Fabrazyme Billing Guide

Transcription

A Guide to Fabrazyme® (agalsidase beta)
Billing and Reimbursement
The material contained in this guide is provided for information purposes only. Many of the topics covered
in this guide are complex and all are subject to change. Healthcare delivery professionals are responsible for
complying with reimbursement related rules and regulations. Providers are also responsible for the accuracy
of any claims, invoices, and related documentation submitted to payers.
Indications 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 wtth 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.
Questions? Contact a Genzyme Case Manager at 1-800-745-4447, option 3.
www.Fabrazyme.com
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 antiFabrazyme IgE antibodies.
Fabrazyme is available by prescription only. Side effects should be reported promptly to
Genzyme Medical Information at 800-745-4447, option 2.
To learn more, please see the full Prescribing Information or contact Genzyme at
1-800-745-4447.
Please see Full Prescribing Information (Appendix E)
and Important Safety Information on Page 1
TABLE OF CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Fabrazyme® (agalsidase beta) Support Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Genzyme Case Managers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Reimbursement Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Support for your Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Genzyme Co-Pay Assistance Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Product Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Updates to this Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Fabrazyme Coverage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Private Payers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Medicare Part B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Medicare Part C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Medicare Part D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Medicaid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Medicaid Managed Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Fabrazyme Reimbursement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Private Payers, Medicare/Medicaid Managed Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Medicare Part B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Medicaid Fee for Service . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Fabrazyme Billing Codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Coding Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Appendix A Sample Letter of Intent to Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Appendix B Sample Statement of Medical Necessity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Appendix C Sample UB 04 Claim Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Appendix D Sample CMS1500 (02-12) Claim Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Appendix E Full Prescribing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
www.Fabrazyme.com
INTRODUCTION
Fabry disease is a rare, inherited lysosomal storage disorder caused by an enzyme deficiency.
Deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-GAL) leads to progressive
accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), in many
body tissues, occurring over a period of years or decades. Clinical manifestations of Fabry
disease include renal failure, cardiomyopathy, and cerebrovascular accidents.
Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme
reduces GL-3 deposition in the 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.
Please see the enclosed full prescribing information in Appendix E.
Genzyme is committed to working with providers, as well as public and private payers, to
help ensure access to treatment for patients who would medically benefit from Fabrazyme.
This guide is designed to help you understand coverage, coding and reimbursement for
Fabrazyme. Providers retain responsibility for determining reimbursement and insurance issues
related to their patients. Genzyme cannot be responsible for failure of a provider to obtain
reimbursement.
If you still have questions after reviewing this guide, please contact a Genzyme Case Manager
at 1-800-745-4447, option 3, Monday-Friday 8:00am-6:00pm ET. Genzyme Case Managers are
healthcare professionals with expertise in reimbursement, insurance, case management, and
the healthcare delivery system, and can help guide physicians and their patients through the
reimbursement process.
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FABRAZYME® (agalsidase beta) SUPPORT SERVICES
Genzyme Case Managers
Genzyme assigns individual Case Managers who provide free and confidential care
coordination, support, and services to both patients living with Fabry disease and their
healthcare providers. Our Case Managers have over 20 years of expertise in insurance coverage,
reimbursement, and billing issues for enzyme replacement therapies. Genzyme Case Managers
can provide assistance to physicians and their staff to help coordinate access to treatment with
Fabrazyme.
Reimbursement Support
With experience navigating the billing and reimbursement process for Fabrazyme under many
types of insurers and plans, Genzyme Case Managers can provide healthcare professionals with
a variety of services, simplifying the reimbursement process for you and your staff:
• Insurance consultations to review, understand, and verify a patient’s coverage for treatment
• Information on billing to support physicians and office staff
• Assistance in obtaining prior authorizations and through the entire coverage approval process
• Assistance in preparing correspondence to third-party payers
• Helping educate insurance companies on Fabry disease
• Assistance with billing and claims issues, including appeal process if coverage is denied
A Genzyme Case Manager is only a phone call away from providing personalized assistance to
you, your staff and your patients.
1-800-745-4447, Option 3
Monday - Friday, 8:00AM to 6:00PM ET
www.GenzymeSupportServices.com
Information you or your patients provide will always be kept confidential. Genzyme offers all
services in compliance with patient privacy regulations (HIPAA).
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www.Fabrazyme.com
Support for your Patients
By working with a Genzyme Case Manager, your patients will receive comprehensive case
management and one-on-one support personalized to their individual needs.
• Information about treatment with Fabrazyme® (agalsidase beta) and related insurance coverage
• Educational materials about Fabry disease
• Access to other Genzyme resources, including field-based support for you and your staff
• Help for insured, underinsured, and uninsured patients with identifying new coverage or alternative funding resources
• Coordination and exchange of information between patients, their healthcare providers, insurers, and others in accordance with HIPAA regulations.
Genzyme Co-Pay Assistance Program
The Genzyme Co-Pay Assistance Program will help eligible patients who are prescribed
treatment with Fabrazyme with their drug related out-of-pocket expenses, including co-pays,
co-insurance, and deductibles.
Please have your patients call their Genzyme Case Manager or visit www.genzyme.com/fzcopay
for more information about the Genzyme Co-Pay Assistance Program, including current
eligibility criteria, program benefit and application process.
Genzyme reserves the right to make eligibility determinations, to set program benefit
maximums, to monitor participation, and to modify or discontinue the program at any time.
Product Information
To learn more about Fabrazyme, please vist www.fabrazyme.com and please see enclosed full
prescribing information in Appendix E.
Updates to this Guide
This guide is reviewed and updated periodically, generally on a yearly basis. As reimbursement
information is subject to continuing changes, please contact a Genzyme Case Manager for the
most up-to-date information.
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FABRAZYME® (agalsidase beta) COVERAGE
Private Payers
Fabrazyme treatment is covered by many private payers; however, individual patients’ insurance
benefits will vary. A patient’s insurance coverage should be understood before treatment is
initiated so that problems obtaining reimbursement may be minimized. Important points
related to private payers include:
•Managed care plans may require a referral from the patient’s primary care provider (PCP)
to a specialist.
Private payers may require the following:
•Prior authorization to establish medical necessity for Fabrazyme® (agalsidase beta).
•Periodic reauthorization or recertification for continued treatment.
•Letter of Intent to Treat. See the example in Appendix A, page 9
•Statement of Medical Necessity. See the example in Appendix B, page 10
Note
• If the patient’s private insurer denies coverage, an appeal process may be initiated.
Genzyme Case Managers are available to assist patients and their physicians in this
process.
