Galsulfase

Prescription

Nombres comerciales: NAGLAZYME

Forma Farmacéutica

Injection

Vía de Administración

INTRAVENOUS

Fabricante

BioMarin Pharmaceutical Inc.

About This Medication

11 DESCRIPTION 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 (glycosaminoglycan N -acetylgalactosamine 4-sulfatase, EC 3.1.6.12) is a lysosomal enzyme that catalyzes the cleavage of the sulfate ester from terminal N –acetylgalactosamine 4-sulfate residues of glycosaminoglycans (GAG), chondroitin 4-sulfate and dermatan sulfate. 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.

Principios Activos

Ingrediente	Concentración
Galsulfase	-

Indicaciones y Uso

1 INDICATIONS 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. NAGLAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ( 1 )

Cómo funciona

12.1 Mechanism of Action Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. MPS VI is characterized by the absence or marked reduction in N-acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction. NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors.

Dosificación y Administración

2 DOSAGE AND ADMINISTRATION Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) The recommended dosage is 1 mg per kg of body weight administered once weekly as an intravenous infusion. ( 2.2 ) 2.1 Recommendations Prior to NAGLAZYME Treatment Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate NAGLAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ] . Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion [see Warnings and Precautions (5.5) ]. 2.2 Recommended Dosage and Administration The recommended dosage regimen of NAGLAZYME is 1 mg per kg of body weight administered once weekly as an intravenous infusion. The total volume of the infusion should be delivered over a period of time of no less than 4 hours. NAGLAZYME should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur. For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting NAGLAZYME in a volume of 100 mL [see Warnings and Precautions (5.3) ] . The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. Each vial of NAGLAZYME provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare NAGLAZYME using low-protein-binding containers and administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted NAGLAZYME with glass containers. 2.3 Instructions for Use Prepare and use NAGLAZYME according to the following steps. Use aseptic techniques. Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg: Patient's weight (kg) × 1 mL/kg of NAGLAZYME = Total number of mL of NAGLAZYME Total number of mL of NAGLAZYME ÷ 5 mL per vial = Total number of vials Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials. Before withdrawing the NAGLAZYME solution from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of NAGLAZYME solution to be added. If using a 100 mL infusion bag, this step is not necessary. Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature NAGLAZYME, rendering it biologically inactive. Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle. Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution. Administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. NAGLAZYME does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted NAGLAZYME solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements. NAGLAZYME must not be infused with other products in the infusion tubing. The compatibility of NAGLAZYME in solution with other products has not been evaluated.

Side Effects Overview

6 ADVERSE REACTIONS Serious and/or clinically significant adverse reactions described elsewhere in labeling include: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Reactions [see Warnings and Precautions ( 5.2 )] Risk of Acute Cardiorespiratory Failure [see Warnings and Precautions ( 5.2 )] Acute Respiratory Complications Associated with Administration [see Warnings and Precautions ( 5.4 )] Infusion Reactions [see Warnings and Precautions ( 5.5 )] Spinal or Cervical Cord Compression [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (≥10%) are: rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea. The most common adverse reactions requiring interventions are infusion-related reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact: BioMarin Pharmaceutical Inc. at 1-866-906-6100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in at least 2 Patients More in the NAGLAZYME Group than in the Placebo Group NAGLAZYME (n = 19) Placebo (n = 20 One of the 20 patients in the placebo group dropped out after Week 4 infusion ) MedDRA Preferred Term No. Patients (%) No. Patients (%) All 19 (100) 20 (100) Abdominal Pain 9 (47) 7 (35) Ear Pain 8 (42) 4 (20) Arthralgia 8 (42) 5 (25) Pain 6 (32) 1 (5) Conjunctivitis 4 (21) 0 Dyspnea 4 (21) 2 (10) Rash 4 (21) 2 (10) Chills 4 (21) 0 Chest Pain 3 (16) 1 (5) Pharyngitis 2 (11) 0 Areflexia 2 (11) 0 Corneal Opacity 2 (11) 0 Gastroenteritis 2 (11) 0 Hypertension 2 (11) 0 Malaise 2 (11) 0 Nasal Congestion 2 (11) 0 Umbilical Hernia 2 (11) 0 Hearing Impairment 2 (11) 0 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. 6.2 Postmarketing 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 ( 5.1 )] . 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.

