Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Shire Human Genetic Therapies AB, Vasagatan 7, 111 20, Stockholm, Sweden
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusion related reactions. Four of 17 (23.5%) paediatric patients ≥7 years of age enrolled in clinical trials experienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration of approx. 4 years). Three of 8 (37.5%) paediatric patients <7 years of age experienced at least one infusion related reaction over a mean observation time of 4.2 years. The most common symptoms have been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious infusion reactions have been reported uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria, nausea/vomiting, angioneurotic oedema with throat tightness, stridor and swollen tongue. Other infusion-related symptoms may include dizziness and hyperhidrosis. A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease.
The onset of infusion related reactions has generally occurred within the first 2-4 months after initiation of treatment with Replagal although later onset (after 1 year) has been reported as well. These effects have decreased with time. If mild or moderate acute infusion reactions occur, medical attention must be sought immediately and appropriate actions instituted. The infusion can be temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be restarted. Mild and transient effects may not require medical treatment or discontinuation of the infusion. In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids, from 1 to 24 hours prior to infusion may prevent subsequent reactions in those cases where symptomatic treatment was required.
Hypersensitivity reactions have been reported. If severe hypersensitivity or anaphylactic reactions occur, the administration of Replagal should be discontinued immediately and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed.
As with all protein pharmaceutical products, patients may develop antibodies to the protein. A low titre IgG antibody response has been observed in approximately 24% of the male patients treated with Replagal. Based on limited data this percentage has been found to be lower (7%) in the male paediatric population. These IgG antibodies appeared to develop following approximately 3-12 months of treatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still antibody positive whereas 7% showed evidence for the development of immunologic tolerance, based on the disappearance of IgG antibodies over time. The remaining 76% were antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increase in the incidence of adverse events was detected for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. Borderline IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients.
The presence of extensive renal damage may limit the renal response to enzyme replacement therapy, possibly due to underlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected range of the natural progression of disease.
Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since these substances have the potential to inhibit intra-cellular α-galactosidase activity.
As α-galactosidase A is itself an enzyme, it would be an unlikely candidate for cytochrome P450 mediated drug-drug interactions. In clinical studies, neuropathic pain medicinal products (such as carbamazepine, phenytoin and gabapentin) were administered concurrently to most patients without any evidence of interaction.
There is very limited data on pregnancies exposed to Replagal. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonic/fetal development when exposed during organogenesis (see Section 5.3). Caution should be exercised when prescribing to pregnant women.
It is not known whether Replagal is excreted in human milk. Caution should be exercised when prescribing to breast-feeding women.
No effects on male fertility were seen in reproductive studies in male rats.
Replagal has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions were infusion associated reactions, which occurred in 13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild to moderate in severity.
Table 1 lists adverse reactions reported for the 177 patients treated with Replagal in clinical trials, including 21 patients with history of end stage renal disease, 24 paediatric patients (7 to 17 years of age) and 17 female patients, and from post-marketing spontaneous reports. Information is presented by system organ class and frequency (very common ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1,000 to <1/100). The adverse reactions categorized as incidence “not known (cannot be estimated from the available data)” are derived from post-marketing spontaneous reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The occurrence of an event in a single patient is defined as uncommon in view of the number of patients treated. A single patient could be affected by several adverse reactions.
The following adverse reactions have been identified for agalsidase alfa:
Table 1:
Common: peripheral oedema
Very common: headache
Common: dizziness, dysgeusia, neuropathic pain, tremor, hypersomnia, hypoesthesia, paraesthesia
Uncommon: parosmia
Common: corneal reflex decreased, lacrimation increased
Common: tinnitus, tinnitus aggravated
Common: tachycardia, palpitations
Not known: cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischaemia, heart failure
Very common: flushing
Common: hypertension
Not known: hypotension
Common: cough, hoarseness, throat tightness, dyspnoea, nasopharyngitis, pharyngitis, throat secretion increased, rhinorrhoea
Uncommon: oxygen saturation decreased
Very common: nausea
Common: diarrhoea, vomiting, abdominal pain/discomfort
Common: acne, erythema, pruritus, rash, livedo reticularis
Uncommon: angioneurotic oedema, urticaria
Not known: hyperhidrosis
Common: musculoskeletal discomfort, myalgia, back pain, limb pain, peripheral swelling, arthralgia, joint swelling
Uncommon: sensation of heaviness
Uncommon: anaphylactic reaction, hypersensitivity
Very common: rigors, pyrexia, pain and discomfort, fatigue
Common: fatigue aggravated, feeling hot, feeling cold, asthenia, chest pain, chest tightness, influenza like illness, injection site rash, malaise
See also section 4.4.
Infusion related reactions reported in the postmarketing setting (also see section 4.4) may include cardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving the heart structures. The most common infusion related reactions were mild and include rigors, pyrexia, flushing, headache, nausea, dyspnea, tremor and pruritus. Infusion-related symptoms may also include dizziness, hyperhidrosis, hypotension, cough, vomiting and fatigue. Hypersensitivity, including anaphylaxis, has been reported.
Adverse drug reactions reported in patients with history of end stage renal disease were similar to those reported in the general patient population.
Adverse drug reactions reported in the paediatric population (children and adolescents) were, in general, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea, chest pain) and pain exacerbation occurred more frequently.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
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