Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients listed in section 6.1.
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. The majority of patients developed IgG antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmunoprecipitation (RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients).
Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These patients should be treated with caution when re-administering agalsidase beta (see section 4.8). Antibody status should be regularly monitored.
In clinical trials, sixty seven percent (67%) of the patients experienced at least one infusionassociated reaction (see section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids.
As with any intravenous protein medicinal product, allergic-type hypersensitivity reactions are possible.
A small number of patients have experienced reactions suggestive of immediate (Type I) hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low dose and a lower infusion rate (½ the therapeutic dose at 1/25 the initial standard recommended rate). Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.
The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal disease.
No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.
Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to a theoretical risk of inhibition of intra-cellular α-galactosidase A activity.
There are no adequate data from the use of agalsidase beta in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal development (see section 5.3). Fabrazyme should not be used during pregnancy unless clearly necessary.
Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates exposed to agalsidase beta via breast milk, it is recommended to stop breast-feeding when Fabrazyme is used.
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.
Fabrazyme may have a minor influence on the ability to drive or use machines on the day of Fabrazyme administration because dizziness, somnolence, vertigo and syncope may occur (see section 4.8).
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs). Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of patients (see section 4.4).
Very common adverse reactions included chills, pyrexia, feeling cold, nausea, vomiting, headache and paraesthesia. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. Anaphylactoid reactions have been reported in the postmarketing setting.
Adverse reactions reported from clinical trials with a total of 168 patients (154 males and 14 females) treated with Fabrazyme administered at a dose of 1 mg/kg every 2 weeks for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common ≥1/10; common ≥1/100 to <1/10 and uncommon ≥1/1000 to <1/100) in the table below. The occurrence of an adverse reaction in a single patient is defined as uncommon in light of the relatively small number of patients treated. Adverse reactions only reported during the Post Marketing period are also included in the table below at a frequency category of “not known” (cannot be estimated from the available data). Adverse reactions were mostly mild to moderate in severity:
Incidence of adverse reactions with Fabrazyme treatment:
Common: nasopharyngitis
Uncommon: rhinitis
Not known: anaphylactoid reaction
Very common: headache, paraesthesia
Common: dizziness, somnolence, hypoaesthesia, burning sensation, lethargy, syncope
Uncommon: hyperaesthesia, tremor
Common: lacrimation increased
Uncommon: eye pruritus, ocular hyperaemia
Common: tinnitus, vertigo
Uncommon: auricular swelling, ear pain
Common: tachycardia, palpitations, bradycardia
Uncommon: sinus bradycardia
Common: flushing, hypertension, pallor, hypotension, hot flush
Uncommon: peripheral coldness
Common: dyspnoea, nasal congestion, throat tightness, wheezing, cough, dyspnoea exacerbated
Uncommon: bronchospasm, pharyngolaryngeal pain, rhinnorhoea, tachypnoea, upper respiratory tract congestion
Not known: hypoxia
Very common: nausea, vomiting
Common: abdominal pain, abdominal pain upper, abdominal discomfort, stomach discomfort, hypoaesthesia oral, diarrhoea
Uncommon: dyspepsia, dysphagia
Common: pruritus, urticaria, rash, erythema, pruritus generalized, angioneurotic oedema, swelling face, rash maculo-papular
Uncommon: livedo reticularis, rash erythematous, rash pruritic, skin discolouration, skin discomfort
Not known: leukocytoclastic vasculitis
Common: pain in extremity, myalgia, back pain, muscle spasms, arthralgia, muscle tightness, musculoskeletal stiffness
Uncommon: musculoskeletal pain
Very common: chills, pyrexia, feeling cold
Common: fatigue, chest discomfort, feeling hot, oedema peripheral, pain, asthenia, chest pain, face oedema, hyperthermia
Uncommon: feeling hot and cold, influenza-like illness, infusion site pain, infusion site reaction, injection site thrombosis, malaise, oedema
Not known: oxygen saturation decreased
For the purpose of this table, ≥1% is defined as reactions occurring in 2 or more patients.
Adverse reaction terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA).
Infusion associated reactions consisted most often of fever and chills. Additional symptoms included mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort, flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnoea, wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, infusion-related pain including pain at the extremities, myalgia, and headache.
The infusion-associated reactions were managed by a reduction in the infusion rate together with the administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or corticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. The frequency of these reactions decreased over time. The majority of these reactions can be attributed to the formation of IgG antibodies and/or complement activation. In a limited number of patients IgE antibodies were demonstrated (see section 4.4).
Limited information from clinical trials suggests that the safety profile of Fabrazyme treatment in paediatric patients ages 5-7, treated with either 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks is similar to that of patients (above the age of 7) treated at 1.0 mg/kg every 2 weeks.
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 in the same infusion.
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