Agalsidase Beta

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Fabrazyme: 5 mg (1 ea); 35 mg (1 ea) [contains mouse (murine) and/or hamster protein]

Pharmacology

Mechanism of Action

Agalsidase beta is a recombinant form of the enzyme alpha-galactosidase-A, which is required for the hydrolysis of GL-3 and other glycosphingolipids. The compounds may accumulate (over many years) within the tissues of patients with Fabry disease, leading to renal and cardiovascular complications. In clinical trials of limited duration, agalsidase been noted to reduce tissue inclusions of a key sphingolipid (GL-3). It is believed that long-term enzyme replacement may reduce clinical manifestations of renal failure, cardiomyopathy, and stroke. However, the relationship to a reduction in clinical manifestations has not been established.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: Children: 247 to 1097 mL/kg; Adults: 81 to 570 mL/kg

Excretion

Clearance: Children: 1.1 to 5.8 mL/minute/kg; Adults: 0.8 to 4.9 mL/minute/kg

Half-Life Elimination

Dose dependent: Children: 86 to 151 minutes; Adults: 45 to 119 minutes

Use: Labeled Indications

Fabry disease: For use in patients with Fabry disease. Agalsidase beta reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.

Contraindications

There are no contraindications listed within the US labeling.

Canadian labeling: Anaphylaxis to agalsidase beta or any component of the formulation.

Dosage and Administration

Dosing: Adult

Fabry disease: IV: 1 mg/kg every 2 weeks

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Fabry disease: Children ≥8 years and Adolescents: IV: 1 mg/kg/dose every 2 weeks; Note: Some experts recommend use in younger males and females (ie, <8 years of age) with symptomatic disease (Hopkin 2016).

Dosing adjustment for toxicity: Children ≥8 years and Adolescents: Patients with IgE antibodies or a positive skin test to agalsidase beta (rechallenge): IV: 0.5 mg/kg every 2 weeks at an initial maximum infusion rate of 0.01 mg/minute; may gradually escalate dose (to maximum of 1 mg/kg every 2 weeks) and/or infusion rate (doubling the infusion rate every 30 minutes to a maximum rate of 0.25 mg/minute) as tolerated.

Dosing: Adjustment for Toxicity

Patient with IgE antibodies or a positive skin test to agalsidase beta (rechallenge): IV: 0.5 mg/kg every 2 weeks at an initial maximum infusion rate of 0.01 mg/minute; may gradually escalate dose (to maximum of 1 mg/kg every 2 weeks) and/or infusion rate (doubling the infusion rate every 30 minutes to a maximum rate of 0.25 mg/minute) as tolerated.

Reconstitution

IV: Allow vials and diluent to reach room temperature prior to reconstitution (~30 minutes). Each 35 mg vial should be reconstituted with 7.2 mL SWFI; reconstitute 5 mg vials with 1.1 mL SWFI; inject down internal side wall of vial; roll and tilt gently; do not shake. Resulting solution contains 5 mg/mL. Do not use filter needle to prepare. To make final infusion solution, add the desired amount of reconstituted solution to NS to make a final volume based on patient weight (see table for dilution volumes). Prior to adding the volume of agalsidase beta dose to the NS, remove an equal volume of NS. Avoid vigorous shaking or agitation.

Table has been converted to the following text:

Recommended minimum total volume for dilution

Patient weight ≤35 kg: 50 mL

Patient weight 35.1 - 70 kg: 100 mL

Patient weight 70.1 - 100 kg: 250 mL

Patient weight >100 kg: 500 mL

Administration

IV: Antipyretics should be administered prior to infusion. Infuse through a low protein binding 0.2 micron in-line filter. Initial infusion rate should not exceed 0.25 mg/minute (15 mg/hour). Interrupt or decrease rate in the event of an infusion reaction; may be restarted after resolution of symptoms and/or after administration of antipyretics, antihistamines, and/or steroids. After patient tolerance to the infusion is established, rate may be increased in increments of 0.05-0.08 mg/minute (3-5 mg/hour) with each subsequent infusion. Maximum infusion rate: Patients <30 kg: 0.25 mg/minute; patients ≥30 kg: Infuse over at least 1.5 hours. An initial maximum infusion rate of 0.01 mg/minute should be used for rechallenge in patients with IgE antibodies or who have had a positive skin test to agalsidase beta; may increase infusion rate (doubling the infusion rate every 30 minutes) to a maximum rate of 0.25 mg/minute as tolerated.

Storage

Store intact vials between 2°C and 8°C (36°F and 46°F). Product is preservative free; use reconstituted and solutions diluted in NS immediately. If not used immediately, reconstituted and diluted solutions are stable for 24 hours at 2°C and 8°C (36°F and 46°F).