Medicare Part B
Medicare Part B coverage is determined by the local Medicare Part B carrier. Medicare will
not prior authorize, so the patient’s coverage policy should be understood before treatment is
initiated. Treatment with Fabrazyme will need to be considered medically necessary in order to
be covered under the Medicare program. Fabrazyme is generally covered by Medicare Part B
when it is administered and billed as incident to a physician’s services. This means that in order
for it to be reimbursed, Fabrazyme and all associated supplies and services must be purchased
by the physician or hospital.
Note
• Confirm the patient’s eligibility under Medicare Part B prior to ordering Fabrazyme.
•M
edicare Part B will not cover Fabrazyme prescriptions dispensed by retail
pharmacies.
Medicare Managed Care (Medicare Part C)
In general, Medicare Managed Care plans work like commercial managed care plans and
may require prior authorization. While different plans have different guidelines, Medicare
Managed Care plans are required by Medicare to provide, at a minimum, the same level of
benefits available under the traditional fee for service Medicare program. Therefore, if the
local Medicare B carrier covers Fabrazyme, the Medicare Managed Care Plan must also cover
Fabrazyme, although prior authorization and other medical management approaches may be
required by the managed care plan.
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Medicare Part D Prescription Drug Coverage
Fabrazyme® (agalsidase beta) may be on formulary under the patient’s medicare Prescription
Drug Plan (PDP) or Medicare Advantage Prescription Drug (MA-PD). The patient’s outof-pocket (OOP) costs will vary depending upon plan coverage. Due to the complexity and
variability of Medicare Part D prescription drug coverage, contact the PDP, MA-PD or contact a
Genzyme Case Manager for further information.
Note
• Medicare Part D reimburses the PDP or MA-PD pharmacy for drug.
Medicaid
Medicaid eligibility and benefit plans vary from state-to-state, so the program’s coverage policy
should be understood before treatment is initiated. Usually, treatment with Fabrazyme will
need to be considered medically necessary in order to be covered under the Medicaid program.
Depending on the state, initial treatment with Fabrazyme may require prior approval by the
state Medicaid program. For information on Medicaid coverage for Fabrazyme in your state,
contact your local Medicaid office or a Genzyme Case Manager.
Medicaid agencies may require the following:
•Prior authorization to establish medical necessity for Fabrazyme.
•Periodic reauthorization or recertification for continued treatment.
•Letter of Intent to Treat. See the example in Appendix A, page 9.
•Statement of Medical Necessity. See the example in Appendix B, page 10.
Note
• Medicaid regularly updates patient eligibility. Therefore, prior to each patient
encounter, physicians should verify eligibility and coverage.
• If Medicaid denies coverage, an appeal process may be initiated. Genzyme Case
Managers are available to assist patients and their physicians with this process.
Medicaid Managed Care
Many states require Medicaid patients to be enrolled in Medicaid Managed Care plans. These
plans vary considerably from state-to-state, and have different documentation and coverage
requirements. For example, referrals for treatment with Fabrazyme may need to be in place
in order for the patient to receive treatment by anyone other than the patient’s primary care
provider. For information on Medicaid coverage for Fabrazyme in your state, contact the
Medicaid Managed Care plan or a Genzyme Case Manager.
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FABRAZYME® (agalsidase beta) REIMBURSEMENT
Obtaining reimbursement for Fabrazyme varies by payer and setting.
Private Payers, Medicare Managed Care and Medicaid Managed Care
Physician Office
•Reimbursement for office-administered drugs is often based on Average Wholesale Price
(AWP) or Average Sales Price (ASP).
•Reimbursement for services varies, depending on the negotiated rate between the provider
and insurance company or the insurance company’s fee schedule.
Hospital Outpatient
•Reimbursement varies, depending on the negotiated rate between the hospital and
insurance company or the insurance company’s fee schedule.
Medicare Part B
Physician Office
•The Medicare allowable amount for Fabrazyme is Average Sales Price (ASP) plus 6%. Rates
are updated quarterly.
•Medicare covers 80% of the allowable amount, and the beneficiary or their supplemental
policy is responsible for the remaining 20%.
•Reimbursement for physician services is based upon the Medicare Physician Fee Schedule
(MPFS).
Hospital Outpatient
•The Medicare allowable amount for Fabrazyme® (agalsidase beta) is Average Sales Price
(ASP) plus 6%. Rates are updated quarterly.
•Medicare covers 80% of the allowable amount, and the beneficiary or their supplemental
policy is responsible for the remaining 20% balance; however, in this site of service, the
patient’s 20% coinsurance liability is limited to the current year’s Part A deductible dollar
amount [Section 1833(t)(8)(C) of the Social Security Act].
- Medicare pays 80% of the allowable amount plus any additional amount remaining
on the beneficiary’s 20% coinsurance when the limitation on the coinsurance
applies [Section 1833(t)(4)(C)].
•Reimbursement for services is based upon the Ambulatory Payment Classification (APC).
Medicaid Fee-For-Service
Physician Office and Hospital Outpatient Setting
•Reimbursement varies from state-to-state.
• For more information, contact your local Medicaid office.
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FABRAZYME® (agalsidase beta) BILLING CODES
Providers are responsible for the selection of appropriate codes. Information in the table below
provides a general framework for understanding possible coding alternatives. It should not
be used as a substitute for a healthcare professional’s own judgment. Any specific guidance or
direction regarding claims submission offered by the payer supersedes the information in this
guide.

ICD-9-CM
272.7 – Lipidosis (Fabry disease)
ICD-10-CM*
E75.21 Fabry (Anderson) disease
NDC
58468-0040-1 – 35 mg vial
58468-0041-1 – 5 mg vial
HCPCS
J0180 – Fabrazyme – injection agalsidase beta, 1 mg
CPT
96365 – Intravenous infusion therapy prophylaxis, or diagnosis (specify
substance or drug); initial, up to 1 hour
96366 – E
ach additional hour. (List separately in addition to primary
procedure code, 96365)
Revenue
260
261
258
636
–
–
–
–
General IV therapy service
Infusion pump
IV solutions
Drugs and biologicals requiring a HCPCS code
*For dates of service starting on October 1, 2014.
Note
•Since third party payers evaluate treatment based on medical necessity, expected
outcome, and cost, they generally require documentation of diagnosis and clinical
symptoms of Fabry disease. Refer to the Statement of Medical Necessity sample in
the back of this guide (Appendix B). This information may need to be submitted with
the claim; for specific requirements check with the payer or contact a Genzyme Case
Manager.
