Imiglucerase

A16A - Other alimentary tract and metabolism products ATC A16AB02 Enzyme approved 1994 Parenteral Black-box warning

JFDA label: Cerezyme

⚠ Black-Box Warning

Mechanism of Action

Hydrolytic Enzyme of Glucocerebroside — Glucocerebroside hydrolytic enzyme

Target	Action	Gene / class
Glucocerebroside efficacy	HYDROLYTIC ENZYME

Indications

Approved

Canadian labeling
Gaucher disease
U.S. labeling

Contraindications

Source: Lexicomp

Severe hypersensitivity to imiglucerase or any component of the formulation Absolute
U.S. labeling: There are no known contraindications in the manufacturer’s labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Tachycardia

Musculoskeletal and connective tissue disorders (1)

Common Back pain (Miscellaneous: Fever (

Dosing

Source: Lexicomp

Note: Dose should be individualized. IV: Gaucher disease, type 1: Initial range: 2.5 units/kg 3 times weekly, up to 60 units/kg every 2 weeks. Note: Dosage adjustments are made based on assessment and therapeutic goals. Most benefits observed with doses of 30 to 60 units/kg every 2 weeks (Charrow 2004). Gaucher disease, type 3 (Canadian labeling; not in US labeling):Initial range: 2.5 units/kg 3 times weekly, up to 60 units/kg every 2 weeks. Doses up to 120 units/kg every 2 weeks have been safely administered.

(For additional information see "Imiglucerase (glucocerebrosidase): Pediatric drug information") Note: Dose should be individualized. IV: Gaucher disease, type 1: Children and Adolescents: Limited data for children Initial: 30 to 60 units/kg/dose every 2 weeks; based on risk for complications (Andersson 2005; Baldellou 2004; Charrow 2004); failure to respond to treatment within 6 months may indicate the need for a higher dosage (Baldellou 2004); doses >60 units/kg/dose are rarely needed (Charrow 2004) High risk for complications: Initial dose: 60 units/kg every 2 weeks. High risk is defined as one or more of the following: symptomatic disease including manifestations of abdominal or bone pain, fatigue, exertional limitations, weakness, and cachexia; growth failure; evidence of skeletal involvement; platelet count ≤60,000 mm3 and/or documented abnormal bleeding episode(s); Hgb ≥2 g/dL below lower limit for age and sex; impaired quality of life (Andersson 2005) Maintenance: Limited data available. Assess calculated dose and patient growth (weight) frequently to maintain consistent dosage per kg body weight (Baldellou 2004). The appropriate dose to prevent long-term complications in pediatric patients is unknown; after therapeutic goals achieved, any dose reduction should be considered with extreme caution and at intervals no more frequent than every 6 months; minimum dose: 30 units/kg/dose every 2 weeks (Andersson 2005; Baldellou 2004) Gaucher disease, type 3 (Canadian labeling; not in US labeling): Children ≥2 years and Adolescents: Limited data for children

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling.

Warnings & Precautions

Source: Lexicomp

Anaphylactic reactions

Have been reported (• Antibody formation: Development of IgG antibodies has been reported in ~15% of patients and has been observed within 6 months from the onset of therapy; antibody formation is rare after 12 months of therapy; may increase risk of hypersensitivity reactions. Disease-related concerns:

Pulmonary hypertension/pneumonia

Has been observed during treatment; causal relationship has not been established as this is a complication of Gaucher disease. Afebrile patients with respiratory symptoms should be assessed for pulmonary hypertension. Dosage form specific issues:

Polysorbate 80

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling. Other warnings/precautions:

Experienced health care provider

Should be administered under the supervision of a health care provider experienced in treatment of Gaucher disease.

Registry

A registry has been established and all patients with Gaucher disease, and physicians who treat Gaucher disease are encouraged to participate. Information on the International Collaborative Gaucher Group (ICGG) Gaucher Registry may be obtained at https://www.registrynxt.com, or by calling 1-800-745-4447 (ext.15500).

Pregnancy & Lactation

Pregnancy

FDA category C

Animal reproduction studies have not been conducted; however, imiglucerase has been used safely during pregnancy based on available data (Sherer, 2003; Zimran, 2009). Doses of imiglucerase should be based on prepregnancy weight and adjusted as clinically indicated (Granovsky-Grisaru, 2011).

Lactation

It is not known if imiglucerase is excreted in breast milk. The manufacturer recommends that caution be exercised when administering imiglucerase to nursing women. A case report described a small amount of imiglucerase excreted into breast milk. The maximum amount of enzyme activity was obtained in the first milk at the end of the imiglucerase infusion; enzyme activity rapidly declined to preinfusion levels (Sekijima, 2010). Enzyme ingested by a nursing infant would likely degrade in their diges

Monitoring

Clinical pearl	CBC, platelets, liver function tests, IgG antibody formation periodically during the first year of treatment (Canadian labeling recommends antibody testing approximately every 3 months during the first year and at ~18 months), chitotriosidase, angiotensin-converting enzyme (ACE), acid phosphatase (AP), iron, iron-binding capacity, ferritin, vitamin B12; MRI or CT scan (liver and spleen volume), skeletal x-rays, DXA; pulmonary function tests; ECG/echocardiography; growth in pediatric patients

Clinical pearl

CBC, platelets, liver function tests, IgG antibody formation periodically during the first year of treatment (Canadian labeling recommends antibody testing approximately every 3 months during the first year and at ~18 months), chitotriosidase, angiotensin-converting enzyme (ACE), acid phosphatase (AP), iron, iron-binding capacity, ferritin, vitamin B12; MRI or CT scan (liver and spleen volume), skeletal x-rays, DXA; pulmonary function tests; ECG/echocardiography; growth in pediatric patients

Biology & Pharmacokinetics

Pharmacokinetics

Half-life	3.6 to 10.4 minutes

Drug–drug interactions (1, DDInter)

Interacting drug	Severity	Management
Miglustat	moderate

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cerezyme	Vial 400 U	1 vial	Ulfa Pharma Co.	—