Safety

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Anaphylaxis and Allergic Reactions

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusion. If anaphylactic or severe allergic reactions occur, immediately discontinue the administration of Fabrazyme and initiate necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered. The risks and benefits of re-administering Fabrazyme following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate medical support measures readily available, if the decision is made to re-administer the product.

Infusion Reactions

In clinical trials with Fabrazyme, approximately 50-55% of patients experienced infusion reactions during Fabrazyme administration, some of which were severe. Severe infusion reactions experienced by more than one patient in clinical studies with Fabrazyme included chills, vomiting, hypotension, and paresthesia. Other infusion reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence. Most patients in clinical trials were pretreated with acetaminophen. In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids. Infusion reactions tended to decline in frequency with continued use of Fabrazyme.

However, infusion reactions may still occur despite extended duration of Fabrazyme treatment. If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms. If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated. Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered. Patients who have experienced infusion reactions should be treated with caution when re-administering Fabrazyme.

Compromised Cardiac Function

Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.

ADVERSE REACTIONS

In Clinical Studies

The most serious adverse reactions reported with Fabrazyme treatment during clinical trials were anaphylactic and allergic reactions.

The most common adverse reactions reported with Fabrazyme were infusion reactions some of which were severe. 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 pretreatment 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 nephritic 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 in the table below reflect exposure of 80 patients, ages 16 to 61 years, to 1.0 mg/kg Fabrazyme 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 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 the rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice.

MedDRA System Organ Class   Fabrazyme Placebo
Preferred Term      n=80 (%) n=60 (%)
Cardiac Disorders
Tachycardia    7 (9)     2 (3)
Ventricular wall thickening     4 (5) 1 (2)
Ear and Labyrinth Disorders
Tinnitus          6 (8)   2 (3)
Hypoacusis    4 (5)         0
Gastrointestinal Disorders
Toothache            5 (6)      2 (3)
Dry mouth      3 (4)   0
General Disorders and Administration Site Conditions
Chills                            34 (43)       7 (12)
Pyrexia                     31 (39) 1   3 (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
Localized 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)
Contusion       3 (4)   0
Thermal burn          3 (4)   0
Investigations
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
Psychiatric Disorders
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)
Wheezing       5 (6) 0
Skin and Subcutaneous Tissue Disorders
Rash   16 (20)  6 (10)
Pruritus     8 (10) 2 (3)
Vascular Disorders
Hypertension                   11 (14)     3 (5)
Hot flush         4(5) 0

 

The table enumerates treatment-emergent adverse reactions (regardless of relationship) that occurred during the doubleblind treatment periods of Study 1 and Study 2. Reported adverse reactions have been classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology System Organ Class and Preferred Term.

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 in pediatric Fabry disease patients, ages 8 to 16 years, was found to be consistent with that seen in adults. The safety of Fabrazyme in patients younger than 8 years of age has not been evaluated.

Immunogenicity

Ninety-five of 121 (79%) adult patients and 11 of 16 (69%) pediatric patients (106 of 137, 74% of all patients) treated with Fabrazyme in clinical studies have developed IgG antibodies to Fabrazyme. 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, a phenomenon rarely observed in adult patients. 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 in clinical studies, four (two adult and two pediatric patients) developed IgG antibodies to Fabrazyme.

IgG antibodies to Fabrazyme 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 time points 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 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 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 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-specific IgE antibodies or had a positive skin test to Fabrazyme. Patients who have had a positive skin test to Fabrazyme, or who have tested positive for Fabrazyme-specific IgE antibodies in clinical trials with Fabrazyme have been rechallenged.

Postmarketing Experience

In postmarketing experience with agalsidase beta, severe infusion-related reactions have been reported, some of which were life-threatening, including anaphylaxis. 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, hypoesthesia,oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased, and hypoxia. 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 causal relationship to drug exposure.

Indication and Usage

Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

Important Safety Information

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. In clinical trials and postmarketing safety experience, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids. If severe allergic or anaphylactic reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

  • In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.
  • Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.
  • If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
  • If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.
  • Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated.
  • Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

Re-administration of Fabrazyme to patients who have previously experienced severe or serious allergic reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel and with appropriate medical support measures readily available.

The most common adverse reactions reported are infusion reactions, some of which were severe. Infusion reactions occurred in approximately 50-55% of patients during Fabrazyme administration in clinical trials. Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, fever, 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.

  • Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.
  • Other serious adverse events reported in clinical studies 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.
  • Severe and serious infusion related reactions have been reported in postmarketing experience, some of which were life threatening including anaphylactic shock. In addition to the above adverse reactions, the following have been reported during postmarketing use of Fabrazyme: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased and hypoxia.
  • Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.

The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients.

In clinical trials, a few patients developed IgE or skin test reactivity specific to Fabrazyme. Physicians should consider testing for IgE in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies.

Fabrazyme is available by prescription only. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1‑800‑FDA‑1088. You may also contact Sanofi Genzyme at 1-800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Sanofi Genzyme at 1-800-745-4447.