Agalsidase Beta

Class: Enzymes
ATC Class: A16AB04
VA Class: RE900
Molecular Formula: C₂₀₂₉H₃₀₈₀N₅₄₄O₅₈₇S₂₇
CAS Number: 104138-64-9
Brands: Fabrazyme

Introduction

Biosynthetic (recombinant DNA origin) form of human α-galactosidase A.^{1 2 3 4 5 6 7 8 9}

Uses for Agalsidase Beta

Fabry’s Disease

Management of Fabry’s disease (designated an orphan drug by FDA for this use).^{1 2 3 4 5 6 7 8 9} Reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidneys and in other cells (i.e., capillary endothelium of the skin and heart; mesangial, interstitial, and noncapillary endothelial cells of the kidneys).^{1 2 3 4 5 6 7 8 9}

Agalsidase Beta Dosage and Administration

General

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  Administer at a medical facility or under close clinician supervision for >6 months of therapy.⁵ If infusions are tolerated after that time, some clinicians suggest that agalsidase beta may be administered in a home-care setting.⁵

  
  


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  Administer only under supervision of qualified clinicians and with appropriate medical support available to patients who have developed a positive skin test or IgE antibodies.^a (See Immunologic Reactions and Antibody Formation under Cautions.)

  
  


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  To minimize the risk of infusion-related reactions, administer antipyretics prior to each infusion. ¹

  
  


• 
  

  If signs or symptoms of an infusion reaction occur, decrease infusion rate or interrupt infusion.¹ (See Infusion Reactions under Cautions.)

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹

May be administered through a low-protein-binding 0.2-mcm filter. ¹

Do not infuse in the same IV line with other drugs. ¹

Use strict aseptic technique since drug product contains no preservative.^a

Reconstitution

Allow vials of lyophilized agalsidase beta and diluent to reach room temperature before reconstitution (approximately 30 minutes). ¹

Determine number of 35- and 5-mg vials needed to achieve the proper dosage based on patient’s body weight in kg.¹

Reconstitute vial containing 35 or 5 mg of agalsidase beta powder with 7.2 or 1.1 mL, respectively, of sterile water for injection to provide a solution containing 5 mg of agalsidase beta per mL.¹ Total extractable amount per 35 or 5 mg vial is 7 or 1 mL, respectively. ¹

Direct the diluent slowly toward the side of the vial; gently roll and tilt vial until lyophilized powder dissolves.¹ Do not shake or agitate.¹

Must be diluted further before IV administration.¹

Dilution

Remove the volume of diluent equal to the total required volume of reconstituted agalsidase beta solution (i.e., patient dose divided by 5 mg/mL) from an infusion bag of 0.9% sodium chloride.^a

Slowly add reconstituted agalsidase beta solution to the bag to a total volume based on patient weight; inject the agalsidase beta solution directly into sodium chloride solution, not into the airspace within the infusion bag.^a (See Table 1.)

Gently invert infusion bag to mix solution; do not agitate or shake vigorously.¹

Table 1. Dilution of Agalsidase Beta Solutions

Patient Weight (kg)	Minimum Total Volume (mL)
≤35	50
35.1–70	100
70.1–100	250
>100	500

Rate of Administration

Infuse at an initial rate ≤0.25 mg/minute (15 mg/hr).¹

If infusion reactions occur, slow infusion rate.¹ (See Infusion Reactions under Cautions.)

Patients weighing ≥30 kg: Once patient tolerance is well established, infusion rate may be increased in increments of 0.05–0.08 mg/minute (3–5 mg/hr) with each subsequent infusion.¹ Duration of infusion should be ≥1.5 hours.^a

Dosage

Dosage of agalsidase beta is expressed in mg.¹ The specific activity of agalsidase beta is approximately 70 units/mg, with 1 unit defined as the amount of activity that results in hydrolysis of 1 mcmol of a synthetic substrate, p-nitrophenyl-α-d-galactopyranoside, per minute under the assay conditions.¹

Pediatric Patients

Fabry’s Disease

IV

Children weighing <30 kg: 1 mg/kg infused at a rate ≤0.25 mg/minute (15 mg/hr) every 2 weeks.^a

Children weighing ≥30 kg: 1 mg/kg every 2 weeks.^a Infuse initally at a rate ≤0.25 mg/minute; infusion rate may be increased gradually after patient tolerance is well established.^a (See Rate of Administration under Dosage and Administration.)