•To help avoid potential problems obtaining reimbursement, the treating physician
should request written confirmation of coverage from the third party payer prior to
initiation of enzyme replacement therapy. A Genzyme Case Manager can assist in
obtaining written authorization for Fabrazyme treatment.
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CODING GLOSSARY OF TERMS
ICD-9-CM (International Classification of Diseases, 9th Edition)
ICD-9-CM codes represent the patient’s medical condition or reason for treatment (diagnosis
code). These codes are used by hospitals and physicians, and are recognized by all insurers.
ICD-10-CM (The International Classification of Diseases, Tenth Revision, Clinical Modification)
ICD-10-CM is a revision to the ICD-9-CM system to classify and code all diagnoses. These codes
are used by hospitals and physicians, and are recognized by all insurers. Official use of the ICD10-CM system in the U.S. will start on October 1, 2014.
NDC (National Drug Code)
NDCs are codes that identify FDA-approved drugs. The NDC identifies the manufacturer,
product, and package size. NDCs are used primarily by retail pharmacies.
HCPCS (Healthcare Common Procedure Coding System)
HCPCS codes are assigned by CMS (Center for Medicare and Medicaid Services) and are used
by Medicare and most private payers to describe products administered in the physician office
or hospital setting.
CPT (Current Procedural Terminology)
CPT codes are used by physicians and hospitals to designate the procedures performed.
Revenue Codes
Revenue codes are used by hospitals to classify services by category, and typically are required by
payers when billing infusions in the hospital setting.
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Appendix A
Sample Letter of Intent to Treat
[Date]
[Contact Name]
[Insurance Company]
[Street Address]
[City], [State] [Zip]
Patient Name:
Subscriber ID#:
Group#:
[Patient Name]
[ID Number]
[Group Number]
Subject: Intent to Treat with Fabrazyme® (agalsidase beta)
Dear [Contact Name]:
[Patient Name] [Patient ID Number] has been diagnosed with Fabry disease and I plan to treat [him/her] with Fabrazyme® (agalsidase beta), an
enzyme replacement therapy. Fabrazyme is indicated for use in patients with Fabry disease. Fabrazyme reduces GL-3 deposition from the capillary
endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression
of Fabry disease; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.
Fabrazyme is administered intravenously and is typically administered on an outpatient basis. Prior to the availability of Fabrazyme, treatment for
Fabry disease was directed only at managing the patient’s symptoms and ameliorating the life threatening complications. Fabrazyme is the first and
only FDA-approved therapy for the treatment of this life-threatening, orphan disease.
Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme a-galactosidase A leads to
progressive accumulation of glycosphingolipids, predominantly GL-3, in many body tissues, starting early in life and continuing over decades. Clinical manifestations of Fabry disease include renal failure, cardiomyopathy, and cerebrovascular accidents. Accumulation of GL-3 in renal
endothelial cells may play a role in renal failure.
Produced by recombinant DNA technology, Fabrazyme has the same amino acid sequence as the native enzyme. Fabrazyme replaces the missing
enzyme and works by clearing the fatty substances that accumulate in certain cells and tissues of Fabry patients.
To this end, I feel it is medically necessary to initiate Fabrazyme treatment for [Patient Name] as soon as possible.
Documentation Enclosed
The attached Statement of Medical Necessity contains information pertaining to [Patient Name]’s clinical history, diagnosis and signs and symptoms
- demonstrating that the use of Fabrazyme is medically indicated and necessary for treatment of [his/her] Fabry disease. Initially, my prescribed
dosing regimen will be [Dose] mg per kilogram, administered every two weeks.
Action Requested
Please send verification of [Patient Name]’s coverage for enzyme replacement therapy with Fabrazyme as soon as possible. If you have any
questions pertaining to [Patient Name]’s clinical history and/or my treatment plan, please call me at [Phone Number].
Thank you for your immediate attention to this request.
Sincerely,
[Physician Name]
Enclosure
cc [Patient Name]
This is only a model letter and should be customized to address patients’ specific issues.
Call a Genzyme Case Manager to request a sample Letter of Intent to Treat.
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Appendix B
Sample Statement of Medical Necessity
STATEMENT OF MEDICAL NECESSITY
FOR THE TREATMENT OF FABRY DISEASE
Patient
Information
Patient’s Name _________________________
Date of Birth ___________________________
Gender:
Male
Female
Social Security No._______________________
Insurance
Information
Insurance Co____________________________ Policyholder’s Name___________________________
Policy Number___________________________ Group Number_______________________________
Address_____________________________
City ____________________ State_______
Phone No. (Home)_____________________
Phone No. (Work) ____________________
Insurance Phone ______________________
Medical
Assessment
________________
___________
___________
___________
Diagnosis
Patient Weight ___________________(kg / lbs)
Patient Height ________________________(cm / in)
Please list signs and symptoms consistent with Fabry disease:
__________________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
□ Fabry Disease (Lipidosis) ICD-9-CM 272.2
□ Fabry (Anderson) Disease ICD-10-CM* E75.21
Method of diagnosis: □ Enzyme Assay □ Genetic Testing □ Tissue Biopsy
□ Other (please specify)_____________
Diagnostic Results (Values):
____________________________________________________________
Treatment
Recommendation
□ Fabrazyme® (agalsidase beta) NDC 58468-0040-1 35mg vial; NDC 58468-0041-1 5mg vial
Dose: _________mg/kg*
Frequency* ______________________________
Therapy Start Date _______/________/_________
* recommended dosage of Fabrazyme is 1 mg/kg body weight infused every 2 weeks
___________
Please list any additional treatment information, including follow-up evaluations:
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
______________________________________________________________________________________
_________________
Physician
Authorization
I certify that the above-indicated therapy is medically necessary, and the information provided is
accurate to the best of my knowledge
Physician Name (printed) _______________________________
Date __________________________
Address _____________________________
City _____________ State_______ ZIP______________
Phone ______________________________
Fax ______________________________________
Physician’s Signature ____________________________
Medical License #___________________
State Issued ___________________
Statement of Medical Necessity
Fabry Disease
IMPORTANT NOTE:
* For dates of service starting on October 1, 2014.
Call a Genzyme Case Manager to request a Statement of Medical Necessity form.
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Appendix C
Sample UB-04 Claim Form
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Appendix D
Sample CMS-1500 (02-12) Claim Form
Box 21: Complete the indicator
field to reflect which diagnosis
code is being reported:
ICD-9-CM or ICD-10-CM
Box 21: Enter the appropriate
diagnosis code: ICD-9-CM for
dates of service 1/1/14-9/30/14.
ICD-10-CM for dates of services
starting 10/1/14.
Box 24G: Note amount
of drug provided in units;
e.g., multiples of 1mg/kg
for Fabrazyme.
