Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions (Ars) of HyQvia were local reactions. The most frequently reported systemic Ars were headache, fatigue, and pyrexia. The majority of these Ars were mild to moderate.

IG 10%

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

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.

Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash, may frequently occur.

Cases of transient aseptic meningitis, transient haemolytic reactions, increase in serum creatinine level and/or acute renal failure have been observed with human normal immunoglobulin, see section 4.4.

Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis have been rarely observed with IVIg and SCIg products.
 rHuPH20

The most frequent adverse reactions reported during post-marketing use of rHuPH20 in similar formulations administered subcutaneously for the dispersion and absorption of subcutaneously administered fluids or medicinal products have been mild local infusion site reactions such as erythema and pain. Oedema has been reported most frequently in association with large volume subcutaneous fluid administration.

Antibodies against rHuPH20

A total of 13 out of 83 subjects who participated in pivotal PID study developed an antibody capable of binding to rHuPH20 at least once during the clinical study. These antibodies were not capable of neutralizing rHuPH20. No temporal association between adverse reactions and the presence of anti- rHuPH20 antibodies could be demonstrated. There was no increase in incidence or severity of adverse reactions in patients who developed antibodies to rHuPH20.
Tabulated list of adverse reactions

The safety of HyQvia was evaluated in 4 clinical studies (160602, 160603, 160902, and 161101) in 124 unique patients with PID receiving 3,202 infusions.

The table presented below is according to the MedDRA System Organ Classification (SOC and Preferred Term Level).

Frequencies per infusion have been evaluated using the following convention: 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), not known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequency of Adverse Reactions (ADRs) with HyQvia
MedDRA              Very common             Common                Uncommon                          Rare System Organ
Class (SOC)
Gastrointestinal                            Vomiting, nausea,
disorders                                   abdominal pain           Abdominal distension (including abdominal upper and lower pain and tenderness), diarrhoea


General            Local reactions          Local reactions (total):    Local reactions           Burning disorders and      (total) a:               Infusion site erythema,     (total):                  sensation administration     Infusion site pain       infusion site swelling      Infusion site site conditions    (including               (including local swelling   discoloration, infusion discomfort,              and oedema), infusion       site bruising tenderness, groin        site pruritus (including    (including hematoma, pain)                    vulvovaginal pruritus)      haemorrhage),
infusion site mass
Pyrexia, asthenic           (including nodule),
conditions (including       infusion site warmth,
asthenia, fatigue,          infusion site lethargy, malaise)          induration,
gravitational oedema/genital swellingb (including genital oedema,
scrotal and,
vulvovaginal swelling)

Oedema (including peripheral, swelling),
chills, hyperhidrosis

Investigations                                                          Direct Coombs’ test positive

Musculoskeletal                             Myalgia,                    Arthralgia, back pain, and connective                              musculoskeletal chest       pain in extremity tissue disorders                            pain

Nervous system                              Headache                    Migraine                  Paresthesia disorders                                                               dizziness 
Skin and                                                                Erythema, rash subcutaneous                                                            (including tissue disorders                                                        erythematous, papular,
maculo-papular),
pruritus, urticaria
Vascular                                                               Hypertension, blood disorders                                                              pressure increase Renal and                                                                                         Hemosiderinuria urinary disorders a
The following ADRs are not listed but also calculated in the frequency for Local reactions: feeling hot, infusion site paresthesia.
b
Gravitational oedema/genital swellin was observed subsequent to lower abdominal quadrants administration.
In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience (frequency of these reactions is not known (cannot be estimated from the available data)):
Infections and infestations: Meningitis aseptic
Immune system disorders: Hypersensitivity
General disorders and administration site conditions: Influenza-like illness, infusion site leakage 
In addition to the adverse reactions listed above, the following additional adverse reactions have been reported for subcutaneously administered immunoglobulin products:
Anaphylactic shock, anaphylactic/anaphylactoid reaction, tremor, tachycardia, hypotension, flushing, pallor, peripheral coldness, dyspnoea , paraesthesia oral, swelling face, dermatitis allergic, musculoskeletal stiffness, injection site urticaria, injection site rash, alanine aminotransferase increased.

Description of selected adverse reactions

Local reactions observed during the pivotal clinical study include mild swelling of the site (present in most infusions) due to the large volumes infused, but in general were not considered an adverse reaction unless they caused discomfort. Only two instances of local adverse reactions were severe, infusion site pain and infusion site swelling. There were two instances of transient genital oedema, one considered severe, that resulted from diffusion of the medicinal product from the infusion site in the abdomen. No skin changes were observed that did not resolve during the clinical study.

Paediatric population

In the pivotal study 160603 there were 2 of the 24 paediatric patients with total anti-rHuPH20 antibody levels at or above 1:160. None had neutralising antibodies.

A prospective, Phase 4, multicentre study in Europe evaluated 42 paediatric subjects (age 2 to <18 years) who had received prior immunoglobulin therapy (Study 161504). No new safety concerns were identified. No subject was positive (titre ≥160) for binding antirHuPH20 antibodies. HyQvia was found to be safe and tolerable among paediatric subjects (2 to <18 years old) with PIDD.

Results of clinical studies indicate similar safety profiles in adults and paediatric population, including the nature, frequency, seriousness and reversibility of adverse reactions.

Elderly Patients

Primary Immunodeficiency
Post-authorisation safety studies (EU 161302, US 161406) included 15 and 77 elderly subjects, respectively. Overall, no significant safety differences were observed between PID subjects above 65 years and those between 18 and 65 years old.

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