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    Imiglucerase

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    Oct.10.2023

    Imiglucerase

    Indications/Dosage

    Labeled

    • Gaucher disease

    Off-Label

      † Off-label indication

      For enzyme replacement therapy in patients with confirmed Gaucher disease type 1 (GD1) who have at least one of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly, or splenomegaly

      Intravenous dosage

      Adults

      30 to 60 units/kg IV every 2 weeks initially.[33013] [49245] [69534] Premedicate patients with hypersensitivity reactions with antihistamines and/or corticosteroids. The FDA-approved labeling recommends a dosage range of 2.5 units/kg IV infused 3 times per week to 60 units/kg IV infused once every 2 weeks.[49245] Individualize maintenance dosages according to patient goals and response; doses more than 60 units/kg every 2 weeks are rarely needed. Although an every 2-week regimen is the most commonly studied schedule, some data suggest that the dosage interval may be extended to every 3 or 4 weeks for certain patients with non-severe GD1.[56815] [56816] However, when using an extended schedule, the overall monthly dosage typically remains approximately the same. The authors of one randomized trial of 95 patients with GD1 concluded that an every 4-week regimen at the same total monthly dose may be considered for clinically stable adult patients who have been on imiglucerase therapy for 2 years or more at 20 to 60 units/kg every 2 weeks; however, long-term follow-up data are needed for extended-interval regimens.[56816] Long-term data from adult patients with GD1 who received imiglucerase every 2 weeks showed a continued favorable response. After 10 years, the majority of patients were receiving 15 to 45 units/kg every 2 weeks.[56817]

      Children and Adolescents 2 to 17 years

      30 to 60 units/kg IV every 2 weeks initially; children at highest risk for complications should receive 60 units/kg IV every 2 weeks initially.[33013] [49245] [69534] Premedicate patients with hypersensitivity reactions with antihistamines and/or corticosteroids. The FDA-approved labeling recommends a dosage range of 2.5 units/kg IV infused 3 times per week to 60 units/kg IV infused once every 2 weeks.[49245] Individualize maintenance dosages according to patient goals and response; doses more than 60 units/kg IV every 2 weeks are rarely needed. Assess the need for dosage adjustments frequently to maintain a constant dose/kg body weight. All children with physical signs or manifestations of Gaucher disease should be treated with enzyme replacement therapy; all children with GD1 will respond to enzyme replacement therapy with appropriate doses.[33013] [69534] Long-term data from pediatric patients with GD1 who received imiglucerase every 2 weeks showed a continued favorable response. After 10 years, the majority of patients were receiving 15 to 45 units/kg every 2 weeks.[56817]

      Therapeutic Drug Monitoring

      Maximum Dosage Limits

        Patients with Hepatic Impairment Dosing

        Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

        Patients with Renal Impairment Dosing

        Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

        † Off-label indication
        Revision Date: 10/10/2023, 03:12:50 PM

        References

        33013 - Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr 2004;144:112-20.49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.56815 - Serratrice C, Swiader L, Serratrice J, et al. Initiation treatment with imiglucerase every 3 weeks in type 1 Gaucher disease. Eur J Intern Med 2012; 23(2):e71-2.56816 - Kishnani P, DiRocco M, Kaplan P, et al. A randomized trial comparing the efficacy and safety of imiglucerase (Cerezyme) infusions every 4 weeks versus every 2 weeks in the maintenance therapy of adult patients with Gaucher disease type 1. Mol Genet Metab 2009;96(4):164-70.56817 - Weinreb N, Goldblatt J, Villalobos J, et al. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 2013;36:543-53.69534 - Kaplan P, Baris H, Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatric 2013;172:447-58.