J0180
96365
96366
Box 24D: Enter the appropriate HCPCS codes:
Drugs: J0180 for Fabrazyme, 1mg
General IV Therapy: 96365 Intravenous infusion
therapy, prophylaxis, or diagnosis (specify
substance or drug); initial, up to 1 hour
96366 Each additional hour (list separately In
addition to primary procedure code, 96365)
12
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Appendix E
5/17/11 3:01
Full Prescribing Information
088705_FZ_MrktPI_FIN.qxp
PM
Page 3
• Infusion reactions occurred in approximately
50 to 55% of patients during Fabrazyme
administration in clinical trials. Some reactions
were severe. In patients experiencing infusion
reactions, pretreatment with an antipyretic and
antihistamine is recommended. 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 (5.2).
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information
needed to use Fabrazyme safely and effectively.
See full prescribing information for Fabrazyme.
Fabrazyme (agalsidase beta)
Injection, powder, lyophilized for solution for
intravenous use
Initial U.S. Approval: 2003
–––––––– INDICATIONS AND USAGE ––––––––
Fabrazyme 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 (1).
–––––– DOSAGE AND ADMINISTRATION ––––––
1 mg/kg body weight given every two weeks as an
IV infusion. Patients should receive antipyretics
prior to infusion (2).
––––– DOSAGE FORMS AND STRENGTHS –––––
• Lyophilized powder for reconstitution with Sterile
Water for Injection, USP to yield 5 mg/mL (3).
• Available as 35 mg or 5 mg single-use vials (3).
–––––––––– CONTRAINDICATIONS ––––––––––
• None (4).
–––––– WARNINGS AND PRECAUTIONS ––––––
• Life-threatening anaphylactic and severe allergic
reactions have been observed in some patients
during Fabrazyme infusions. If severe allergic
or anaphylactic reactions occur, immediately
discontinue administration of Fabrazyme and
provide necessary emergency treatment.
Appropriate medical support measures should
be readily available when Fabrazyme is
administered because of the potential for severe
infusion reactions (5.1).
• 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, IV fluids and/or oxygen as
clinically indicated (5.2).
• Patients with advanced Fabry disease may have
compromised cardiac function, which may
predispose them to a higher risk of severe
complications from infusion reactions, and
these patients should be monitored closely
during Fabrazyme administration (5.3).
• 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 (5.4).
–––––––––– ADVERSE REACTIONS ––––––––––
• The most common adverse reactions reported
are infusion reactions. Serious and/or frequently
occurring (> 5% incidence) related adverse
reactions, including infusion 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 (6).
To report SUSPECTED ADVERSE REACTIONS,
contact Genzyme at 1-800-745-4447 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
2.2 Instructions for Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Anaphylaxis and Allergic Reactions
5.2 Infusion Reactions
5.3 Compromised Cardiac Function
5.4 Immunogenicity and Re-challenge
5.5 Monitoring: Laboratory Tests
6
ADVERSE REACTIONS
6.1 Adverse Reactions in Clinical Studies
6.2 Immunogenicity
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Interference with Other Drugs
7.2 Interference with Laboratory Tests
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Responses in Women
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis,
Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full
prescribing information are not listed.
–––––––––– DRUG INTERACTIONS ––––––––––
• No drug interaction studies were performed (7).
• No in vitro metabolism studies were performed
(7).
–––––– USE IN SPECIFIC POPULATIONS ––––––
• Pregnancy: Registry available (8.1).
• Nursing Mothers: Registry available (8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: [May/2010]
13
Appendix E
088705_FZ_MrktPI_FIN.qxp 5/17/11 3:01 PM Page 4
Full
Prescribing Information - Continued
FULL PRESCRIBING INFORMATION
Slowly withdraw the reconstituted solution from each vial up to the total
volume required for the patient dose. Inject the reconstituted Fabrazyme
solution directly into the Sodium Chloride solution. Do not inject in the
airspace within the infusion bag. Discard any vial with unused
reconstituted solution.
5. Gently invert infusion bag to mix the solution, avoiding vigorous shaking
and agitation.
6. Do not infuse Fabrazyme in the same intravenous line with other products.
7. Administer Fabrazyme using an in-line low protein-binding 0.2 µm filter.
1
INDICATIONS 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.
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every
two weeks as an intravenous (IV) infusion. Patients should receive antipyretics
prior to infusion [see Warnings and Precautions (5.2)].
The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hr). The
infusion rate may be slowed in the event of infusion reactions. After patient
tolerance to the infusion is well established, the infusion rate may be increased
in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hr) with each
subsequent infusion. For patients weighing < 30 kg, the maximum infusion rate
should remain at 0.25 mg/min (15 mg/hr). For patients weighing > 30 kg, the
administration duration should not be less than 1.5 hours (based on individual
patient tolerability).
Patients who have had a positive skin test to Fabrazyme or who have tested
positive for anti-Fabrazyme IgE may be successfully re-challenged with
Fabrazyme. The initial re-challenge administration should be a low dose at a
lower infusion rate, e.g., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial
standard recommended rate (0.01 mg/min). Once a patient tolerates the
infusion, the dose may be increased to reach the approved dose of 1 mg/kg and
the infusion rate may be increased by slowly titrating upwards (doubled every
30 minutes up to a maximum rate of 0.25 mg/min), as tolerated.
3
DOSAGE FORMS AND STRENGTHS
Fabrazyme is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized
cake or powder for reconstitution with Sterile Water for Injection, USP to yield
a concentration of 5 mg/mL; and then further diluted with 0.9% Sodium
Chloride Injection, USP for intravenous infusion.
Single-use vials are available in 35 mg and 5 mg dosages.
4
CONTRAINDICATIONS
None.
5
2.2 Instructions for Use
Fabrazyme does not contain any preservatives. Vials are for single use only.
Discard any unused product.
Avoid shaking or agitating this product. Do not use filter needles during the
preparation of the infusion.
Reconstitution and Dilution (using Aseptic Technique)
1. Allow Fabrazyme vials and diluent to reach room temperature prior to
reconstitution (approximately 30 minutes). The number of 35 mg and 5 mg
vials needed is based on the patient’s body weight (kg) and the
recommended dose of 1 mg/kg.
Select a combination of 35 mg and 5 mg vials so that the total number of
mg is equal to or greater than the patient’s number of kg of body weight.
2. Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of
Sterile Water for Injection, USP down the inside wall of each vial. Roll and
tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution
(total extractable amount per vial is 35 mg, 7 mL).
