administration               Injection site reactions                   Very common site conditions                                               Fatigue                         Very common Investigations                                 Blood homocysteine increasedc                   Common a
Includes pruritus, eczema, erythema, rash, rash pruritic, urticaria.
b
Includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased eGFR), renal impairment.
c     Includes blood homocysteine abnormal, hyperhomocysteinemia, blood homocysteine increased.


Description of selected adverse reactions

Liver function tests
In the placebo-controlled study, 7 (14.6 %) patients treated with givosiran and one (2.2 %) patient treated with placebo had an increased alanine aminotransferase (ALT) more than 3 times the ULN. In 5 patients treated with givosiran the transaminase elevations resolved with ongoing dosing at 2.5 mg/kg. Per protocol, one patient (with variegate porphyria) with ALT more than 8 times the ULN discontinued treatment and one patient with ALT more than 5 times the ULN interrupted treatment and resumed dosing at 1.25 mg/kg. ALT elevations in both patients resolved.

Injection site reactions
In placebo-controlled and open-label clinical studies, injection site reactions have been reported in 36 % of patients and generally have been mild or moderate in severity, mostly transient and resolved without treatment. The most commonly reported symptoms included erythema, pain, and pruritus.
Injection-site reactions occurred in 7.8 % of injections and did not result in discontinuation of treatment. Three patients (2.7 %) experienced single, transient, recall reactions of erythema at a prior injection site with a subsequent dose administration.

Immunogenicity
In placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9 %), developed treatment emergent anti-drug antibodies (ADA) during treatment with givosiran. ADA titres were low and transient with no evidence of an effect on clinical efficacy, safety, pharmacokinetic or pharmacodynamic profiles of the medicinal product.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/