        How Supplied

        Imiglucerase Lyophilisate for solution for injection

        Cerezyme 200unit Powder for Injection (58468-1983) (Genzyme Corp, a subsidiary of Sanofi) (off market)Cerezyme 200unit Powder for Injection package photo

        Imiglucerase Lyophilisate for solution for injection

        Cerezyme 400unit Powder for Injection (58468-4663) (Genzyme Corp, a subsidiary of Sanofi) nullCerezyme 400unit Powder for Injection package photo

        Description/Classification

        Description

        Imiglucerase is an intravenous enzyme replacement therapy indicated for the long term management of adult and pediatric patients 2 years and older with type 1 Gaucher disease. Imiglucerase is a hydrolytic lysosomal glucocerebrosidase-specific enzyme, an analogue of the human enzyme beta-glucocerebrosidase.[49245] In type 1 Gaucher disease, a genetic disease found most commonly among Ashkenazi Jews, patients are deficient in the enzyme glucocerebrosidase, which is responsible for degradation of glucosylceramide. Glucosylceramide arises mainly from the breakdown of red and white blood cells and turnover of lipids during CNS myelin sheath formation. As evident in type 1 Gaucher disease, excess storage of glucosylceramide occurs within the macrophage lysosome, leading to progressive organ enlargement (liver, spleen, bone marrow), thrombocytopenia, anemia, recurrent infection, and skeletal weakening (e.g., osteonecrosis, osteopenia).[27584] Imiglucerase is able to break down glucocerebrosidase into its more basic elements, glucose and ceramide, thereby reducing the build up of waste products in cells. The most commonly reported adverse reactions are hypersensitivity and infusion-related reactions.[49245]

        Classifications

        • Alimentary Tract and Metabolism
          • Metabolic Disorder Agents
            • Lysosomal Storage Disorder Agents
              • Gauchers Disease Agents
        Revision Date: 10/10/2023, 03:12:50 PM

        References

        27584 - Zimran A, Elstein D. Gaucher disease and the clinical experience with substrate reduction therapy. Philos Trans R Soc Lond B Biol Sci 2003;358:961-6.49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.

        Administration Information

        General Administration Information

        For storage information, see the specific product information within the How Supplied section.

        Route-Specific Administration

        Injectable Administration

        • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Imiglucerase is a white to off-white lyophilized powder.[49245]

        Intravenous Administration

        Reconstitution

        • Determine the number of vials to be reconstituted based on the individual patient's dosage regimen and remove the vials from the refrigerator.
        • Reconstitute each 400 unit vial with 10.2 mL of Sterile Water for Injection for a resultant concentration of 40 units/mL.
        • Roll and tilt the vial to allow the powder to dissolve completely. Visually inspect the solution after reconstitution for particulate matter and discoloration. Discard if opaque particles or discoloration are observed.
        • Storage: If the reconstituted vial is not used immediately, store at room temperature at 68 to 77 degrees F (20 to 25 degrees C) or refrigerated at 36 to 46 degrees F (2 to 8 degrees C) for up to 12 hours.

         

        Dilution

        • Withdraw the appropriate calculated dosage from the reconstituted vial(s) and further dilute with 0.9% Sodium Chloride Injection.
          • Adults and Pediatric patients weighing 18 kg or more: Dilute to a final volume of 100 to 200 mL.
          • Pediatric patients weighing less than 18 kg: Dilute to a final volume of 100 mL.
        • Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation. Being a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after preparing the infusion; this does not affect the quality of the product.
        • Storage: After dilution, the solution is stable for up to 12 hours when stored refrigerated at 36 to 46 degrees F (2 to 8 degrees C).

         

        Intravenous infusion

        • Adults and Pediatric patients weighing 18 kg or more: Infuse over 1 to 2 hours.
        • Pediatric patients weighing less than 18 kg: Infuse over 1 hour.
        • During administration, the diluted solution may be filtered through an in-line low protein-binding 0.2 micron filter.[49245]