Reconstitute each 5 mg vial of Fabrazyme by slowly injecting 1.1 mL of
Sterile Water for Injection, USP down the inside wall of each vial. Roll and
tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution
(total extractable amount per vial is 5 mg, 1 mL).
3. Visually inspect the reconstituted vials for particulate matter and
discoloration. Do not use the reconstituted solution if there is particulate
matter or if it is discolored.
4. The reconstituted solution should be further diluted with 0.9% Sodium
Chloride Injection, USP to a total volume based on patient weight specified
in Table 1 below. Prior to adding the volume of reconstituted Fabrazyme
required for the patient dose, remove an equal volume of 0.9% Sodium
Chloride Injection, USP from the infusion bag.
5.2 Infusion Reactions
In clinical trials with Fabrazyme, approximately 50-55% of patients experienced
infusion reactions during Fabrazyme administration, some of which were
severe [see Warnings and Precautions (5.1)]. 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.
Table 1
Patient Weight (kg)
< 35
Minimum Total Volume (mL)
50
35.1 – 70
100
70.1 – 100
250
> 100
500
WARNINGS AND PRECAUTIONS
5.1 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 [see Warnings and Precautions
(5.4) and Clinical Studies (14)].
Patient dose (in mg) ÷ 5 mg/mL = Number of mL of reconstituted
Fabrazyme required for patient dose
Example: Patient dose = 80 mg
80 mg ÷ 5 mg/mL = 16 mL of Fabrazyme
2
14
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Appendix E
Full
5.3 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 [see Warnings and Precautions (5.1) and (5.2)]. Patients
with compromised cardiac function should be monitored closely if the decision
is made to administer Fabrazyme.
Table 2
Summary of Adverse Reactions (regardless of relationship) Occurring in Fabrazyme®-Treated
Patients at an Incidence Greater than 2.5% Compared to Placebo-Treated Patients
MedDRA System Organ Class/
Preferred Term
Cardiac Disorders
Tachycardia
Ventricular wall thickening
Ear and Labyrinth Disorders
Tinnitus
Hypoacusis
Gastrointestinal Disorders
Toothache
Dry mouth
General Disorders and Administration Site Conditions
Chills
Pyrexia
Fatigue
Edema peripheral
Pain
Feeling cold
Adverse event
Chest discomfort
Infections and Infestations
Upper respiratory tract infection
Lower respiratory tract infection
Sinusitis
Pharyngitis
Fungal infection
Viral infection
Localized infection
Injury, Poisoning and Procedural Complications
Procedural pain
Post-procedural complication
Excoriation
Fall
Contusion
Thermal burn
Investigations
Blood creatinine increased
Musculoskeletal and Connective Tissue Disorders
Pain in extremity
Back pain
Myalgia
Muscle spasms
Nervous System Disorders
Headache
Paresthesia
Dizziness
Burning sensation
Psychiatric Disorders
Anxiety
Depression
Respiratory, Thoracic and Mediastinal Disorders
Cough
Nasal congestion
Dyspnea
Respiratory tract congestion
Wheezing
Skin and Subcutaneous Tissue Disorders
Rash
Pruritus
Vascular Disorders
Hypertension
Hot flush
5.4 Immunogenicity and Re-challenge
In clinical trials with Fabrazyme, a few patients developed IgE antibodies or skin
test reactivity specific to Fabrazyme. Two of six patients in the re-challenge
study discontinued treatment with Fabrazyme prematurely due to recurrent
infusion reactions. Four serious infusion reactions occurred in three patients
during Fabrazyme infusions, including bronchospasm, urticaria, hypotension,
and development of Fabrazyme-specific antibodies. Other infusion-related
reactions occurring in more than one patient during the study included rigors,
hypertension, nausea, vomiting, and pruritus. Physicians should consider
testing for IgE antibodies in patients who experienced suspected allergic
reactions and consider the risks and benefits of continued treatment in patients
with anti-Fabrazyme IgE antibodies [see Warnings and Precautions (5.1) and
Dosage and Administration (2)].
Patients who have had a positive skin test to Fabrazyme or who have tested
positive for Fabrazyme-specific IgE antibody have been re-challenged with
Fabrazyme using a re-challenge protocol [see Clinical Studies (14)].
Re-challenge of these patients should only occur under the direct supervision
of qualified personnel, with appropriate medical support measures readily
available.
5.5 Monitoring: Laboratory Tests
There are no marketed tests for antibodies against Fabrazyme. If testing is
warranted, contact your local Genzyme representative or Genzyme Corporation
at (800) 745-4447.
6
ADVERSE REACTIONS
6.1 Adverse Reactions in Clinical Studies
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.
The most serious adverse reactions reported with Fabrazyme treatment during
clinical trials were anaphylactic and allergic reactions [see Warnings and
Precautions (5.1)].
The most common adverse reactions reported with Fabrazyme are infusion
reactions, some of which were severe [see Warnings and Precautions (5.1)
and (5.2)]. 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 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 every two weeks in two separate double-blind, placebocontrolled 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.
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 (14)].
Reported adverse reactions have been classified by Medical Dictionary for
Regulatory Activities (MedDRA) terminology System Organ Class and Preferred
Term.
Fabrazyme®
n=80 (%)
Placebo
n=60 (%)
7 (9)
4 (5)
2 (3)
1 (2)
6 (8)
4 (5)
2 (3)
0
5 (6)
3 (4)
2 (3)
0
34 (43)
31 (39)
19 (24)
17 (21)
13 (16)
9 (11)
8 (10)
4 (5)
7 (12)
13 (22)
10 (17)
4 (7)
8 (13)
1 (2)
3 (5)
1 (2)
35 (44)
14 (18)
7 (9)
5 (6)
4 (5)
4 (5)
3 (4)
18 (30)
4 (7)
2 (3)
1 (2)
0
0
0
20 (25)
8 (10)
7 (9)
5 (6)
3 (4)
3 (4)
12 (20)
1 (2)
1 (2)
2 (3)
0
0
7 (9)
3 (5)
15 (19)
13 (16)
11 (14)
4 (5)
5 (8)
6 (10)
3 (5)
1 (2)
31 (39)
25 (31)
17 (21)
5 (6)
17 (28)
11 (18)
5 (8)
0
5 (6)
5 (6)
2 (3)
1 (2)
26 (33)
15 (19)
6 (8)
6 (8)
5 (6)
15 (25)
9 (15)
1 (2)
1 (2)
0
16 (20)
8 (10)
6 (10)
2 (3)
11 (14)
4 (5)
3 (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 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 (8.4) and Clinical Studies (14)]. The safety of Fabrazyme in
patients younger than 8 years of age has not been evaluated.
