Brand Name
Naglazyme
Generic Name
Galsulfase
View Brand Information FDA approval date: June 09, 2005
Classification: Hydrolytic Lysosomal Glycosaminoglycan-specific Enzyme
Form: Solution
What is Naglazyme (Galsulfase)?
NAGLAZYME is indicated for patients with Mucopolysaccharidosis VI . NAGLAZYME has been shown to improve walking and stair-climbing capacity. NAGLAZYME is a hydrolytic lysosomal glycosaminoglycan -specific enzyme indicated for patients with Mucopolysaccharidosis VI . NAGLAZYME has been shown to improve walking and stair-climbing capacity .
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Brand Information
NAGLAZYME (galsulfase)
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.
Initiate NAGLAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue NAGLAZYME and immediately initiate appropriate medical treatment, including use of epinephrine.
Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur
1INDICATIONS AND USAGE
NAGLAZYME is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity.
2DOSAGE FORMS AND STRENGTHS
Injection: 5 mg/5 mL (1 mg/mL) as a colorless to pale yellow, clear to slightly opalescent solution single-dose vials
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
Serious and/or clinically significant adverse reactions described elsewhere in labeling include:
- Hypersensitivity Reactions Including Anaphylaxis
- Immune-Mediated Reactions
- Risk of Acute Cardiorespiratory Failure
- Acute Respiratory Complications Associated with Administration
- Infusion Reactions
- Spinal or Cervical Cord Compression
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 patients received placebo; of the 39 patients 66% were female, and 62% were White, non-Hispanic. Patients were aged 5 years to 29 years. NAGLAZYME-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively).
Serious adverse reactions experienced in this trial include apnea, pyrexia, and respiratory distress. Severe adverse reactions include chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions requiring interventions were infusion reactions
Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME‑treated group than in the placebo-treated group.
Four open-label clinical trials were conducted in MPS VI patients aged 3 months to 29 years with NAGLAZYME administered at doses of 0.2 mg/kg (n = 2), 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of NAGLAZYME (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of NAGLAZYME for 105 and 81 weeks, respectively.
In addition to those listed in Table 1, common adverse reactions observed in the open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and vomiting. The most common adverse reactions requiring interventions were infusion reactions. Serious adverse reactions included laryngeal edema, urticaria, angioedema, and other hypersensitivity reactions. Severe adverse reactions included urticaria, rash, and abdominal pain.
Observed adverse events in four open-label studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the placebo-controlled study. No patients discontinued during open-label treatment with NAGLAZYME due to adverse events.
4.2Postmarketing Experience
The following adverse reactions have been identified during post approval use of NAGLAZYME. Because these reactions are 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.
Serious infusion reactions: anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure [see Warnings and Precautions (.
Additional infusion reactions: pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia.
During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase‑immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive NAGLAZYME.
5DESCRIPTION
NAGLAZYME is a formulation of galsulfase, which is a purified human enzyme that is produced by recombinant DNA technology in a Chinese hamster ovary cell line.
Galsulfase is a glycoprotein with a molecular weight of approximately 56 kDa. The recombinant protein consists of 495 amino acids and possesses six asparagine‑linked glycosylation sites, four of which carry a bis‑mannose-6–phosphate residue for specific cellular recognition. Post-translational modification of Cys53 produces the catalytic amino acid residue, Cα-formylglycine, which is required for enzyme activity. NAGLAZYME has a specific activity of approximately 70 units per mg of protein content. One activity unit is defined as the amount of enzyme required to convert 1 micromole of 4-methylumbelliferyl sulfate to 4-methylumbelliferone and free sulfate per minute at 37°C.
NAGLAZYME is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride Injection, USP, prior to administration. NAGLAZYME is supplied in clear Type I glass 5 mL vials. Each vial provides 5 mg galsulfase, 43.8 mg sodium chloride, 6.20 mg sodium phosphate monobasic monohydrate, 1.34 mg sodium phosphate dibasic heptahydrate, and 0.25 mg polysorbate 80 in a 5 mL extractable solution with pH of approximately 5.8. NAGLAZYME does not contain preservatives. Each vial is for single use only.
6CLINICAL STUDIES
A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in four clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance.
In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 38 patients with MPS VI received 1 mg/kg NAGLAZYME or placebo, once-weekly for 24 weeks. The patients’ ages ranged from 5 to 29 years. Enrollment was restricted to patients with a 12‑minute walk distance of 5 to 400 meters. All patients were treated with antihistamines prior to each infusion.
The NAGLAZYME-treated group showed greater mean increases in the distance walked in 12 minutes (12‑minute walk test, 12‑MWT) and in the rate of stair climbing in a 3-minute stair climb test, compared with the placebo group (Table 3).
Following the 24-week placebo-controlled study period, 38 patients received open-label NAGLAZYME for 72 weeks. Among the 19 patients who were initially randomized to NAGLAZYME and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed compared to the start of the open-label period (mean [ ± SD] change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively). Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with NAGLAZYME, the increases after 72 weeks of NAGLAZYME treatment compared to the start of the open-label period, (mean [ ± SD] change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively.
Bioactivity was evaluated with urinary GAG concentration. Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with NAGLAZYME. No patient receiving NAGLAZYME reached the normal range for urinary GAG levels
In an additional open-label extension study, patients receiving NAGLAZYME showed maintenance of initial improvement in endurance for approximately 240 weeks.
7HOW SUPPLIED/STORAGE AND HANDLING
NAGLAZYME injection is supplied as a sterile colorless to pale yellow, clear to slightly opalescent solution in clear Type I glass 5 mL vials, containing 5 mg galsulfase (expressed as protein content) per 5 mL solution. The closure consists of a siliconized chlorobutyl rubber stopper and an aluminum seal with a plastic flip-off cap.
NDC 68135-020-01, 5 mL vial
Store NAGLAZYME under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. This product contains no preservatives.
8Packaging Components
NDC 68135-020-01
Naglazyme
(GALSULFASE)
(GALSULFASE)
5 mg/5 mL
Concentrated Solution For Intravenous Infusion Only
Must be diluted prior to use.
Rx Only