Drug Interactions

Amiodarone: May diminish the therapeutic effect of Agalsidase Beta. Avoid combination

Chloroquine: May diminish the therapeutic effect of Agalsidase Beta. Avoid combination

Gentamicin (Systemic): May diminish the therapeutic effect of Agalsidase Beta. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (21%), hypertension (14%)

Central nervous system: Chills (43%), headache (39%), paresthesia (31%), fatigue (24%), dizziness (21%), pain (16%), sensation of cold (11%)

Dermatologic: Skin rash (20%)

Immunologic: Development of IgG Antibodies (69% to 79%)

Local: Infusion site reaction (59%)

Neuromuscular & skeletal: Limb pain (19%), back pain (16%), myalgia (14%)

Respiratory: Upper respiratory tract infection (44%), cough (33%), nasal congestion (19%), lower respiratory tract infection (18%)

Miscellaneous: Fever (39%)

1% to 10%:

Cardiovascular: Tachycardia (9%), bradycardia (≥5%), chest pain (≥5%), facial edema (≥5%), flushing (≥5%), hypotension (≥5%), chest discomfort (5%)

Central nervous system: Anxiety (6%), burning sensation (6%), depression (6%), falling (6%), drowsiness (≥5%)

Dermatologic: Pruritus (10%), excoriation (9%), pallor (≥5%), urticaria (≥5%)

Endocrine & metabolic: Hot flash (5%)

Gastrointestinal: Toothache (6%), abdominal pain (≥5%), diarrhea (≥5%), nausea (≥5%), vomiting (≥5%)

Hypersensitivity: Anaphylaxis (≤1%), hypersensitivity reaction (≤1%)

Infection: Fungal infection (5%), viral infection (5%)

Neuromuscular & skeletal: Muscle spasm (5%)

Otic: Tinnitus (8%), hypoacusis (5%)

Renal: Increased serum creatinine (9%)

Respiratory: Sinusitis (9%), dyspnea (8%), respiratory congestion (8%), pharyngitis (6%), wheezing (6%), pharyngeal edema (≥5%)

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, low cardiac output

Central nervous system: Ataxia, vertigo

Genitourinary: Nephrotic syndrome

<1%, postmarketing, and/or case reports: Angioedema, arthralgia, asthenia, bronchospasm, cardiac failure, cerebrovascular accident, dysphagia, erythema, hyperhidrosis, hypersensitivity angiitis, hypoesthesia, hypoxia, increased lacrimation, lymphadenopathy, myocardial infarction, oral hypoesthesia, palpitations, pneumonia, renal failure, respiratory failure, rhinorrhea, sepsis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/allergic reactions: Life-threatening anaphylactic and severe allergic reactions have been reported. Reactions may include angioedema, bronchospasm, chest discomfort, dysphagia, dyspnea, flushing, hypotension, nasal congestion, pruritus, rash, and urticaria. Stop infusion if severe reactions occur; immediate medical support should be readily available. Use caution when administering to patients with history of an anaphylactic or severe allergic reaction.
• Antibody formation: Development of IgG antibodies is common and has been observed within 3 months from the onset of therapy. Some patients may also develop IgE antibodies or skin test reactivity; consider IgE testing in patients with allergic reaction. Rechallenge of patients with IgE-mediated reaction or who have had a positive skin test may be done with caution.
• Infusion reactions: Infusion-related reactions are common, and may be severe (chills, vomiting, hypotension, paresthesia); pretreatment with antipyretics and antihistamines is advised. Decrease infusion rate, temporarily discontinue infusion, and/or administer additional antipyretics, antihistamines, and/or steroids to manage infusion reactions. Immediate discontinuation of infusion should be considered for severe reactions. Appropriate medical support for the management of infusion reactions should be readily available. Infusion reactions have occurred despite premedication. Use with caution when readministering to patients with history of infusion reactions.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with compromised cardiac function; may have increased risk of complications from infusion reactions; monitor closely.

Other warnings/precautions:

• Registry: A registry has been created to monitor therapeutic responses and adverse effects during long-term treatment, as well as effects on pregnant and breast-feeding women and their offspring; patients should be encouraged to register (www.registrynxt.com or 1-800-745-4447).

Monitoring Parameters

Development of IgG or IgE antibodies in patients with suspected allergic reactions (test available from manufacturer). Monitor for infusion-related reactions.

Pregnancy

Pregnancy Considerations

Information related to the use of agalsidase beta in pregnancy is limited (Germain 2010; Madsen 2019; Politei 2010; Senocak Tasci 2015).

Data collection to monitor pregnancy and infant outcomes following exposure to Fabrazyme is ongoing. Pregnant females may enroll in the Fabry registry by calling 1-(800)-745-4447 extension 15500 (www.registrynxt.com).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience common cold symptoms, cough, anxiety, muscle spasm, sore throat, tooth pain, or back pain. Have patient report immediately to prescriber trouble hearing, hearing loss, noise or ringing in the ears, depression, dizziness, passing out, shortness of breath, or signs of infusion reactions (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.