Adverse Reactions in Clinical Studies
The most serious adverse reactions reported with Fabrazyme (agalsidase beta) treatment during clinical trials were anaphylactic and allergic reactions [see WARNINGS AND PRECAUTIONS].
The most common adverse reactions reported with Fabrazyme (agalsidase beta) are infusion reactions, some of which were severe [see WARNINGS AND PRECAUTIONS]. Serious and/or frequently occurring ( ≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence. The occurrence of somnolence can be attributed to clinical trial specified pre-treatment with antihistamines. Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids.
Other reported serious adverse events included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.
The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg Fabrazyme (agalsidase beta) every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months). All 58 patients enrolled in one of the two studies continued into an open-label extension study of Fabrazyme (agalsidase beta) treatment for up to 54 additional months. Patients were treated with antipyretics and antihistamines prior to the infusions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice.
Table 2 enumerates treatment-emergent adverse reactions (regardless of relationship) that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies]. Reported adverse reactions have been classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology System Organ Class and Preferred Term.
Table 2 : Summary of Adverse Reactions (regardless of relationship) Occurring in Fabrazyme (agalsidase beta) Treated Patients at an Incidence Greater than 2.5% Compared to Placebo Treated Patients
|MedDRA System Organ Class/ Preferred Term||Fabrazyme
|Tachycardia||7 (9)||2 (3)|
|Ventricular wall thickening||4 (5)||1 (2)|
|Ear and Labyrinth Disorders|
|Tinnitus||6 (8)||2 (3)|
|Toothache||5 (6)||2 (3)|
|Dry mouth||3 (4)||0|
|General Disorders and Administration Site Conditions|
|Chills||34 (43)||7 (12)|
|Pyrexia||31 (39)||13 (22)|
|Fatigue||19 (24)||10 (17)|
|Edema peripheral||17 (21)||4 (7)|
|Pain||13 (16)||8 (13)|
|Feeling cold||9 (11)||1 (2)|
|Adverse event||8 (10)||3 (5)|
|Chest discomfort||4 (5)||1 (2)|
|Infections and Infestations|
|Upper respiratory tract infection||35 (44)||18 (30)|
|Lower respiratory tract infection||14 (18)||4 (7)|
|Sinusitis||7 (9)||2 (3)|
|Pharyngitis||5 (6)||1 (2)|
|Fungal infection||4 (5)||0|
|Viral infection||4 (5)||0|
|Localised infection||3 (4)||0|
|Injury, Poisoning and Procedural Complications|
|Procedural pain||20 (25)||12 (20)|
|Post procedural complication||8 (10)||1 (2)|
|Excoriation||7 (9)||1 (2)|
|Fall||5 (6)||2 (3)|
|Thermal burn||3 (4)||0|
|Blood creatinine increased||7 (9)||3 (5)|
|Musculoskeletal and Connective Tissue Disorders|
|Pain in extremity||15 (19)||5 (8)|
|Back pain||13 (16)||6 (10)|
|Myalgia||11 (14)||3 (5)|
|Muscle spasms||4 (5)||1 (2)|
|Nervous System Disorders|
|Headache||31 (39)||17 (28)|
|Paresthesia||25 (31)||11 (18)|
|Dizziness||17 (21)||5 (8)|
|Burning sensation||5 (6)||0|
|Anxiety||5 (6)||2 (3)|
|Depression||5 (6)||1 (2)|
|Respiratory, Thoracic and Mediastinal Disorders|
|Cough||26 (33)||15 (25)|
|Nasal congestion||15 (19)||9 (15)|
|Dyspnea||6 (8)||1 (2)|
|Respiratory tract congestion||6 (8)||1 (2)|
|Skin and Subcutaneous Tissue Disorders|
|Rash||16 (20)||6 (10)|
|Pruritus||8 (10)||2 (3)|
|Hot flush||4 (5)||0|
Observed adverse reactions in the Phase 1/2 study and the open-label treatment period for the extension study following the controlled study were not different in nature or intensity.
The safety profile of Fabrazyme (agalsidase beta) in pediatric Fabry disease patients, ages 8 to 16 years, was found to be consistent with that seen in adults [see Use in Specific Populations and Clinical Studies]. The safety of Fabrazyme (agalsidase beta) in patients younger than 8 years of age has not been evaluated.
Ninety-five of 121 (79%) adult patients and 11 of 16 (69%) pediatric patients (106 of 137, 74% of all patients) treated with Fabrazyme (agalsidase beta) in clinical studies have developed IgG antibodies to Fabrazyme (agalsidase beta) . Most patients who develop IgG antibodies do so within the first 3 months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme (agalsidase beta) , a phenomenon rarely observed in adult patients [see CLINICAL PHARMACOLOGY and Use in Specific Populations]. A possible cause for this prolongation likely pertains to the ability of antibodies to act as “carriers” for their antigens. Among the 14 female patients exposed to Fabrazyme (agalsidase beta) in clinical studies, four (two adult and two pediatric patients) developed IgG antibodies to Fabrazyme (agalsidase beta) .
IgG antibodies to Fabrazyme (agalsidase beta) were purified from 15 patients with high antibody titers ( ≥ 12,800) and studied for inhibition of in vitro enzyme activity. Under the conditions of this assay, most of these 15 patients had inhibition of in vitro enzyme activity ranging between 21-74% at one or more timepoints during the study. Assessment of inhibition of enzyme uptake in cells has not been performed. No general pattern was seen in individual patient reactivity over time. The clinical significance of binding and/or inhibitory antibodies to Fabrazyme (agalsidase beta) is not known. In patients followed in the open-label extension study, reduction of GL-3 in plasma and GL-3 inclusions in superficial skin capillaries was maintained after antibody formation.
As with all therapeutic proteins, there is potential for immunogenicity. The data reflect the percentage of patients whose test results were considered positive for antibodies to Fabrazyme (agalsidase beta) using an ELISA and radioimmunoprecipitation (RIP) assay for antibodies. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Fabrazyme (agalsidase beta) with the incidence of antibodies to other products may be misleading.
Testing for IgE was performed in approximately 60 patients in clinical trials who experienced moderate to severe infusion reactions or in whom mast cell activation was suspected. Seven of these patients tested positive for Fabrazyme (agalsidase beta) -specific IgE antibodies or had a positive skin test to Fabrazyme (agalsidase beta) . Patients who have had a positive skin test to Fabrazyme (agalsidase beta) , or who have tested positive for Fabrazyme (agalsidase beta) -specific IgE antibodies in clinical trials with Fabrazyme have been re-challenged [see Clinical Studies, WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
In postmarketing experience with agalsidase beta, severe infusion-related reactions have been reported, some of which were life-threatening, including anaphylaxis [see WARNINGS AND PRECAUTIONS]. Reactions have included localized angioedema (including auricular swelling, eye swelling, dysphagia, lip swelling, edema, pharyngeal edema, face swelling, and swollen tongue), generalized urticaria, bronchospasm, and hypotension.
In addition to the adverse reactions reported in Adverse Reactions in Clinical Studies, the following adverse reactions have been reported during postmarketing use of agalsidase beta: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, oral hypoesthesia, palpitations, and rhinorrhea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.