Rechallenge Protocol in Patients Developing Positive Skin Test or IgE Antibodies

IV

Initially, 0.5 mg/kg infused at a rate of 0.01 mg/minute.^a Once patient tolerates infusion, gradually titrate dose and infusion rate upward to 1 mg/kg at a maximum rate of 0.25 mg/minute.^a

Adults

Fabry’s Disease

IV

1 mg/kg every 2 weeks. ¹

Rechallenge Protocol in Patients Developing Positive Skin Test or IgE Antibodies

IV

Initially, 0.5 mg/kg infused at a rate of 0.01 mg/minute.^a Once patient tolerates infusion, gradually titrate dose and infusion rate upward to 1 mg/kg at a maximum rate of 0.25 mg/minute.^a

Cautions for Agalsidase Beta

Contraindications

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  No known contraindications.¹

  
  

Warnings/Precautions

Warnings

Infusion Reactions

Potentially severe infusion reactions (e.g., chills, fever, dyspnea, nausea, vomiting, hypotension, paresthesia, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, peripheral edema) reported.^a Infusion reactions may occur in patients pretreated with acetaminophen and in patients pretreated with antipyretics, an antihistamine, and an oral corticosteroid.¹

Administer antipyretics prior to infusion.^a If an infusion reaction occurs, decrease infusion rate or interrupt infusion; institute appropriate supportive treatment (i.e., additional antipyretics, antihistamines, and/or corticosteroids) as indicated.^a

Incidence of infusion reactions decreases with continued infusions; however, such reactions may occur even with extended duration of therapy.^a

Sensitivity Reactions

Immunologic Reactions and Antibody Formation

Development of IgG antibodies to agalsidase beta reported in most patients, usually within the first 3 months of therapy; however, antibodies did not appear to affect efficacy and did not have a neutralizing effect.^{1 2 3 5}

Possible development of IgE antibodies or skin test reactivity to agalsidase beta.^a Consider testing for IgE antibodies if allergic reaction is suspected; consider risks and benefits of continued treatment in patients with evidence of IgE antibody development.¹

Following discontinuance of therapy because of development of positive skin test or IgE antibodies to agalsidase beta, therapy may be reinitiated using a rechallenge protocol.^a (See Dosage under Dosage and Administration.)

General Precautions

Cardiovascular Disease

Increased risk of severe complications from infusion reactions in patients with compromised cardiac function; monitor such patients closely.¹ (See Infusion Reactions under Cautions.)

Fabry’s Disease Registry

A registry has been established to monitor the variability and progression of Fabry’s disease, to monitor and evaluate the long-term treatment effects of agalsidase beta, to monitor the effect of agalsidase beta on pregnant women and their developing fetuses, and to determine whether the drug is distributed into breast milk.¹ Information is available at and 800-745-4447.^a

Specific Populations

Pregnancy

Category B.^a Pregnancy registry at 800-745-4447. ¹

Lactation

Not known whether agalsidase beta is distributed into milk.^a Caution if used in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <8 years of age;^a however, experts recommend initiation of enzyme replacement therapy in children with clinical manifestations of Fabry's disease.^{3 5}

IgG seroconversion in pediatric patients associated with increased half-life and plasma agalsidase beta concentrations; this phenomenon is rarely observed in adult patients.^a (See Immunologic Reactions and Antibody Formation under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Females

Response in females does not appear to differ from that in males.^a

Common Adverse Effects

Infusion reactions (e.g., vomiting, chills, fever, fatigue, feeling cold, hypertension), anemia, peripheral edema, pain, respiratory tract infection, nasopharyngitis, procedural pain.^a

