FABRY DISEASE: PROGRESSIVE. OFTEN LIFE THREATENING.1-3
Time is of the essence for diagnosing and managing Fabry disease.
FABRY DISEASE IS MULTISYSTEMIC, IMPACTING ESSENTIAL ORGANS SUCH AS THE KIDNEY, HEART, AND BRAIN.4
Fabry disease is a genetic, X-linked disorder that affects men, women, and children. It is classified into 2 main phenotypes, classic and nonclassic, both of which can lead to organ failure and serious complications in adulthood and reduction in life expectancy.4,5
UNDIAGNOSED AND UNMANAGED, FABRY DISEASE CAN REDUCE LIFE EXPECTANCY BY APPROXIMATELY2,3:
PROGRESSIVE ACCUMULATION OF GL-3 AND LYSO-GL-3 IS THE HALLMARK OF FABRY DISEASE.7,8
Fabry disease is caused by pathogenic variants in the galactosidase-alpha (GLA) gene that lead to complete or partial deficiency in α-galactosidase (α-GAL A) enzyme activity.7 This results in progressive accumulation of glycolipids−globotriaosylceramide (GL-3) and globotriaosylsphingosine (Lyso-GL-3)—in lysosomes throughout the body.7,8
Lyso-GL-3, the deacylated form of GL-3 is structurally similar to GL-3. Lyso-GL-3 may correlate with disease severity and organ involvement.
Accumulation of GL-3 and Lyso-GL-3 starts in utero, causing cellular damage that can progress before overt clinical signs, often leading to organ damage and premature death.
The role of lyso-GL-3 as a key factor in disease pathology makes it an important biomarker for monitoring disease progression and can help inform clinical decision making in Fabry disease.8-10
THE HALLMARK OF FABRY DISEASE IS GL-3 ACCUMULATION
Globotriaosylceramide (GL-3) buildup starts in utero and can progress to life-threatening complications.
Progression of Fabry disease can be subclinical for years, even as GL-3 is continually accumulating at the cellular level.11
Over time, this buildup may lead to irreversible damage and life-threatening events such as kidney failure, heart failure, early stroke, or premature death.1
Fabry disease can also cause life-altering symptoms, including GI issues, pain, angiokeratomas, and heat and cold intolerance.5
REGULAR ASSESSMENTS ARE IMPORTANT FOR EVALUATING AND MANAGING FABRY DISEASE.5
It is important to monitor pediatric and adult patients in order to identify early symptoms and manage previously identified symptoms before they progress to life-threatening conditions.5
It is important to identify symptoms that are just starting to emerge.
Previously identified symptoms should be monitored to see if they have gotten worse.
DISEASE-RELATED ASSESSMENTS FOR PATIENTS <18 YEARS OF AGE.10,12-14
The following assessments enable you to evaluate your patients on a regular basis. In addition to monitoring GL-3 and Lyso-GL-3, this guidance considers other important factors that can help you monitor the progression of Fabry disease.10,12-16
These assessments are based on published guidelines and recommendations developed by the Fabry Registry Board of Advisors, a group of physicians who have experience in managing patients with Fabry disease. The Fabry Registry is sponsored by Sanofi.10,12-14
The Recommended Schedule of Assessments represents the core Fabry disease—related assessments that allow evaluation of a patient’s disease progression over time. Physicians will determine the actual frequency of necessary assessments according to a patient’s individualized need for medical care and routine follow-up. Assessments appropriate to individual patients may vary depending upon the clinical judgment of the treating physician, and the patient's need.
*Initiation of Laboratory Tests, Imaging, and Other Studies: There is variability in the clinical complications and progression of Fabry disease. Children are at risk for life-threatening complications. There are no biomarkers available to discern mildly affected from severely affected patients. In children with a family history of early presenting or severe disease, complete evaluations should be done at the time of diagnosis. Other patients should be completely evaluated at no later than 5 years of age.