Advertencias y Precauciones

5 WARNINGS AND PRECAUTIONS Immune-Mediated Reactions : Immune-mediated reactions can occur with NAGLAZYME. Monitor patients for the development of immune complex-mediated reactions while receiving NAGLAZYME. ( 5.2 ) Risk of Acute Cardiorespiratory Failure : Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload. Consider a decreased total infusion volume and infusion rate when administering NAGLAZYME to these patients. Appropriate medical monitoring and support measures should be available during infusion. ( 2.2 , 5.3 ) Acute Respiratory Complications : Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Appropriate respiratory support should be available during infusion. ( 5.4 ) Infusion Reactions : Pretreatment with antihistamines with or without antipyretics is recommended prior to the start of infusion to reduce the risk of infusion-reactions. If infusion reactions occur, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antihistamines and/or antipyretics is recommended. ( 2.2 , 5.5 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been observed in patients treated with enzyme replacement therapies, including NAGLAZYME. These reactions have occurred during and up to 24 hours after completion of the NAGLAZYME infusion. Some of the reactions included shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension [see Adverse Reactions (6.1 , 6.2 )] . Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. 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. In patients who have experienced anaphylaxis or other serious hypersensitivity reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge . Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. 5.2 Immune-Mediated Reactions Type III immune complex-mediated reactions, including membranous glomerulonephritis have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of NAGLAZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering NAGLAZYME following an immune-mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive NAGLAZYME under close clinical supervision [see Adverse Reactions (6.2) ] . 5.3 Risk of Acute Cardiorespiratory Failure Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload, such as patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion and some patients may require prolonged observation times that should be based on the individual needs of the patient [see Adverse Reactions ( 6.2 )] . 5.4 Acute Respiratory Complications Associated with Administration Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use. Consider delaying NAGLAZYME infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of NAGLAZYME. 5.5 Infusion Reactions Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with NAGLAZYME. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema, and conjunctivitis [see Adverse Reactions ( 6.1 , 6.2 )] . The most common symptoms of drug-related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of NAGLAZYME treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks. Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of NAGLAZYME administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids. If severe infusion reactions occur, immediately discontinue the infusion of NAGLAZYME and initiate appropriate treatment. The risks and benefits of re-administering NAGLAZYME following a severe reaction should be considered. No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies. 5.6 Spinal or Cervical Cord Compression Spinal or cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on NAGLAZYME. There have been postmarketing reports of patients treated with NAGLAZYME who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.

Contraindicaciones

4 CONTRAINDICATIONS None. None. (4)

Farmacocinética

12.3 Pharmacokinetics The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of NAGLAZYME as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2. Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Table 2: Pharmacokinetic Parameters (Median, Range) of Galsulfase in Patients with MPS VI Pharmacokinetic Parameter Week 1 Week 24 C max (mcg/mL) 0.8 (0.4 to 1.3) 1.5 (0.2 to 5.5) AUC 0-t (hr•mcg/mL) Area under the plasma galsulfase concentration-time curve from start of infusion to 60 minutes post infusion 2.3 (1.0 to 3.5) 4.3 (0.3 to 14.2) Vz (mL/kg) 103 (56 to 323) 69 (59 to 2,799) CL (mL/kg/min) 7.2 (4.7 to 10.5) 3.7 (1.1 to 55.9) Half-life (min) 9 (6 to 21) 26 (8 to 40)

Frequently Asked Questions

1 INDICATIONS 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. NAGLAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) The recommended dosage is 1 mg per kg of body weight administered once weekly as an intravenous infusion. ( 2.2 ) 2.1 Recommendations Prior to NAGLAZYME Treatment Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate …

5 WARNINGS AND PRECAUTIONS Immune-Mediated Reactions : Immune-mediated reactions can occur with NAGLAZYME. Monitor patients for the development of immune complex-mediated reactions while receiving NAGLAZYME. ( 5.2 ) Risk of Acute Cardiorespiratory Failure : Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload. Consider a decreased total infusion volume and infusion rate when administering NAGLAZYME to these patients. Appropriate medical monitoring and support measures should be available during infusion. ( 2.2 , 5.3 ) Acute …

4 CONTRAINDICATIONS None. None. (4)

Galsulfase is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Galsulfase drug label (National Library of Medicine)
• openFDA — Galsulfase label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 578037 (NLM Normalized Drug Names)
• NDC Directory — Galsulfase (FDA National Drug Code)

Aviso Médico

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Fuentes de datos: DailyMed (NLM), openFDA, MFDS