        Clinical Pharmaceutics Information

        From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

        Imiglucerase

        pH Range
        pH of approximately 6.1.
        ReferencesCerezyme (imiglucerase) package insert. Cambridge, MA. Genzyme Corporation. 2022; Dec
        Sodium Content
        The formulation contains trisodium citrate 52 mg and disodium hydrogen citrate 18 mg per 200 units of imiglucerase.
        ReferencesCerezyme (imiglucerase) package insert. Cambridge, MA. Genzyme Corporation. 2022; Dec
        Light Exposure
        The manufacturer makes no statement in the official labeling regarding light exposure of imiglucerase.
        ReferencesCerezyme (imiglucerase) package insert. Cambridge, MA. Genzyme Corporation. 2022; Dec
        Filtration
        A slight flocculation of the protein (described as thin translucent fibers) may occur occasionally in the solution diluted for administration. For this reason, the manufacturer states that the diluted drug may be administered using a low-protein-binding 0.2-micron inline filter.
        ReferencesIpema HJ, Tanzi-Samaan MG, Moody ML, et al. Drugs to be used with a filter for preparation and/or administration. Hosp pharm. 2012; 47
        ReferencesCerezyme (imiglucerase) package insert. Cambridge, MA. Genzyme Corporation. 2022; Dec
        Sorption Leaching
        The manufacturer makes no statement in the official labeling regarding types of containers suitable for use with imiglucerase.
        ReferencesCerezyme (imiglucerase) package insert. Cambridge, MA. Genzyme Corporation. 2022; Dec
          Revision Date: 10/10/2023, 03:12:50 PMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

          References

          49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.

          Adverse Reactions

          Moderate

          • antibody formation
          • chest pain (unspecified)
          • dyspnea
          • erythema
          • hypotension
          • infusion-related reactions
          • sinus tachycardia

          Mild

          • abdominal pain
          • back pain
          • chills
          • cough
          • diarrhea
          • dizziness
          • fatigue
          • fever
          • flushing
          • headache
          • injection site reaction
          • nausea
          • pruritus
          • rash
          • urticaria
          • vomiting

          Severe

          • anaphylactoid reactions
          • angioedema
          • cyanosis
          • pulmonary hypertension

          Serious hypersensitivity and infusion-related reactions, including anaphylaxis and anaphylactoid reactions, have been reported with imiglucerase treatment. Reactions that have been reported during or shortly after infusion have included pruritus, flushing, urticaria, rash, angioedema, chest pain (unspecified), dyspnea, cough, cyanosis, sinus tachycardia, and hypotension. Approximately 15% of patients receiving imiglucerase develop IgG antibody formation during the first year of treatment. In most patients, the development of antibodies does not prohibit continued drug administration. Antibodies are most likely to develop within the first 6 to 12 months of treatment. While patients with IgG antibodies are at higher risk of developing imiglucerase hypersensitivity, the development of antibodies is not necessary for a hypersensitivity reaction to occur. Approximately 46% of with detectable IgG antibodies experience symptoms of hypersensitivity. If a severe hypersensitivity reaction occurs, discontinue imiglucerase and initiate appropriate medical treatment. Consider the risk and benefit of readministering treatment. If the decision is made to readminister imiglucerase, consider pretreatment with antihistamines and/or corticosteroids and a reduced rate of infusion and monitor patients for the occurrence of new signs and symptoms of a severe hypersensitivity reaction.[49245]

          Injection site reactions have been reported during imiglucerase treatment. An injection site reaction may present as infusion-site burning, discomfort, or swelling (erythema).[49245]

          General adverse reactions reported during imiglucerase treatment include dizziness, headache, fatigue, fever, chills, and back pain.[49245]

          Nausea, vomiting, abdominal pain, and diarrhea have been reported during imiglucerase treatment.[49245]

          Pneumonia and pulmonary hypertension have been reported during imiglucerase treatment.[49245]

          Revision Date: 10/10/2023, 03:12:50 PM

          References

          49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.

          Contraindications/Precautions

          Absolute contraindications are italicized.

