Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally in connection with intravenous administration of human immunoglobulin.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions (including cutaneous lupus erythematosus – frequency unknown) have been observed with human normal immunoglobulin.

Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB in immunomodulatory treatment. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see section 4.4).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Transfusion related acute lung injury (TRALI) and thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses.

Tabulated list of adverse reactions
Seven clinical studies were performed with Privigen, which included patients with PID, ITP and CIDP. In the pivotal PID study, 80 patients were enrolled and treated with Privigen. Of these, 72 completed the 12 months of treatment. In the PID extension study, 55 patients were enrolled and treated with Privigen. Another clinical study included 11 PID patients in Japan. Two ITP studies were performed with 57 patients each. Two CIDP studies were performed with 28 and 207 patients, respectively.

Most adverse drug reactions (ADRs) observed in the seven clinical studies were mild to moderate in nature.

The following table shows an overview of the ADRs observed in the seven clinical studies, categorized according the MedDRA System Organ Class (SOC), Preferred Term Level (PT) and frequency.
Frequencies were evaluated according to the following conventions: 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). For spontaneous post-marketing ADRs, the reporting frequency is categorized as unknown.
Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.


MedDRA System        Adverse Reaction                                 Frequency per          Frequency per Organ Class                                                           patient                infusion (SOC)
Infections and       Aseptic meningitis                               Uncommon               Rare infestations

Blood and lymphatic Anaemia, haemolysis (including haemolytic         Common                 Uncommon system disorders    anaemia) β, leukopenia


Anisocytosis (including microcytosis)            Uncommon               Uncommon 

Thrombocytosis                                                          Rare 

Decreased neutrophil count                       Unknown                Unknown 

Immune system        Hypersensitivity                                 Common                 Uncommon disorders
Anaphylactic shock                               Unknown                Unknown Nervous system       Headache (including sinus headache, migraine,    Very common            Very common disorders            head discomfort, tension headache)

Dizziness (including vertigo)                    Common                 Uncommon 

Somnolence                                       Uncommon               Uncommon 

Tremor                                                                  Rare Cardiac disorders     Palpitations, tachycardia                      Uncommon         Rare Vascular disorders    Hypertension, flushing (including hot flush,   Common           Uncommon hyperaemia)

Hypotension                                                     Rare

Thromboembolic events, vasculitis (including   Uncommon         Rare peripheral vascular disorder)

Transfusion related acute lung injury          Unknown          Unknown 
Respiratory,          Dyspnoea (including chest pain, chest          Common           Uncommon thoracic              discomfort, painful respiration) and mediastinal disorders

Gastrointestinal      Nausea, vomiting, diarrhoea                    Common           Common disorders



Abdominal pain                                                  Uncommon 


Hepatobiliary         Hyperbilirubinaemia                            Common           Rare disorders

Skin and            Skin disorder (including rash, pruritus, urticaria, Common        Common subcutaneous        maculo-papular rash, erythema, skin tissue disorders    exfoliation)
Musculoskeletal and Myalgia (including muscle spasms,                   Common        Uncommon connective tissue   musculoskeletal stiffness, musculoskeletal pain) disorders


Renal and urinary     Proteinuria, increased blood creatinine        Uncommon         Rare disorders

Acute renal failure                            Unknown          Unknown 

General disorders     Pain (including back pain, pain in extremity,     Very common   Common and                   arthralgia, neck pain, facial pain) pyrexia administration site   (including chills), influenza-like illness conditions            (including nasopharyngitis, pharyngolaryngeal pain, oropharyngeal blistering, throat tightness)
Fatigue                                                 Common
Common

Asthenia (including muscular weakness)                                            Uncommon 

Injection site pain (including infusion site      Uncommon                        Rare discomfort)
Investigations       Decreased haemoglobin (including decreased        Common                          Uncommon red blood cell count, decreased haematocrit),
Coombs' (direct) test positive, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood lactate dehydrogenase
β
The frequency is calculated based on studies completed prior to implementation of the Immunoaffinity Chromatography isoagglutinin reduction step (IAC) into Privigen production. In a Post-Authorization Safety Study PASS : Privige Use a d Hae olytic A ae ia in Adults and Children and the Privigen Safety Profile in Children with CIDP – An Observational Hospital-Based Cohort Study i the US , assessing data of 7,759 patients who received Privigen identifying 4 haemolytic anaemia cases after IAC versus 9,439 patients who received Privigen identifying 47 haemolytic anaemia cases prior to IAC (baseline), an 89% statistically significant reduction in the overall rate of probable haemolytic anaemia was demonstrated based on an incidence rate ratio of 0.11 adjusted for in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use (one-sided p-value <0.01). Probable cases of haemolytic anaemia were defined by an International Classification of Disease (ICD)-9 or ICD-10 hospital discharge code specific for haemolytic anaemia. Possible cases of haemolytic anaemia consisted of an unspecified transfusion reaction identified via ICD-9 or ICD-10 discharge codes or via review of hospital charge descriptions in temporal association with a haptoglobin, a direct antiglobulin test or indirect antiglobulin performed in the workup of haemolytic anaemia.

For safety with respect to transmissible agents and additional details on risk factors, see section         4.4.

Paediatric Population
In Privigen clinical studies with paediatric patients, the frequency, nature and severity of adverse reactions did not differ between children and adults. In post marketing reports it is observed that the proportion of haemolysis cases to all case reports occurring in children is slightly higher than in adults. Please refer to section 4.4 for details on risk factors and monitoring recommendations.

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 and emailed to the Registration Holder’s Patient Safety Unit at: PV-IL@cslbehring.com