ABCERTIN

Imiglucerase is a hydrolytic lysosomal glucocerebrosidase-specific enzyme.

It is an analogue of the human enzyme b-glucocerebrosidase (b-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45), 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 glucocerebrosidase.

CEREZYME (imiglucerase) for injection is intended for intravenous use.

It is supplied as a sterile, nonpyrogenic, white to off-white lyophilized powder for reconstitution with Sterile Water for Injection, USP.

Each single-dose vial contains 424 units imiglucerase, mannitol (340 mg), polysorbate 80, NF (1.06 mg), and sodium citrates: disodium hydrogen citrate (36 mg) and trisodium citrate (104 mg).

An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-b-D-glucopyranoside (pNP-Glc) per minute at 37°C. Reconstituted solutions have a pH of approximately 6.1.

is indicated for the treatment of non-central nervous system (CNS) manifestations of Type 1 or Type 3 Gaucher disease in adults and pediatric patients.

CEREZYME is a hydrolytic lysosomal glucocerebrosidase-specific enzyme indicated for the treatment of non-central nervous system (CNS) manifestations of Type 1 or Type 3 Gaucher disease in adults and pediatric patients.

Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, which results in accumulation of glucocerebroside in various tissues including liver, spleen, and bone marrow.

The mannose sugars on imiglucerase mediate binding to and internalization by cells including macrophages.

CEREZYME catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. 12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with CEREZYME. 12.3 Pharmacokinetics During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 units/kg) of CEREZYME, steady-state enzymatic activity was achieved by 30 minutes.

Following infusion, the half-life of plasma enzymatic activity ranged from 3.6 to 10.4 minutes.

Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± SD, 14.5 ± 4.0 mL/min/kg).

The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (mean ± SD, 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.

Antidrug Antibody Effects on Pharmacokinetics 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis Infusion-Associated Reactions Adverse reactions reported in adults and pediatric patients include back pain, chills, dizziness, fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and vomiting.fda.gov/medwatch. 6.1 Clinical Trials and Postmarketing Experience The following adverse reactions associated with the use of imiglucerase were identified in clinical studies or postmarketing reports.

Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table for adverse reactions occurring in adults and pediatric patients treated with CEREZYME in clinical trials and the postmarketing setting.

Table 2: Adverse Reactions in Adults and Pediatric Patients Treated with CEREZYME Adverse Reactions Nervous system disorders dizziness, headache Cardiac disorders tachycardia Vascular disorders cyanosis, Signs and symptoms suggestive of hypersensitivity reactions including anaphylaxis and other infusion-associated reactions. flushing, hypotension, hypertension Respiratory, thoracic and mediastinal disorders cough, dyspnea, pneumonia, pulmonary hypertension Gastrointestinal disorders abdominal pain, diarrhea, nausea, vomiting Immune system disorders anaphylaxis, hypersensitivity Skin and subcutaneous tissue disorders angioedema, pruritus, rash, urticaria Musculoskeletal and connective tissue disorders back pain General disorders and administration site conditions chest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia 6.2 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of CEREZYME or of other imiglucerase products.

Approximately 15% of patients treated and tested to date have developed IgG antibody to CEREZYME 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 higher risk of hypersensitivity reaction.

Patients who developed IgG antibody to

CEREZYME had increased elimination half-life compared to patients without antibody.

CEREZYME under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

The recommended dosage is 2.5 units/kg three times a week to 60 units/kg once every two weeks administered intravenously.

Titrate the dosage based on disease severity and therapeutic goals for the patient.

See the full prescribing information for dosage modifications due to hypersensitivity reactions and/or IARs.

See the full prescribing information for preparation and administration instructions. 2.1 Recommendations Prior to CEREZYME Treatment Administer CEREZYME under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

CEREZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.

For patients who experience hypersensitivity reactions to CEREZYME, premedicate with antihistamines and/or corticosteroids.

Monitor patients for the occurrence of new hypersensitivity reactions. 2.2 Recommended Dosage and Administration Ensure physicians knowledgeable in the management of patients with Gaucher disease direct therapy with CEREZYME.

The recommended dosage of

CEREZYME is 2.5 units/kg three times a week to 60 units/kg once every two weeks administered intravenously.

For adults and pediatric patients weighing greater than 20 kg, infuse the diluted CEREZYME solution over to 2 hours.

For pediatric patients weighing 20 kg or less, infuse the diluted CEREZYME solution over 2 hours. 2.3 Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions If a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe infusion-associated reaction (IAR) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment.

If a mild or moderate hypersensitivity reaction or a mild or moderate IAR occurs, consider decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids. 2.4 Preparation Instructions Use aseptic technique during preparation.

Reconstitution 1.

Determine the number of

CEREZYME vials to be reconstituted based on the individual patient's dosage regimen and remove vial(s) from the refrigerator. 2.

Reconstitute each vial of

CEREZYME by slowly injecting 10.2 mL of Sterile Water for Injection, down the inside wall of each vial. 3.

Roll and tilt the vial to allow the powder to dissolve completely.

Visually inspect the reconstituted solution for particulate matter and discoloration.

Discard if opaque particles or discoloration are observed.

After reconstitution, each vial will yield CEREZYME at a concentration of 40 units/mL. 4.

Withdraw the required volume of

CEREZYME from the vial(s).

Dilution Dilute the

CEREZYME solution for infusion promptly with 0.9% Sodium Chloride Injection to a final volume that is calculated based on prescribed dose.

CEREZYME administered at a dose of 60 units/kg, use the following final volumes.