†Frequency of assessment information is from the Fabry Registry Schedule of Assessments.
aPatients receiving ERT are recommended to undergo these evaluations every 6 months; for those not on ERT or with milder disease, once per year may be sufficient.
bBlood pressure should be measured 3 times at each assessment; only the last 2 measurements should be recorded.
cGFR should be measured directly every 24−36 months until age 15, and annually thereafter. If direct measurement is not possible, serum creatinine levels should be obtained at the recommended intervals for an estimation of GFR, which is a less sensitive method.
dFirst morning voided urine for protein, albumin, and creatinine in order to calculate a protein/creatinine ratio and albumin/creatinine ratio. Protein, albumin, and creatinine measurements can also be performed on timed samples (eg, 24 hours).
eElectrocardiogram should be performed starting at ages 10–12 years. If abnormal and/or clinical symptoms arise, Holter monitoring is recommended.
fEchocardiogram should be performed starting at ages 10–12 years.
gCardiac MRI is recommended to be performed in patients under age 25 if cardiac hypertrophy or significant arrhythmia is present.
hCranial MRIs should be performed at ages 10, 15, and 18 years.
h1At the time of a cerebrovascular event, a cranial MRI should also include diffused, weighted images and apparent diffusion coefficient (DWI/ADC).
iMonitor yearly if retinal vessel tortuosity noted.
jAudiologic evaluation should be performed at the earliest age that is practical.
Monitor pediatric patients with Fabry disease for new or worsening symptoms.
Boys and girls with Fabry disease begin developing symptoms at an early age (median age of 6 years for boys and 9 years for girls).13
DISEASE-RELATED ASSESSMENTS FOR PATIENTS ≥18 YEARS OF AGE.14,15
*Frequency of assessment information is from the Fabry Registry Schedule of Assessments.
aDirectly measuring glomerular filtration rate (GFR) is recommended if a more precise evaluation is desired.
b24 hour or first morning void urine for protein, creatinine, and albumin.
cIf electrocardiogram is abnormal and/or clinical symptoms arise, Holter monitoring is recommended.
dAnnual 24-hour Holter monitoring is recommended for males 30 years of age or older and females 40 years of age or older.
eCardiac MRI is recommended at Fabry diagnosis for patients ages 25 and older. It is recommended to be performed under age 25 if cardiac hypertrophy or significant arrhythmia is present.
e1If first MRI is abnormal: 1) patients with moderate or severe left ventricular hypertrophy (LVH) receiving ERT should have MRI annually; 2) patients with significant arrhythmia should have MRI at least every 2 years or at frequency factoring cardiac disease severity and the physician’s clinical judgment; 3) males with no or mild LVH receiving ERT should have MRI every 2 years.
e2If first MRI is normal, repeat every 5 years or earlier if ECG/ECHO results are abnormal on annual exam.
fIf spirometry is abnormal, perform yearly.
gAt the time of an event, a cranial MRI should also include diffused weighted images and DWI/ADC.
hMonitor yearly if retinal vessel tortuosity noted.
Fabry disease is progressive.
Monitor adult patients regularly, and at time of an event or therapy change.9,12
Adverse events relating to FABRAZYME (agalsidase beta) should be reported to Sanofi Medical Information at 800-745-4447, Option 2.
KNOW WHEN TO TREAT
ENZYME REPLACEMENT THERAPY (ERT) SHOULD BE CONSIDERED IN SYMPTOMATIC PEDIATRIC PATIENTS.16*
Signs and symptoms warranting treatment16
SEE HOW FABRAZYME CAN HELP FEMALES WITH FABRY
Physicians should consider initiating treatment at approximately 8-10 years of age in asymptomatic boys with classic Fabry mutations.16
- In asymptomatic male patients with classic mutations, timing of treatment should be based on individual cases, weighing the risks and benefits
- In asymptomatic female patients and asymptomatic male patients with late-onset mutations, a decision to defer treatment should be based on comprehensive longitudinal monitoring for the development of symptoms; family history should also be considered
*Patients younger than 2 years of age were not included in clinical studies of Fabrazyme. The safety and efficacy of Fabrazyme in patients younger than 2 years of age have not been evaluated.