Interactions for Agalsidase Beta

Specific Drugs

Drug	Interaction	Comments
Amiodarone	Potential inhibition of intracellular α-galactosidase activity5	Concomitant use not recommended by some clinicians5
Chloroquine	Potential inhibition of intracellular α-galactosidase activity5	Concomitant use not recommended by some clinicians5
Gentamicin	Potential inhibition of intracellular α-galactosidase activity5	Concomitant use not recommended by some clinicians5
Monobenzone	Potential inhibition of intracellular α-galactosidase activity5	Concomitant use not recommended by some clinicians5

Agalsidase Beta Pharmacokinetics

Absorption

AUC does not increase proportionately with increased dose.^a

Elimination

Half-life

82–199 minutes.¹

Special Populations

Half-life is increased in pediatric patients who develop IgG antibodies.^a

Stability

Storage

Parenteral

Powder for Injection

2–8°C.¹

Following reconstitution and dilution, 2–8°C up to 24 hours; however, immediate use following reconstituion and dilution preferred since product contains no preservatives.^a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%1

ActionsActions

• 
  

  Provides exogenous source of α-galactosidase that catalyzes the hydrolysis of glycosphingolipids, including GL-3, in patients with Fabry’s disease.^{1 2 3 5}

  
  


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  May reverse histologic abnormalities and decrease clinical manifestations of Fabry's disease.^{2 5}

  
  


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  Reduces GL-3 inclusions in the capillary endothelium of the kidney, heart, and skin.^a

  
  

Advice to Patients

• 
  

  Importance of notifying clinician immediately if manifestations of infusion reaction (fever, rigors, chest tightness, hypertension, hypotension, pruritus, myalgia, dyspnea, urticaria, abdominal pain, headache) occur.¹

  
  


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  Importance of informing patients that a registry has been established to monitor the variability and progression of Fabry’s disease and to evaluate long-term treatment effects of agalsidase beta.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^a

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^a

  
  


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  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Agalsidase Beta

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	5 mg	Fabrazyme (preservative-free)	Genzyme
		37 mg	Fabrazyme (preservative-free)	Genzyme

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Genzyme Corporation. Fabrazyme (agalsidase beta) for intravenous infusion prescribing information. Cambridge, MA. 2003 Apr.

2. Eng CM, Guffon N, Wilcox WR et al. Safety and efficacy of recombinant human α-galactosidase A replacement therapy in Fabry's disease. N Engl J Med. 2001; 345:9-16. [IDIS 465960] [PubMed 11439963]

3. Desnick RJ, Banikazemi M, Wasserstein M. Enzyme replacement therapy for Fabry disease, an inherited nephropathy. Clin Nephrol. 2002; 57:1-8. [IDIS 475903] [PubMed 11837797]

4. Mehta A. New developments in the management of Anderson-Fabry disease. QJM. 2002; 95:647-53. [PubMed 12324636]

5. Desnick RJ, Brady R, Barranger J et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003; 138:338-46. [IDIS 493067] [PubMed 12585833]

6. US Food and Drug Administration. FDA approves first treatment for Fabry disease. Rockville, MD; 2003 Apr 24. Press release No. P03-32.

7. Gahl WA. New therapies for Fabry's disease. N Engl J Med. 2001; 345:55-7. [IDIS 465964] [PubMed 11439950]

8. Barngrover D. Fabrazyme—recombinant protein treatment for Fabry's disease. J Biotechnol. 2002; 95:280-2. [PubMed 12080957]

9. Lee K, Jin X, Zhang K et al. A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology. 2003; 13:305-13. [PubMed 12626384]

10. Fabry Registry.

11. Genzyme Corporation, Cambridge, MA: Personal communication.

a. Genzyme Corporation. Fabrazyme (agalsidase beta) for intravenous infusion prescribing information. Cambridge, MA. 2006 Sep.

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