6.2 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 three months of exposure. IgG seroconversion in pediatric
patients was associated with prolonged half-life of Fabrazyme, a phenomenon
rarely observed in adult patients [see Clinical Pharmacology (12.3) and Use in
Specific Populations (8.4)]. 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, six (adult
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
3
15
Appendix E
Full
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 antibodies 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 re-challenged [see Clinical Studies (14), Warnings and
Precautions (5.4) and Dosage and Administration (2)].
8.2 Labor and Delivery
There is no information on the effect of Fabrazyme during labor and delivery.
Pregnant females are encouraged to enroll in the Fabry registry [see Patient
Counseling Information (17)].
6.3 Postmarketing Experience
The following adverse reactions have been identified during post approval
use of Fabrazyme. 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.
In postmarketing experience with agalsidase beta, severe and serious
infusion-related reactions have been reported, some of which were
life-threatening, including anaphylactic shock [see Warnings and
Precautions (5.1)]. 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.
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.
In addition to the adverse reactions reported in Adverse Reactions in Clinical
Studies (6.1), 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.
8.6 Responses in Women
Fabry disease is an X-linked genetic disorder. However, some heterozygous
women will develop signs and symptoms of Fabry disease due to the variability
of the X-chromosome inactivation within cells.
A total of 12 adult female patients with Fabry disease were enrolled in two
separate randomized, double-blind, placebo-controlled clinical studies with
Fabrazyme, and two female pediatric patients with Fabry disease, ages 11 years,
were evaluated in an open-label, uncontrolled pediatric study [see Use in
Specific Populations (8.4) and Clinical Studies (14)]. Although the safety and
efficacy data available in female patients in these clinical studies are limited,
there is no indication that female patients respond differently to Fabrazyme
compared to males.
7
8.3 Nursing Mothers
It is not known whether Fabrazyme is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when Fabrazyme
is administered to a nursing woman.
Nursing mothers should be encouraged to enroll in the Fabry registry [see Use
in Specific Populations (8.1) and Patient Counseling Information (17)].
8.4 Pediatric Use
The safety and efficacy of Fabrazyme were assessed in a multi-national,
multi-center, uncontrolled, open-label study in 16 pediatric patients with Fabry
disease (14 males, 2 females), ages 8 to 16 years [see Clinical Studies (14)].
Patients younger than 8 years of age were not included in clinical studies.
The safety and efficacy in patients younger than 8 years of age have not
been evaluated.
8.5 Geriatric Use
Clinical studies of Fabrazyme did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects.
10 OVERDOSAGE
There have been no reports of overdose with Fabrazyme. In clinical trials,
patients received doses up to 3 mg/kg body weight. The adverse reactions
experienced by patients who received treatment with 3 mg/kg were similar to
the adverse reactions experienced by patients who received treatment with
1 mg/kg.
11 DESCRIPTION
Fabrazyme (agalsidase beta) is a recombinant human α-galactosidase A
enzyme with the same amino acid sequence as the native enzyme. Purified
agalsidase beta is a homodimeric glycoprotein with a molecular weight of
approximately 100 kD. The mature protein is comprised of two subunits of 398
amino acids (approximately 51 kD), each of which contains three N-linked
glycosylation sites. α-galactosidase A catalyzes the hydrolysis of
globotriaosylceramide (GL-3) and other α-galactyl-terminated neutral
glycosphingolipids, such as galabiosylceramide and blood group B substances
to ceramide dihexoside and galactose. The specific activity of Fabrazyme
is approximately 70 U/mg (one unit is defined as the amount of activity
that results in the hydrolysis of 1 µmole of a synthetic substrate,
p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions).
Fabrazyme is produced by recombinant DNA technology in a Chinese Hamster
Ovary mammalian cell expression system.
Fabrazyme is intended for intravenous infusion. It is supplied as a sterile,
nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution
with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of
agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate
monobasic monohydrate, and 59.2 mg sodium phosphate dibasic
heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta
(7 mL) may be extracted from each 35 mg vial.
Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol,
3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium
phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of
agalsidase beta (1 mL) may be extracted from each 5 mg vial.
DRUG INTERACTIONS
7.1 Interference with Other Drugs
No drug interaction studies were performed.
No in vitro metabolism studies were performed.
7.2 Interference with Laboratory Tests
There is no known interference by Fabrazyme with laboratory tests. Antibody
samples should be collected prior to Fabrazyme infusions.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B –
There are no adequate and well-controlled studies of Fabrazyme use in pregnant
women. Reproduction studies performed in rats at doses up to 30 times the
human dose have revealed no evidence of impaired fertility or negative effects
on embryo fetal development due to Fabrazyme. Because animal reproduction
studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Women of childbearing potential should be encouraged to enroll in the Fabry
patient registry. The registry will monitor the effect of Fabrazyme on pregnant
women and their offspring. For more information, visit www.fabryregistry.com
or call (800) 745-4447 [see Patient Counseling Information (17)].
4
16
www.Fabrazyme.com
Appendix E
Full
12
CLINICAL PHARMACOLOGY
Study 1 was a randomized, double-blind, placebo-controlled, multi-national,
multi-center study of 58 Fabry patients (56 males and 2 females), ages 16 to 61
years, all naïve to enzyme replacement therapy. Patients received either 1 mg/kg
of Fabrazyme or placebo every two weeks for five months (20 weeks) for a total
of 11 infusions. All patients were pretreated with acetaminophen and an
antihistamine to decrease or prevent infusion reactions. Oral steroids were an
additional option to the pretreatment regimen for patients who exhibited severe
or recurrent infusion reactions. The primary efficacy endpoint of GL-3
inclusions in renal interstitial capillary endothelial cells, was assessed by light
microscopy and was graded on an inclusion severity score ranging from 0
(normal or near normal) to 3 (severe inclusions).
A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated
with Fabrazyme compared to 0 of 29 treated with placebo (p<0.001). Similar
reductions in GL-3 inclusions were observed in the capillary endothelium of the
heart and skin (Table 4). No differences between groups in symptoms or renal
function were observed during this five-month study.
12.1 Mechanism of Action
Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism.
Deficiency of the lysosomal enzyme α-galactosidase A leads to progressive
accumulation of glycosphingolipids, predominantly GL-3, in many body tissues,
starting early in life and continuing over decades. Clinical manifestations
of Fabry disease include renal failure, cardiomyopathy, and cerebrovascular
accidents. Accumulation of GL-3 in renal endothelial cells may play a role in
renal failure.
