atment for igg antibody formation [see adverse reactions (6.2) ] . if a severe hypersensitivity reaction occurs, discontinue cerezyme treatment and initiate appropriate medical treatment. consider the risks and benefits of readministering cerezyme to individual patients following a severe reaction. if the decision is made to readminister the product, consider reducing the rate of infusion and pretreat with antihistamines and/or corticosteroids and monitor patients for the occurrence of new signs and symptoms of a severe hypersensitivity reaction.

d therapeutic goals for the patient. for patients who experience hypersensitivity reactions to cerezyme premedicate with antihistamines and/or corticosteroids. monitor patients for the occurrence of new hypersensitivity reactions [see warnings and precautions (5.1) ] . 2.2 preparation and administration instructions cerezyme does not contain preservatives. reconstitution and dilution using aseptic technique determine the number of cerezyme vials to be reconstituted based on the individual patient's dosage regimen and remove vial(s) from the refrigerator. reconstitute each 400 unit vial of cerezyme by slowly injecting 10.2 ml of sterile water for injection, usp, down the inside wall of each vial. roll and tilt the vial to allow the powder to dissolve completely. each vial will yield a concentration of cerezyme after reconstitution of 40 units/ml. visually inspect the solution after reconstitution for particulate matter and discoloration. discard if opaque particles or discoloration are observed. withdraw up to 10 ml per vial. discard unused portion. dilute the cerezyme solution promptly with 0.9% sodium chloride injection, usp, to a final volume of 100 to 200 ml. for patients weighing less than 18 kg, dilute cerezyme to a final volume of 100 ml. gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation. visually inspect the 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. for patients weighing 18 kg and greater, infuse the diluted cerezyme solution over 1 to 2 hours. for patients weighing less than 18 kg, infuse the diluted cerezyme solution over 2 hours. the diluted solution may be filtered through an in-line low protein-binding 0.2 µm filter during administration. storage and handling if the reconstituted cerezyme vial is not used immediately, store at room temperature at 68°f to 77°f (20°c to 25°c) or refrigerated at 36°f to 46°f (2°c to 8°c) for up to 12 hours. after dilution, cerezyme is stable for up to 24 hours when stored refrigerated at 36°f to 46°f (2°c to 8°c).

her infusion-associated reactions [see warnings and precautions (5.1)] . flushing, hypotension 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 adverse reactions reported in pediatric patients 2 years of age and older were similar to adults. 6.2 immunogenicity as with all therapeutic proteins, there is potential for immunogenicity. the detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. for these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other imiglucerase products may be misleading. 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 [see warnings and precautions (5.1) ] . patients who developed igg antibody to cerezyme had increased elimination half-life compared to patients without antibody [see clinical pharmacology (12.3) ] .

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. clinical considerations disease-associated 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 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. 8.2 lactation risk summary available published literature suggests a small amount of imiglucerase is present in breast milk immediately following an infusion of imiglucerase. published case reports and postmarketing reports of breastfed infants have not reported adverse effects due to cerezyme exposure. there are no data available on the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cerezyme and any potential adverse effects on the breastfed infant from imiglucerase or from the underlying maternal condition. lactating women with gaucher disease treated with cerezyme should be encouraged to enroll in the gaucher patient registry [see use in specific populations (8.1) ] . 8.4 pediatric use the safety and effectiveness of cerezyme for treatment of type 1 gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly have been established in pediatric patients 2 years of age and older. use of cerezyme for this indication is supported by evidence from adequate and well-controlled studies of cerezyme and alglucerase in adults and pediatric patients 12 years of age and older, with additional data obtained from the medical literature and from postmarketing experience in pediatric patients as young as 2 years of age [see adverse reactions (6.1) , clinical studies (14) ] . the safety and effectiveness of cerezyme have not been established in pediatric patients younger than 2 years of age.

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. clinical considerations disease-associated 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 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.

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 [see adverse reactions (6.2) ] .

€“ alglucerase) [95% ci] confidence intervals were calculated using the t distribution (appropriate for small sample sizes) and the standard error of the difference in sample means (i.e. the pooled estimate of the common standard deviation, computed as the weighted average of the standard deviations in the two treatment groups); there was no evidence that the assumption of equal variances between the groups was violated. hemoglobin concentration (g/dl) baseline 10.7 10.9 – absolute change from baseline 1.9 1.6 0.3 [-0.6, 1.3] platelet count (× 10 3 /ml 3 ) baseline 68.5 74.2 – absolute change from baseline 22.7 15.8 6.9 [-10.4, 24.1] liver volume (ml) baseline 2521 2788 – absolute change from baseline -310 -307 -3 [-246, 240] percent change from baseline (%) -11 -10 -1 [-9, 7] spleen volume (ml) baseline 2369 2603 – absolute change from baseline -902 -874 -28 [-652, 596] percent change from baseline (%) -35 -30 -5 [-14, 4] bone x-rays showed improvements in cortical thickness and lucencies in 7 of 11 cerezyme treated patients. in study rc 92-0501, twenty-nine patients continued treatment for total duration of 24 months. patients were unblinded at 9 months and allowed to cross-over to cerezyme treatment. at 24 months, mean increase in hemoglobin was 2.4 g/dl, mean increase in platelet count was 40 ×10 3 /ml 3 , mean change in liver volume was -20%, and mean change in spleen volume was -57%.

and may involve long-term follow-up. for information regarding the registry program, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.