For patients weighing between 1.5 kg and less than 6 kg, dilute CEREZYME to a final volume of 12 mL in a syringe for infusion.

For patients weighing between 6 kg and less than 13 kg, dilute CEREZYME to a final volume of 26 mL in a syringe for infusion.

For patients weighing between 13 kg and less than or equal to 20 kg, dilute CEREZYME to a final volume of 100 mL in an infusion bag.

For patients weighing greater than 20 kg and less than or equal to 100 kg, dilute CEREZYME to a final volume of 200 mL in an infusion bag.

For patients weighing greater than 100 kg, dilute CEREZYME to a final volume of 400 mL in an infusion bag.

If CEREZYME is prescribed at a dose lower than 60 units/kg, dilute the required total units of reconstituted CEREZYME (at a concentration of 40 units/mL) with 0.9% Sodium Chloride Injection to a final concentration between 6 units/mL and 30 units/mL inclusive.

If the determined dose of

CEREZYME translates into a total volume of 26 mL or less, administer using a syringe for infusion via a syringe pump.

For accuracy of dilution, if less than 2 mL of reconstituted CEREZYME (40 units/mL) is needed for the preparation of the determined dose, prepare a larger final volume of CEREZYME for infusion initially maintaining the final concentration of the diluted CEREZYME solution between 6 units/mL to 30 units/mL.

Subsequently, discard the excess volume and administer only the volume of CEREZYME solution corresponding to the prescribed dose.

Gently invert the syringe for infusion or the infusion bag to mix the solution.

CEREZYME preparation, avoid vigorous shaking, agitation and foaming.

Vials are for single dose only.

Discard any unused solution. 2.5 Administration Instructions Visually inspect the diluted solution prior to administration of the final product for particulate matter and discoloration.

Slight flocculation of protein particles (described as thin translucent fibers) may occur after dilution and does not affect the quality of the product.

CEREZYME as an intravenous infusion with a 0.2 micron in-line low protein-binding filter.

Table 1: Total Infusion Volumes and Infusion Time for CEREZYME Patient Weight Total Infusion Volume Final concentration of diluted CEREZYME solution is between 6 units/mL and 30 units/mL.

Rate 1.5 kg to < 6 kg 12 mL 2 hours 6 mL/hour 6 kg to < 13 kg 26 mL 2 hours 13 mL/hour 13 kg to ≤ 20 kg 100 mL 2 hours 50 mL/hour > 20 kg to ≤ 100 kg 200 mL to 2 hours 200 mL/hour > 100 kg 400 mL to 2 hours 400 mL/hour 2.6 Storage and Handling If the reconstituted CEREZYME vial is not used immediately: Refrigerate the reconstituted solution at 2°C to 8°C (36°F to 46°F) or store at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours.

Refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

(imiglucerase) for injection is supplied as a white to off-white lyophilized powder in a carton containing one single-dose vial: NDC 58468-4663-1.

Each vial contains 400 units of imiglucerase.

CEREZYME does not contain any preservatives.

Store refrigerated at 2°C to 8°C (36°F to 46°F).

For storage of reconstituted and diluted solution.

Store refrigerated at 2°C to 8°C (36°F to 46°F).

For storage of reconstituted and diluted solution.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CEREZYME during pregnancy.

Pregnant women exposed to

CEREZYME and health care providers are encouraged to contact the Gaucher patient registry at 1-800-745-4447, extension 15500 or visit Risk Summary Available data on more than 500 pregnancies from the international Gaucher Disease registry, postmarketing reports, published observational studies and case reports with CEREZYME or non–US-licensed imiglucerase use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

There are risks associated with symptomatic Type I Gaucher disease in pregnancy.

No animal reproduction studies have been conducted with imiglucerase.

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryo/Fetal Risk Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations.

Untreated symptomatic

Type 1 Gaucher disease may lead to complications during pregnancy, including hepatosplenomegaly, which can interfere with the normal growth of a pregnancy and thrombocytopenia, which can lead to excessive bleeding.

The safety and effectiveness of

CEREZYME for the treatment of non-CNS manifestations of Type 1 or Type 3 Gaucher disease have been established in pediatric patients.

Use of CEREZYME for the treatment of non-CNS manifestations of Type 1 Gaucher disease is supported by evidence from adequate and well-controlled trials in adults and pediatric patients 12 years of age and older and additional safety and efficacy data from an observational study of Type 1 Gaucher disease in pediatric patients.

Use of CEREZYME for the treatment of non-CNS manifestations of Type 3 Gaucher disease is supported by evidence from adequate and well-controlled trials in adults and pediatric patients 12 years of age and older with Type I Gaucher disease and additional safety and efficacy data from an observational study of Type 3 Gaucher disease in adults and pediatric patients.

Among the patients with

Type 1 Gaucher disease in Study 3 who had hemoglobin or platelet count measurements to 3 years after initiating CEREZYME (n = 1,053), 6% of patients were and over and 1% were and over.

No overall differences in effectiveness of

CEREZYME were observed between patients 65 years of age and older and younger adult patients with Type 1 Gaucher disease.

The safety evaluation for patients 65 years of age and older with Type 1 Gaucher disease was conducted using data from a pharmacovigilance database that collected individual case safety reports and did not reveal new safety findings.

Clinical studies of

CEREZYME did not include sufficient numbers of patients 65 years of age and older to detect differences in safety between older and younger adult patients with Type 1 Gaucher disease.

CEREZYME did not include sufficient numbers of patients 65 years of age and older to detect differences in efficacy and safety between older and younger adult patients with Type 3 Gaucher disease.