Fabrazyme is intended to provide an exogenous source of α-galactosidase A in
Fabry disease patients. Nonclinical and clinical studies evaluating a limited
number of cell types indicate that Fabrazyme will catalyze the hydrolysis of
glycosphingolipids, including GL-3.
12.2 Pharmacodynamics
In a placebo-controlled study conducted in patients with Fabry disease after
intravenous administration of 1 mg/kg of Fabrazyme every two weeks for 20
weeks, a reduction of GL-3 was observed in the capillary endothelium (vasculature) of kidney, heart and skin as determined by histological assessment, and
in plasma as determined by ELISA [see Clinical Studies (14)].
Table 4: Reduction of GL-3 Inclusions to Normal or Near Normal Levels
(0 Score) in the Capillary Endothelium of the Kidney, Heart, and Skin
5 Months of the Controlled Study
Placebo
Fabrazyme®
(n=29)
(n=29)
12.3 Pharmacokinetics
Plasma pharmacokinetic profiles of Fabrazyme were characterized at 0.3, 1,
and 3 mg/kg in adult patients with Fabry disease. The area under the plasma
concentration-time curve (AUC∞) and the clearance (CL) did not increase
proportionately with increasing doses, demonstrating that the enzyme follows
non-linear pharmacokinetics (Table 3). Plasma pharmacokinetic profiles were
also characterized in adult patients with Fabry disease given 1 mg/kg Fabrazyme
every 14 days for a total of 11 infusions. Refer to Table 3 below for more
details.
In 15 pediatric Fabry patients (ranging in age from 8 to 16 years old and weighing
between 27.1 to 64.9 kg) who were dosed with 1 mg/kg every 14 days,
Fabrazyme pharmacokinetics were not weight-dependent (Table 3). Fabrazyme
concentrations were about five times higher after IgG seroconversion, without
any detectable impact on GL-3 clearance.
IgG seroconversion in pediatric patients was associated with prolonged half-life
and plasma concentrations of Fabrazyme, a phenomenon rarely observed in
adult patients. A possible cause for this prolongation likely pertains to the ability
of antibodies to potentially act as “carriers” for their antigens [see Adverse
Reactions (6.2) and Use in Specific Populations (8.4)].
Regimen
Mean
Infusion
Length (min)
Infusion
Number
(n= patients)
AUC(0-∞)
µg min/mL
Cmax
µg/mL
Half-life
min
CL
mL/min/kg
q14 days x 5
Vss*
mL/kg
1 mg/kg
q14 days x 5
3 mg/kg
q14 days x 5
132
1 (n=3)
79 ± 24
0.6 ± 0.2
92 ± 27
4.1 ± 1.2
225 ± 62
128
5 (n=3)
74 ± 30
0.6 ± 0.2
78 ± 67
4.6 ± 2.2
330 ± 231
5.0 ± 1.1
115
1 (n=3)
67 ± 12
2.1 ± 0.7
112 ± 13
120
5 (n=2)
466 ± 382
4.74 ± 4.3
45 ± 3
3.2 ± 2.6
243 ± 236
129
1 (n=2)
4168 ± 1401
496 ± 137
29.7 ± 14.6
102 ± 4
0.8 ± 0.3
81 ± 45
300
5 (n=2)
4327 ± 2074
19.8 ± 5.8
87 ± 21
0.8 ± 0.4
165 ± 80
Study AGAL-1-002-98: Phase 3 Study in Adult Patients with Fabry Disease
1 mg/kg
q14 days x 11
1-3 (n=11)
649 ± 226
3.5 ± 1.6
280
7 (n=11)
372 ± 223
2.1 ± 1.14
82 ± 25
4.9 ± 5.6
570 ± 710
300
280
11 (n=11)
784 ± 521
3.5 ± 2.2
119 ± 49
89 ± 20
2.3 ± 2.2
1.8 ± 0.8
280 ± 230
120 ± 80
Study AGAL-016-01: Phase 2 Study in Pediatric Patients with Fabry Disease
1 mg/kg
q14 days x 24
208
1 (n=8-9)
344 ± 307
2.2 ± 1.9
86 ± 27
5.8 ± 4.6
1097 ± 912
111
12 (n=15)
1007 ± 688
4.9 ± 2.4
130 ± 41
1.6 ± 1.2
292 ± 185
108
24 (n=9-10)
1238 ± 547
7.1 ± 4.4
151 ± 59
1.1 ± 0.8
247 ± 146
All data reported as the mean ± standard deviation.
*Vss = volume of distribution at steady state
13
0/29
20/29
24/24
Heart
1/29
21/29
13/18
19/22
Skin
1/29
29/29
25/26
26/27
23/25
All 58 patients in Study 1 participated in an open-label extension study of
Fabrazyme at 1 mg/kg every two weeks, which continued for an additional 54
months. At the end of six months of open-label treatment, most patients
achieved a GL-3 inclusion score of 0 in capillary endothelium (Table 4). GL-3
was decreased to normal or near normal levels in mesangial cells, glomerular
capillary endothelium, interstitial cells, and non-capillary endothelium. GL-3
deposition was still present in vascular smooth muscle cells, tubular epithelium
and podocytes, at variably reduced levels. Forty-four of the 58 patients completed
54 months of the open-label extension study. Thirty-six of these 44 patients
underwent follow-up skin biopsy, and 31 of these patients showed sustained
GL-3 clearance in the capillary endothelium of the skin. Follow-up heart and
kidney biopsies were assessed in only 8 of the 44 patients, which showed
sustained GL-3 clearance in the capillary endothelium of the kidney in 8
patients, and sustained GL-3 clearance in the capillary endothelium of the heart
in 6 patients. Plasma GL-3 levels were reduced to normal levels
(< 7.03 µg/mL determined by LC/MS/MS) and remained at normal levels after
up to 60 months of treatment. 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.
Study 2 was a randomized (2:1 Fabrazyme to placebo), double-blind, placebocontrolled, multi-national, multi-center study of 82 patients (72 males and 10
females), ages 20 to 72 years, all naïve to enzyme replacement therapy. Patients
received either 1 mg/kg of Fabrazyme or placebo every two weeks for up to a
maximum of 35 months (median 18.5 months). There was significant
difference in post-baseline plasma GL-3 levels in the Fabrazyme-treated
patients compared to placebo. The reduction in plasma GL-3 levels in the
Fabrazyme group compared to the placebo group was significant at one year
(p<0.0001) and at two years (p=0.0019). Fourteen patients (8 in Fabrazymetreated and 6 in placebo) had skin biopsies at first infusion and final visit. All
Fabrazyme-treated patients had capillary endothelium and deep vessel
endothelium scores of zero at the final visit. Four (4) of 6 placebo patients had
non-zero capillary endothelium scores (p=0.0150), and 6 of 6 had non-zero
deep vessel endothelium scores (p=0.0003).