          • antibody formation
          • breast-feeding
          • infusion-related reactions
          • pregnancy
          • requires an experienced clinician

          The use of imiglucerase requires an experienced clinician knowledgeable in the management of Gaucher's disease.[49245]

          Serious hypersensitivity and infusion-related reactions, including anaphylaxis, have been reported with imiglucerase treatment. Reactions that have been reported during or shortly after infusion have included pruritus, flushing, urticaria, rash, angioedema, chest pain (unspecified), dyspnea, cough, cyanosis, tachycardia, and hypotension. Patients with antibody formation to imiglucerase have a higher risk of hypersensitivity reactions. However, not all patients with symptoms of hypersensitivity have detectable IgG antibody. Consider periodic monitoring of patients during the first year of treatment for IgG antibody formation. If a severe hypersensitivity reaction occurs, discontinue imiglucerase and initiate appropriate medical treatment. Consider the risk and benefit of readministering treatment. If the decision is made to readminister imiglucerase, consider pretreatment with antihistamines and/or corticosteroids and a reduced rate of infusion and monitor patients for the occurrence of new signs and symptoms of a severe hypersensitivity reaction.[49245]

          Data on more than 500 pregnancies from the international Gaucher Disease registry, postmarketing reports, published observational studies, and case reports with imiglucerase during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction study data are not available.[49245] A report from a panel of clinicians that treat Gaucher's disease indicated that treatment with enzyme replacement therapy during pregnancy led to a reduced risk of spontaneous abortion and a reduced risk of Gaucher-related complications during delivery and during the postpartum period. No adverse effects on the fetus have been reported secondary to imiglucerase therapy.[49246] Imiglucerase has thus been suggested, based on the data available, as an agent for consideration for the treatment of Gaucher's disease during pregnancy.[56701] There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to imiglucerase; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-745-4447, extension 15500.[49245]

          Available literature suggests a small amount of imiglucerase is present in breast milk immediately following imiglucerase administration. Case reports and postmarketing reports have not reported adverse effects in breastfed infants due to imiglucerase exposure. No data are available on the effects of imiglucerase on milk production.[49245] Enzymes such as imiglucerase are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with enzyme replacement therapy postpartum. No adverse effects on the nursing infant were reported secondary to imiglucerase therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] There are published reports of the successful use of imiglucerase in a pregnant, and subsequently lactating, patient. The case report stated a small amount of imiglucerase was found to be excreted into human breast milk, but only in the first milk produced after infusion, and the patient was able to successfully breast-feed the infant.[56702] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Encourage individuals who are breast-feeding while receiving imiglucerase to enroll in the Gaucher patient registry; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-745-4447, extension 15500.[49245]

          Revision Date: 10/10/2023, 03:12:50 PM

          References

          49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.49246 - Zimran A, Morris E, Mengel E et al. The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause). Blood Cells Mol Dis 2009;43:264-88.56701 - Granovsky-Grisaru S, Belmatoug N, vom Dahl S, et al. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol. 2011;156:3-8. Epub 2011 Jan 26. Review.56702 - Sekijima Y, Ohashi T, Ohira S, et al. Successful pregnancy and lactation outcome in a patient with Gaucher disease receiving enzyme replacement therapy, and the subsequent distribution and excretion of imiglucerase in human breast milk. Clin Ther. 2010;32:2048-2052.

          Mechanism of Action

          Imiglucerase substitutes for the deficient enzyme glucocerebrosidase in patients with Gaucher disease. Gaucher disease is characterized by a deficiency of glucocerebrosidase, a necessary catalyst for the hydrolysis of glucosylceramide, an endogenous, very insoluble glycolipid. Patients with this condition have a build-up of glucosylceramide in lysosomes of phagocytic cells, which are found in storage cells of the liver, spleen, and bone marrow as well as in the lung, kidney, and intestine. Clinically, this build-up is associated with splenomegaly, hepatomegaly, increased skin pigmentation, and bone lesions. Treatment with imiglucerase results in hydrolysis of the accumulated glucosylceramide within macrophages and improvement in hemoglobin, hematocrit, and platelet counts, and a decrease in hepatomegaly and splenomegaly. Reductions in size of an enlarged liver and spleen correspond to hematological improvement and patients' subjective improvement.[27584][49245]

          Revision Date: 10/10/2023, 03:12:50 PM

          References

          27584 - Zimran A, Elstein D. Gaucher disease and the clinical experience with substrate reduction therapy. Philos Trans R Soc Lond B Biol Sci 2003;358:961-6.49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.

