Neurologists

Neurological symptoms in Fabry disease are common1-3 and, like many manifestations of Fabry disease, progressive.

In childhood, neurological manifestations may include neuropathic pain, hypohidrosis or anhidrosis, and intolerance to heat and cold. As the disease progresses, vertigo, diplopia, and hemiparesis may develop.1

In adulthood, signs and symptoms may include brainstem dysfunction, progressive cerebral vasculopathy, large and small vessel vascular disease, dolichoectasia, premature stroke, progressive white matter lesions, and/or altered cerebral blood flow.1

Fabry disease should be included in the differential diagnosis in younger patients who present with stroke.4,5


White matter lesions on MRI, demonstrating evidence of cerebrovascular infarct.

Numerous studies have confirmed the diverse neurological manifestations of Fabry disease:

  • A descriptive meta-analysis of 53 Fabry disease patients showed that cerebrovascular symptoms in both males and females are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur and indicate a poor prognosis, with a recurrence rate of 76% for males and 86% for females.1
  • A screening of 721 stroke patients (432 males, 289 females) ages 18-55 showed that 21 males (4.9%) and 7 females (2.4%) had a biologically significant alpha-GAL mutation, corresponding to an incidence of 1.2% in all young stroke patients.4
  • A quantitative analysis of cerebral vasculopathy in 50 Fabry patients ages 6 to 63 found that the youngest patient with detectable cerebral lesions was aged 27, the mean age was 43, and all patients over 54 had cerebrovascular involvement.2
  • Another analysis found that 27% of 165 females and 12% of 201 males with Fabry disease experienced stroke, TIA or prolonged reversible ischemic neurologic defect.3
  • A review of 14 females and 13 males with Fabry disease found white matter lesions in 36% of females and 31% of males, at comparable levels of severity.6

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.

Since Fabry disease is progressive, early diagnosis is important. If you suspect Fabry disease in a patient, a geneticist can help provide a definitive diagnosis. Learn more about Diagnosing Fabry Disease.

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.

References

  1. Mitsias P, Levine SR. Cerebrovascular Complications of Fabry disease. Ann Neurol 1996:40;8-17.
  2. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998; 50:1746-9.
  3. Mehta A, Ricci R, Widener U, et al. Fabry disease defined: Baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Euro J Clin Invest 2004:34;236-242.
  4. Rolfs A, Bottcher T, Zschiesche M, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005:366;1794-96.
  5. Fellgiebel A, Muller MJ. CNS manifestations of Fabry’s disease. Lancet Neuro 2006:5;791-95.
  6. Fellgiebel A, Muller MJ, Mazanek M, et al. White matter lesion severity in male and female patients with Fabry disease. Neurology 2005;65:600-602.