Agalsidase alfa

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Agalsidase alfa may be confused with agalsidase beta, alglucerase, alglucosidase alfa

PHARMACOLOGIC CATEGORY
Enzyme

DOSING: ADULTS — Note: 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: PEDIATRIC — Note: Premedication with oral antihistamines and corticosteroids may alleviate infusion-related reactions associated with agalsidase alfa.

Fabry disease: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — No dosage adjustment necessary.

DOSING: HEPATIC IMPAIRMENT — No data available.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name

Injection, solution [preservative free]:
Replagal™ [CAN]: 1 mg/1mL (3.5 mL) [not available in the U.S.]

DOSAGE FORMS: CONCISE — [CAN] = Canadian brand name

Injection, solution [preservative free]:
Replagal™ [CAN]: 1 mg/1mL (3.5 mL) [not available in the U.S.]

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Infuse 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.

COMPATIBILITY — Stable in NS. Do not mix or infuse with other products.

USE — Replacement therapy for Fabry disease

ADVERSE REACTIONS SIGNIFICANT — Note: 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).

>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

CONTRAINDICATIONS — Hypersensitivity to agalsidase alfa or any component of the formulation; concomitant use with chloroquine, amiodarone, monobenzone, or gentamicin (these agents have the potential to inhibit intracellular agalsidase alfa activity)

WARNINGS / PRECAUTIONS
Concerns 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.

RESTRICTIONS — Not available in U.S.

DRUG INTERACTIONS
Amiodarone: May inhibit the intracellular activity of agalsidase alfa; concomitant use is contraindicated.

Chloroquine: May inhibit the intracellular activity of agalsidase alfa; concomitant use is contraindicated.

Gentamicin: May inhibit the intracellular activity of agalsidase alfa; concomitant use is contraindicated.

Monobenzone: May inhibit the intracellular activity of agalsidase alfa; concomitant use is contraindicated.

PREGNANCY IMPLICATIONS — Adverse 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.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS — Creatinine clearance, ECG, echocardiography, Gb-3 levels (serum and urine)

CANADIAN BRAND NAMES — Replagal™

INTERNATIONAL BRAND NAMES — Replagal (AU, BE, CH, CZ, DK, EE, ES, FI, IL, NO, NZ, SE, TW)

MECHANISM OF ACTION — Agalsidase 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 / KINETICS
Distribution: Vd: 17% of body weight

Metabolism: Plasma; via peptide hydrolysis

Half-life elimination: ~1.5-2 hours