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Agalsidase alfa

Agalsidase alfa
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Brand Names: Canada

  • Replagal™
Pharmacologic Category

  • Enzyme
Dosing: AdultNote: Premedication with oral antihistamines and corticosteroids may alleviate infusion-related reactions associated with agalsidase alfa.

Fabry disease: I.V.: 0.2 mg/kg every 2 weeks

Dosing: PediatricNote: Premedication with oral antihistamines and corticosteroids may alleviate infusion-related reactions associated with agalsidase alfa.

Fabry disease: Refer to adult dosing.

Dosing: GeriatricRefer to adult dosing.

Dosing: Renal ImpairmentNo dosage adjustment necessary.

Dosing: Hepatic ImpairmentNo data available.

Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]:

Replagal™: 1 mg/1 mL (3.5 mL)

Product AvailabilityNot available in U.S.

AdministrationInfuse over 40 minutes using a dedicated I.V. line with filter. Do not infuse other agents through same I.V. line. Interrupt infusion in the presence of infusion-related reactions (eg, chills, flushing, dyspnea, rigors, tachycardia, urticaria). Infusion may be restarted after 5-10 minutes if symptoms subside or after administration of analgesics, antipyretics, antihistamines, and/or corticosteroids.

CompatibilityStable in NS. Do not mix or infuse with other products.

UseReplacement therapy for Fabry disease

Medication Safety Issues

Sound-alike/look-alike issues:

Agalsidase alfa may be confused with agalsidase beta, alglucerase, alglucosidase alfa

Adverse Reactions SignificantNote: The most common and serious adverse reactions are infusion reactions (symptoms may include chills, dyspnea, facial flushing, fever, hypertension, nausea, rigors, tachycardia, urticaria, and vomiting).

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>10%:

Cardiovascular: Flushing (24%)

Central nervous system: Fever (20%), headache (11%)

Neuromuscular & skeletal: Rigors (20%)

Miscellaneous: IgG antibody formation (55%), infusion-related reactions (13%)

1% to 10%:

Cardiovascular: Chest tightness (7%), hypertension (4%), tachycardia (4%), chest pain (2%), edema (2%), peripheral coldness (2%), peripheral edema (2%)

Central nervous system: Dizziness (9%), fatigue (9%), fatigue aggravated (7%), hypersomnia (2%), hypoesthesia (2%), panic attack (2%), pain/discomfort (7%), somnolence (2%), vertigo (2%)

Dermatologic: Acne (9%), erythema (7%), mottled skin(4%), pruritus (4%), dry skin (2%), eczema (2%), rash (2%)

Gastrointestinal: Nausea (9%), dysgeusia (6%), diarrhea (4%), vomiting (4%), abdominal pain (2%), dyspepsia (2%), gastrointestinal upset (2%), stomach cramps (2%), stomach discomfort (2%)

Neuromuscular & skeletal: Myalgia (6%), neuropathic pain (6%), tremor (4%), musculoskeletal discomfort (2%), back pain (2%), limb pain (2%), paraesthesia (2%), weakness (2%)

Ocular: Lacrimation increased (2%), periorbital edema (2%)

Respiratory: Hoarseness (6%), throat tightness (6%), cough (4%), dyspnea (4%), nasopharyngitis (4%), pharyngitis (4%), nasal congestion (2%), snoring (2%), throat irritation (2%)

Miscellaneous: Feeling hot (4%), influenza-like syndrome(2%), parosmia (2%)

<1% (Limited to important or life-threatening): Chills, facial flushing, urticaria

Warnings/PrecautionsConcerns related to adverse effects:

• Antibody formation: The presence IgG antibodies has been observed within 3 months from the onset of therapy in ~55% of treated patients. Approximately 60% of these patients are free of antibodies and >80% demonstrate immune tolerance, based on reduced titers of antibody within 12-18 months.

• Infusion reactions: Mild acute reactions (chills, facial flushing) are common and may occur during or within 1 hour after infusion. Severe reactions (nausea, pyrexia, rigors, tachycardia, urticaria, vomiting) are rare and usually occur within 2-4 months from the onset of therapy. Patients with a history of reactions may be premedicated with oral corticosteroids and antihistamines 1-3 hours prior to subsequent infusions.

Disease-related concerns:

• Fabry disease: Common symptoms observed in this patient population may be confused with adverse reactions related to treatment.

• Hepatic impairment: Safety and efficacy have not been established.

Pregnancy ImplicationsAdverse events were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. The benefits versus risks should be considered carefully before initiating agalsidase alfa therapy in pregnant women.

LactationExcretion in breast milk unknown/use caution

Monitoring ParametersCreatinine clearance, ECG, echocardiography, Gb-3 levels (serum and urine)

International Brand Names

  • Replagal (AU, BE, CH, CZ, DK, EE, ES, FI, IL, NO, NZ, SE, TW)
Mechanism of ActionAgalsidase alfa is a recombinant form of the enzyme alpha-galactosidase-A, which catalyzes the hydrolysis of globotriaosylceramide (Gb-3) and other glycosphingolipids. These compounds may accumulate (over many years) within the tissues of patients with Fabry disease, leading to renal and cardiovascular complications. Agalsidase has been noted to reduce cellular levels of Gb-3 within the liver, heart, kidney, blood vessels, and in plasma.

Pharmacodynamics/KineticsDistribution: Vd: 17% of body weight

Metabolism: Plasma; via peptide hydrolysis

Half-life elimination: ~1.5-2 hours

REFERENCES
  1. Lidove O, Joly D, Barbey F, et al, “Clinical Results of Enzyme Replacement Therapy in Fabry Disease: A Comprehensive Review of Literature”, Int J Clin Pract, 2007, 61(2):293-302. [PubMed 17263716]
  2. Ries M, Clarke JT, Whybra C, et al, “Enzyme-Replacement Therapy With Agalsidase Alfa in Children With Fabry Disease,” Pediatrics, 2006, 118(3):924-32. [PubMed 16950982]
January 2015
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