Sixty-seven patients who participated in Study 2 were subsequently entered
into an open-label extension study in which all patients received 1 mg/kg of
Fabrazyme every two weeks for up to a maximum of 18 months. There was a
statistically significant reduction in mean plasma GL-3 levels with durability in
effect through the additional 18 months of treatment in the extension study
from pretreatment baseline.
Study 3 (Pediatric Study) was an open-label, uncontrolled, multi-national,
multi-center study to evaluate safety, pharmacokinetics, and pharmacodynamics
of Fabrazyme treatment in 16 pediatric patients with Fabry disease (14 males, 2
females), who were ages 8 to 16 years at first treatment. All patients received
Fabrazyme 1 mg/kg every two weeks for up to 48 weeks. At baseline, all 14
males had elevated plasma GL-3 levels (i.e., > 7.03 µg/mL), whereas the two
Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease
0.3 mg/kg
Kidney
* Results reported where biopsies were available
Table 3: Fabrazyme® Pharmacokinetic Summary
Dose
6 Months of the Open-label Extension Study
Placebo/Fabrazyme®
Fabrazyme/Fabrazyme®
(n=29)*
(n=29)*
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no animal or human studies to assess the carcinogenic or mutagenic
potential of Fabrazyme. There are no studies assessing the potential effect of
Fabrazyme on fertility in humans.
14 CLINICAL STUDIES
The safety and efficacy of Fabrazyme were assessed in four clinical studies in
patients with Fabry disease.
5
17
Appendix E
Full
female patients had normal plasma GL-3 levels. Twelve of the 14 male patients,
and no female patients, had GL-3 inclusions observed in the capillary
endothelium on skin biopsies at baseline. At Weeks 24 and 48 of treatment, all
14 males had plasma GL-3 within the normal range. The 12 male patients with
GL-3 inclusions in capillary endothelium at baseline achieved GL-3 inclusion
scores of 0 at Weeks 24 and 48 of treatment. The two female patients’ plasma
GL-3 levels remained normal through study Week 48.
No new safety concerns were identified in pediatric patients in this study, and
the overall safety and efficacy profile of Fabrazyme treatment in pediatric
patients was found to be consistent with that seen in adults. Immunologic
responses in pediatric patients may differ from those in adults, as IgG seroconversion in pediatric patients was associated with prolonged half-life
concentrations of Fabrazyme, a phenomenon rarely observed in adult patients
[see Clinical Pharmacology (12.3), Adverse Reactions (6.2), and Use in
Specific Populations (8.4)].
Study 4 was an open-label, re-challenge study to evaluate the safety of
Fabrazyme treatment in patients who had a positive skin test to Fabrazyme or
who had tested positive for Fabrazyme-specific IgE antibodies. In this study, six
adult male patients, who had experienced multiple or recurrent infusion
reactions during previous clinical trials with Fabrazyme, were re-challenged
with Fabrazyme administered as a graded infusion, for up to 52 weeks of
treatment [see Warnings and Precautions (5.4)]. The initial two re-challenge
doses of Fabrazyme were administered as a 0.5 mg/kg dose per week at an
initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25th the usually
recommended maximum infusion rate). The infusion rate was doubled every 30
minutes thereafter, as tolerated, for the remainder of the infusion up to a
maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose
was increased to 1 mg/kg every two weeks (usually recommended dose), and
the infusion rate was increased by slow titration upwards [see Dosage and
Administration (2)]. Four of the six patients treated in this study received at
least 26 weeks of study medication, and two patients discontinued prematurely
due to recurrent infusion reactions [see Warnings and Precautions (5.4)].
16 HOW SUPPLIED/STORAGE AND HANDLING
Fabrazyme is supplied as a sterile, nonpyrogenic, white to off-white lyophilized
cake or powder. Fabrazyme 35 mg vials are supplied in single-use, clear Type I
glass 20 mL (cc) vials. The closure consists of a siliconized butyl stopper and
an aluminum seal with a plastic purple flip-off cap. Fabrazyme 5 mg vials are
supplied in single-use, clear Type I glass 5 mL (cc) vials. The closure consists
of a siliconized butyl stopper and an aluminum seal with a plastic gray flip-off cap.
35 mg vial: NDC 58468-0040-1
5 mg vial: NDC 58468-0041-1
Refrigerate vials of Fabrazyme at 2° to 8°C (36° to 46°F). DO NOT USE
Fabrazyme after the expiration date on the vial. Reconstituted and diluted
solutions of Fabrazyme should be used immediately. This product contains no
preservatives. If immediate use is not possible, the reconstituted and diluted
solution may be stored for up to 24 hours at 2° to 8°C (36° to 46°F).
17 PATIENT COUNSELING INFORMATION
Patients should be informed that a Registry has been established in order
to better understand the variability and progression of Fabry disease in the
population as a whole and in women [see Use in Specific Populations (8.6)],
and to monitor and evaluate long-term treatment effects of Fabrazyme. The
Registry will also monitor the effect of Fabrazyme on pregnant women and their
offspring. Patients should be encouraged to participate and advised that their
participation is voluntary and may involve long-term follow-up. For more
information, visit www.fabryregistry.com or call (800) 745-4447.
Fabrazyme is manufactured and distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
1-800-745-4447 (phone)
U.S. License Number: 1596
5031 (07/10)
www.fabrazyme.com
©2011 Genzyme Corporation. All rights reserved. Fabrazyme and
Genzyme are registered trademarks of Genzyme Corporation.
FZ-US-P004-04-11
6
18
www.Fabrazyme.com
An Ongoing Commitment
For more than 30 years, Genzyme has been committed to researching and developing
products for people living with lysosomal storage disorders such as Fabry disease.
Providing comprehensive and confidential support services that address the unique
needs of those living with Fabry disease is part of this ongoing commitment.
To learn more about these support services, call a Genzyme Case Manager at
800-745-4447 (option 3).
www.fabrazyme.com
www.fabrycommunity.com
www.fabryregistry.com
Genzyme
500 Kendall Street
Cambridge, MA 02142 U.S.A.
1-800-745-4447, option 3
Fax 800-737-3642 or 617-591-7178
Monday - Friday 8:00 am-6:00 pm ET
Please see enclosed full Prescribing Information in Appendix E.
©2014 Genzyme. Fabrazyme is a registered trademark of Genzyme. All rights reserved.
FZ-US-P001-03-14
www.Fabrazyme.com