ERT SHOULD BE CONSIDERED FOR MEN AT TIME OF DIAGNOSIS.15
Classic Fabry mutation (symptomatic or asymptomatic):
- ERT should be considered and is appropriate at any age of presentation†
- Treatment decisions may be influenced by advanced age and severe comorbidity
Nonclassic Fabry mutation or missense GLA VUS*:
- ERT should be considered and is appropriate if there is laboratory, histologic, or imaging evidence of injury to the kidney, heart, or central nervous system, even in the absence of typical Fabry symptoms
- The abnormalities should be attributable to Fabry disease with a histological assessment or biochemical evidence of GL-3 accumulation
- The advice of an expert in genetics and management of Fabry disease should be sought for interpretation of the pathogenicity of any VUS
VUS=variant of unknown significance.
*Nonclassic or missense GLA VUS have the same recommendation for males and females.
†Fabrazyme has not been studied in patients under the age of 2.
While Fabrazyme lowers GL-3 in the capillary endothelium of the kidney, heart, and skin, it has not been shown to affect specific signs and symptoms of Fabry disease.
IMPORTANT SAFETY INFORMATION
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Anaphylaxis and Hypersensitivity Reactions
In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion. Life-threatening anaphylactic and severe hypersensitivity 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, antihistamines, epinephrine, and IV corticosteroids.
- If anaphylactic or severe hypersensitivity reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe hypersensitivity reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
In clinical trials with Fabrazyme, some patients developed IgE antibodies or skin test reactivity specific to Fabrazyme.
- Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-Fabrazyme antibodies and in adult patients with high antibody titer compared to that in antibody negative adult patients.
- Physicians should consider testing for IgE antibodies in patients who experienced suspected hypersensitivity reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies. Rechallenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available.
In clinical trials with Fabrazyme, 59% of patients experienced infusion-associated reactions, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion-associated reactions was higher in patients who were positive for anti-Fabrazyme antibodies than in patients who were negative for anti-Fabrazyme antibodies.
- In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment.
- If an infusion-associated 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-associated 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-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
- Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-associated reactions. Monitor closely patients with compromised cardiac function if Fabrazyme is administered to these patients
- Common adverse reactions reported (≥20% and >2.5% compared to placebo) were upper respiratory tract infection (53% vs 42%), chills (49% vs 13%), pyrexia (39% vs 22%), headache (39% vs 28%), cough (33% vs 25%), paresthesia (31% vs 18%), fatigue (24% vs 17%), peripheral edema (21% vs 7%), dizziness (21% vs 8%), and rash (20% vs 10%).
INDICATION AND USAGE
Fabrazyme® is indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease.
Please see full Prescribing Information for Fabrazyme.
References: 1. Eng CM, Fletcher J, Wilcox WR, et al. J Inherit Metab Dis. 2007;30(2):184-192. 2. MacDermot KD, Holmes A, Miners AH. J Med Gen. 2001;38(11):750-760. 3. MacDermot KD, Holmes A, Miners AH. J Med Gen. 2001;38(11):769-807. 4. Germain DP. Orphanet J Rare Dis. 2010;5:30. 5. Eng CM, Germain DP, Banikazemi M, et al. Genet Med. 2006;8(9):539-548. 6. Waldek S, et al. Genet in Med. 2009;11(11):790-796. 7. Mehta A. Q J Med. 2002;95(10):647-653. 8. Biomarker standards for Fabry disease diagnosis and monitoring. Newsletter for Glyco/Sphingolipid Research. Matreya LLC website. Published June 2017. Accessed June 21, 2018. https://www.matreya.com/files/matreya-newsletter-jun-2017.pdf. 9. Germain DP. Orphanet J Rare Dis. 2010;5:30. 10. Spada M, Kasper D, Pagliardini V, et al. Ital J Pediatr. 2017;43(1):1. 11. Ellaway C. Transl Pediatr. 2016;5(1):37-42. 12. Martins AM, D’Almeida V, Kyosen SO, et al. J Pediatr. 2009;155(4 suppl):S19-S31. 13. Hopkin RJ, Bissler J, Banikazemi M, et al. Pediatr Res. 2008; 64(5):550-555. 14. Fabry Registry. Schedule of Assessments. 15. Ortiz A, Germain DP, Desnick RJ, et al. Mol Genet Metab. 2018;123(4): 416-427. 16. Hopkin RJ, Jefferies JL, Laney DA, et al. Mol Genet Metab. 2016;117(2):104-113.