Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Infantile-onset Pompe disease
In clinical trials, 39 infantile-onset patients were treated with Myozyme for more than three years (168 weeks with a median of 121 weeks; see section 5.1). Adverse reactions reported in at least 2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild to moderate in intensity and almost all occurred during the infusion or during the 2 hours following the infusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnoea, periorbital oedema and hypertension have been reported.

Late-onset Pompe disease
In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to 70 years, were treated with Myozyme or placebo randomized in a 2:1 ratio (see section 5.1). Overall, the numbers of patients experiencing adverse reactions and serious adverse reactions were 
comparable between the two groups. The most common adverse reactions observed were IARs.
Slightly more patients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). The majority of these reactions were non-serious, mild to moderate in intensity and resolved spontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adverse reactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throat tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients were IgE-mediated hypersensitivity reactions.

Tabulated list of adverse reactions

Table 1: Adverse reactions (reported in at least 2 patients) and adverse reactions reported in post- marketing setting, expanded access programs and non-controlled clinical trials, per System Organ Class, presented by frequency categories: 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) and not known (cannot be estimated from the available data). Due to the small patient population, an adverse reaction reported in 2 patients is classified as common. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ       Frequency                     Adverse reaction                 Additional adverse Class                                         (Preferred Term Level)                 reactions4 
Infantile-onset          Late-onset       Infantile- and Late-
Pompe disease1         Pompe disease2     onset Pompe disease
Immune system      common                                   Hypersensitivity disorders
Psychiatric        common         Agitation disorders          not known                                                    Agitation Restlessness
Nervous system     common         Tremor                    Dizziness disorders                                                   Paraesthesia Headache3 not known                                                    Tremor
Headache
Somnolence
Syncope
Burning sensation
Eye disorders      not known                                                    Conjunctivitis Cardiac            very           Tachycardia disorders          common common         Cyanosis not known                                                    Cardiac arrest Bradycardia
Tachycardia
Cyanosis
Palpitations
Vascular           very           Flushing disorders          common common         Hypertension              Flushing
Pallor not known                                                    Hypertension Hypotension
Vasoconstriction
Pallor
Respiratory,       very           Tachypnoea thoracic and       common         Cough
mediastinal        common                           Throat tightness disorders          not known                                           Respiratory arrest Apnoea
Respiratory distress
Asthma
Bronchospasm
Wheezing
Pharyngeal oedema
Dyspnoea
Tachypnoea
Throat tightness
Throat irritation
Stridor
Cough
Hypoxia
Gastrointestinal   very        Vomiting disorders          common common      Retching             Diarrhoea
Nausea               Vomiting
Nausea3 not known                                           Abdominal pain
Retching
Dyspepsia
Dysphagia
Skin and           very        Urticaria subcutaneous       common      Rash tissue disorders   common      Erythema             Urticaria
Rash maculopapular   Rash papular
Rash macular         Pruritus
Rash papular         Hyperhidrosis
Pruritus not known                                           Periorbital oedema Livedo reticularis
Lacrimation increased
Rash
Erythema
Hyperhidrosis
Palmar erythema
Transient skin discoloration
Blister
Musculoskeletal    common                           Muscle spasms and connective                                      Muscle twitching tissue disorders                                    Myalgia not known                                           Arthralgia
Renal and          not known                                           Nephrotic syndrome urinary                                                                Proteinuria disorders
General            very        Pyrexia disorders and      common administration     common      Irritability         Pyrexia site conditions                Chills               Chest discomfort
Peripheral oedema
Local swelling
Fatigue3
Feeling hot not known                                                                   Chest pain Face oedema
Feeling hot
Pyrexia
Chills
Chest discomfort
Irritability
Peripheral coldness
Asthenia
Malaise
Feeling cold
Infusion site pain
Infusion site reaction
Infusion site swelling
Infusion site induration
Infusion site extravasation
Infusion site erythema
Infusion site urticaria
Infusion site pruritus
Investigations         very              Oxygen saturation common            decreased common            Heart rate increased            Blood pressure
Blood pressure                  increased increased
Body temperature increased not known                                                                   Oxygen saturation decreased
Heart rate increased
Blood pressure decreased
1
Reactions reported in 39 infantile-onset patients in 2 clinical trials.
2
Reactions reported in 60 late-onset patients in a placebo-controlled clinical trial.
3
Reactions reported more frequently in the placebo group than in the Myozyme group in late-onset patients.
4
Additional adverse reactions from post-marketing, expanded access programs and non-controlled clinical trials.

Description of selected adverse reactions

A small number of patients (<1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures.
Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, oedematous and/or cutaneous in nature (see section 4.4).

Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring post-infusion and lasting usually for a few days, have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully re-challenged with alglucosidase alfa using lower doses and/or pre-treatment with anti- inflammatory drugs and/or corticosteroids and have continued to receive treatment under close clinical supervision.

Patients with moderate to severe or recurrent IARs have been evaluated for alglucosidase alfa specific IgE antibodies; some patients tested positive including some who experienced an anaphylactic reaction.
Nephrotic syndrome as well as severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4).

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