Cerezyme® (imiglucerase for injection) is an analogue of the human enzyme β-glucocerebrosidase, produced by recombinant DNA technology. β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.

Cerezyme® is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental gluco-cerebrosidase. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.

Cerezyme® is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product. The quantitative composition of the lyophilized drug is provided in the following table:

Ingredient	200 Unit Vial	400 Unit Vial
Imiglucerase (total amount)*	212 units	424 units
Mannitol	170 mg	340 mg
Sodium Citrates	70 mg	140 mg
(Trisodium Citrate)	(52 mg)	(104 mg)
(Disodium Hydrogen Citrate)	(18 mg)	(36 mg)
Polysorbate 80, NF	0.53 mg	1.06 mg
Citric Acid and/or Sodium Hydroxide may have been added at the time of manufacture to adjust pH.

*This provides a respective withdrawal dose of 200 and 400 units of imiglucerase. An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. The product is stored at 2-8°C (36-46°F). After reconstitution with Sterile Water for Injection, USP, the imiglucerase concentration is 40 U/mL (see DOSAGE AND ADMINISTRATION for final concentrations and volumes). Reconstituted solutions have a pH of approximately 6.1.

Last updated on RxList: 10/9/2008

Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:

1. anemia
2. thrombocytopenia
3. bone disease
4. hepatomegaly or splenomegaly

Cerezyme® (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient's clinical manifestations.

Cerezyme® should be stored at 2-8°C (36-46°F). After reconstitution, Cerezyme® should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme® after the expiration date on the vial.

On the day of use, after the correct amount of Cerezyme® to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table:

	200 Unit Vial	400 Unit Vial
Sterile water for reconstitution	5.1 mL	10.2 mL
Final volume of reconstituted product	5.3 mL	10.6 mL
Concentration after reconstitution	40 U/mL	40 U/mL
Withdrawal volume	5.0 mL	10.0 mL
Units of enzyme within final volume	200 units	400 units

A nominal 5.0 mL for the 200 unit vial (10.0 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme® for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Cerezyme® is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme® does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme® , after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25°C) and at 2-8°C. Cerezyme® , when diluted, has been shown to be stable for up to 24 hours when stored at 2-8°C.

Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered.

Cerezyme® (imiglucerase for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available as follows:

200 Units per Vial NDC 58468-1983-1
400 Units per Vial NDC 58468-4663-1

Store at 2-8°C (36-46°F).

Cerezyme® (imiglucerase for injection) is manufactured by: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142 ,USA. Certain manufacturing operations may have been performed by other firms. (4/05). FDA revision date: 3/3/2005

Last updated on RxList: 10/9/2008

Since the approval of Cerezyme® (imiglucerase for injection) in May 1994, Genzyme has maintained a worldwide post-marketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme® since 1994. Actual patient exposure is difficult to obtain due to the voluntary nature of the database and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme® since 1994 is likely to be greater than estimated from these voluntary sources and, therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences.

Experience in patients treated with Cerezyme® has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme® administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Each of these events was found to occur in < 1% of the total patient population.

Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported (see WARNINGS). Each of these events was found to occur in <1.5% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme® in most patients. Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme® include: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in <1.5% of the total patient population.

Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as ages 2 – 12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 – 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritis, and rash.

In addition to the adverse reactions that have been observed in patients treated with Cerezyme® , transient peripheral edema has been reported for this therapeutic class of drug.

No information provided.

Last updated on RxList: 10/9/2008

Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme® (imiglucerase for injection) during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to Cerezyme® after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity. Patients with antibody to Cerezyme® have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.

Treatment with Cerezyme® should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product.

Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids.

General

In less than 1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme® (imiglucerase for injection). Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme®. No causal relationship with Cerezyme® has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.

Therapy with Cerezyme® should be directed by physicians knowledgeable in the management of patients with Gaucher disease.

Caution may be advisable in administration of Cerezyme® to patients previously treated with Ceredase® (alglucerase injection) and who have developed antibody to Ceredase® or who have exhibited symptoms of hypersensitivity to Ceredase®.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme® (imiglucerase for injection) on carcinogenesis, mutagenesis, or impairment of fertility.

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Cerezyme® (imiglucerase for injection). It is also not known whether Cerezyme® can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme® should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cerezyme® (imiglucerase for injection) is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Cerezyme® (imiglucerase for injection) have been established in patients between 2 and 16 years of age. Use of Cerezyme® in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme® and Ceredase® (alglucerase injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term post-marketing experience. Cerezyme® has been administered to patients younger than 2 years of age, however the safety and effectiveness in patients younger than 2 have not been established.

Last updated on RxList: 10/9/2008

Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose there have been no reports of obvious toxicity.

There are no known contraindications to the use of Cerezyme® (imiglucerase for injection). Treatment with Cerezyme® should be carefully re-evaluated if there is significant clinical evidence of hypersensitivity to the product.

Last updated on RxList: 10/9/2008

Mechanism of Action/Pharmacodynamics

Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, resulting in accumulation of glucocerebroside in tissue macrophages which become engorged and are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly, skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures. Cerezyme® (imiglucerase for injection) catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, Cerezyme® improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase® (alglucerase injection).

Pharmacokinetics

During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 U/kg) of Cerezyme® (imiglucerase for injection), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± S.D., 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. The pharmacokinetics of Cerezyme® do not appear to be different from placental-derived alglucerase (Ceredase® ).

In patients who developed IgG antibody to Cerezyme® , an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody (see WARNINGS).

Last updated on RxList: 10/9/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 10/9/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

IMIGLUCERASE - INJECTION

(im-eh-GLUE-ser-aze)

COMMON BRAND NAME(S): Cerezyme

USES: Imiglucerase is used to treat a certain rare genetic problem (Gaucher disease). Imiglucerase replaces a certain natural substance (an enzyme called glucocerebrosidase) that is missing in people with Gaucher disease.

This medication improves blood, bone, liver, and spleen problems caused by Gaucher disease. Imiglucerase does not correct the genetic problem, and treatment must be continued for life.

HOW TO USE: Follow all instructions for proper mixing and dilution with the correct IV fluids. If you have questions about using this medication properly, consult your pharmacist.

Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

This medication is given slowly into a vein by a health care professional over 1 to 2 hours or as directed by your doctor. Your dose and how often it is given depends on your weight, condition, and response to treatment. Your doctor may direct you to receive it as often as 3 times per week or as little as once every 2 weeks. Follow your doctor's directions carefully.

Tell your doctor if your condition persists or worsens. Blood, liver, and spleen problems usually improve in the first year of treatment. It may take 2 to 3 years of treatment to see the full benefit to your bones.

SIDE EFFECTS: Fever, headache, nausea, vomiting, swelling of the hands/feet (edema), or redness/pain/itching/swelling at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, flushing, chest pain, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using imiglucerase, tell your doctor or pharmacist if you are allergic to it; or to alglucerase; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: antibodies to alglucerase.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., IgG antibodies) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light and moisture. Do not store in the bathroom. After mixing, discard any unused solution. Do not save for later use. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.