          Pharmacokinetics

          Imiglucerase is administered by IV infusion. The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (mean +/- SD, 0.12 +/- 0.02 L/kg). The clearance of imiglucerase from plasma is reported to range from 9.8 to 20.3 mL/minute/kg (mean +/- SD, 14.5 +/- 4 mL/minute/kg). The enzymatic activity has a plasma half-life of approximately 3.6 to 10.4 minutes. These variables do not appear to be influenced by dose or duration of infusion. Patients who develop IgG antibodies to imiglucerase exhibit decreased volume of distribution and clearance and increased half-life compared to patients who do not develop these antibodies.[49245]

          Route-Specific Pharmacokinetics

          Intravenous Route

          During 1-hour intravenous infusions of 4 doses (7.5, 15, 30, 60 units/kg) of imiglucerase, steady-state enzymatic activity was achieved by 30 minutes.[49245]

          Revision Date: 10/10/2023, 03:12:50 PM

          References

          49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.

          Pregnancy/Breast-feeding

          pregnancy

          Data on more than 500 pregnancies from the international Gaucher Disease registry, postmarketing reports, published observational studies, and case reports with imiglucerase during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction study data are not available.[49245] A report from a panel of clinicians that treat Gaucher's disease indicated that treatment with enzyme replacement therapy during pregnancy led to a reduced risk of spontaneous abortion and a reduced risk of Gaucher-related complications during delivery and during the postpartum period. No adverse effects on the fetus have been reported secondary to imiglucerase therapy.[49246] Imiglucerase has thus been suggested, based on the data available, as an agent for consideration for the treatment of Gaucher's disease during pregnancy.[56701] There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to imiglucerase; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-745-4447, extension 15500.[49245]

          breast-feeding

          Available literature suggests a small amount of imiglucerase is present in breast milk immediately following imiglucerase administration. Case reports and postmarketing reports have not reported adverse effects in breastfed infants due to imiglucerase exposure. No data are available on the effects of imiglucerase on milk production.[49245] Enzymes such as imiglucerase are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with enzyme replacement therapy postpartum. No adverse effects on the nursing infant were reported secondary to imiglucerase therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] There are published reports of the successful use of imiglucerase in a pregnant, and subsequently lactating, patient. The case report stated a small amount of imiglucerase was found to be excreted into human breast milk, but only in the first milk produced after infusion, and the patient was able to successfully breast-feed the infant.[56702] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Encourage individuals who are breast-feeding while receiving imiglucerase to enroll in the Gaucher patient registry; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-745-4447, extension 15500.[49245]

          Revision Date: 10/10/2023, 03:12:50 PM

          References

          49245 - Cerezyme (imiglucerase) package insert. Cambridge, MA: Genzyme Corporation; 2022 Dec.49246 - Zimran A, Morris E, Mengel E et al. The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause). Blood Cells Mol Dis 2009;43:264-88.56701 - Granovsky-Grisaru S, Belmatoug N, vom Dahl S, et al. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol. 2011;156:3-8. Epub 2011 Jan 26. Review.56702 - Sekijima Y, Ohashi T, Ohira S, et al. Successful pregnancy and lactation outcome in a patient with Gaucher disease receiving enzyme replacement therapy, and the subsequent distribution and excretion of imiglucerase in human breast milk. Clin Ther. 2010;32:2048-2052.

          Interactions

          Level 2 (Major)

          • Miglustat
          migLUstat: (Major) Combination therapy with miglustat and imiglucerase is not indicated for Gaucher disease. Miglustat may increase the clearance of imiglucerase, although the clinical significance of this interaction is not yet known. [49418]
          Revision Date: 10/10/2023, 03:12:50 PM

          References

          49418 - Zavesca (miglustat) package insert. South San Francisco, CA: Actelion Pharmaceuticals US Inc.; 2020 Dec.

          Monitoring Parameters

          • laboratory monitoring not necessary

          US Drug Names

          • Cerezyme
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