Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequently occurring adverse reactions reported in Onpattro-treated patients were peripheral oedema (29.7%) and infusion-related reactions (18.9%). One patient (0.7%) discontinued treatment during clinical studies due to an infusion-related reaction.

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 reported for Onpattro 300 micrograms per kg System Organ Class                 Adverse Reaction                         Frequency Infections and infestations                       Bronchitis                            Common Sinusitis                            Common
Rhinitis                             Common
Immune system disorders                    Infusion-related reaction                  Very common Ear and labyrinth disorders                        Vertigo                              Common Respiratory, thoracic and mediastinal
Dyspnoea                               Common disorders
Gastrointestinal disorders                        Dyspepsia                             Common Skin and subcutaneous tissue disorders            Erythema                              Common Musculoskeletal and connective tissue             Arthralgia                            Common disorders                                       Muscle spasms                           Common General disorders and administration site     Peripheral oedema                       Very common conditions                                      Extravasation                          Uncommon 
Description of selected adverse reactions

Infusion-related reactions
Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnoea or cough, dysphonia, chest discomfort or chest pain, headache, rash, pruritus, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension which may include syncope, hypertension, facial oedema.

In clinical studies, all patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers to reduce the risk of IRRs. In the double-blind placebo-controlled study, 18.9% of Onpattro-treated patients experienced IRRs, compared to 9.1% of placebo-treated patients. In Onpattro-treated patients, all IRRs were either mild (95.2%) or moderate (4.8%) in severity. Among Onpattro-treated patients who experienced an IRR, 78.6% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. Few IRRs led to infusion interruption. IRRs resulted in permanent discontinuation of Onpattro in < 1% of patients in clinical studies. For clinical management of IRRs, see section 4.4.

Peripheral oedema
In the placebo-controlled study, peripheral oedema was reported in 29.7% of Onpattro-treated patients and 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead to treatment discontinuation. In Onpattro-treated patients, the events decreased in frequency over time.

Extravasation
Extravasation was observed in < 0.5% of infusions in clinical studies. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

Other special population(s)

Liver transplant recipients
In an open-label study in 23 hATTR amyloidosis patients with polyneuropathy progression post liver transplant, the safety profile of patisiran was consistent with previous clinical studies (see section 5.1).


Immunogenicity

Anti-drug antibodies to Onpattro were evaluated by measuring antibodies specific to PEG2000-C-DMG, a lipid component exposed on the surface of Onpattro. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with Onpattro. One additional patient had pre-existing anti-drug antibodies. Anti- drug antibody titres were low and transient with no evidence of an effect on clinical efficacy, the safety profile, or the pharmacokinetic or pharmacodynamic profiles of Onpattro.

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/