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Indications And Usage

NAGLAZYME (galsulfase) 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).

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Dosage Forms And Strengths

Injection; 5 mL vials (5 mg per 5 mL). Injection: 5 mg per 5 mL vial (3).

Contraindications

None. None (4).

Warning and Cautions

Anaphylaxis and Allergic Reactions: Life-threatening anaphylactic reactions have been observed in some patients during NAGLAZYME infusions and up to 24 hours after infusion. If anaphylaxis or severe allergic reactions occur, immediately discontinue infusion and initiate appropriate treatment, which may include resuscitation, epinephrine, administering additional antihistamines, antipyretics or corticosteroids (5.1). 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 (2.1, 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 (2.1, 5.5). 5.1 Anaphylaxis and Allergic Reactions Anaphylaxis and severe allergic reactions have been observed in patients during and up to 24 hours after NAGLAZYME infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension. If anaphylaxis or other severe allergic reactions occur, NAGLAZYME should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion [see Adverse Reactions (6) ]. 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 (6.3) ]. 5.3 Risk of Acute Cardiorespiratory Failure Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload; such as in 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 (6.3) ]. 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) ]. 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 post-marketing 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.

Adverse Reactions

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 go to 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 MedDRA Preferred Term NAGLAZYME (n = 19) Placebo (n = 20 One of the 20 patients in the placebo group dropped out after Week 4 infusion ) 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 allergic 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 Immunogenicity Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion‑associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake. The data reflect the percentage of patients whose test results were considered positive for antibodies to galsulfase using specific assays and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to galsulfase with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval 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. In addition to infusion reactions reported in clinical trials, serious reactions which occurred during NAGLAZYME infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure. Additional infusion reactions included 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.

Use In Specific Populations

Pregnancy and Nursing Mothers: Clinical Surveillance Program available (8.1, 8.3, 17.2). 8.1 Pregnancy Pregnancy Category B. Adequate and well-controlled studies have not been conducted with NAGLAZYME in pregnant women. Reproduction studies have been performed in rats at intravenous doses up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in rabbits at intravenous doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to NAGLAZYME. NAGLAZYME should be used during pregnancy only if clearly needed. Pregnant women with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 [see Patient Counseling Information (17.2)]. 8.3 Nursing Mothers It is not known whether NAGLAZYME is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAGLAZYME is administered to a nursing mother. Nursing mothers with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 [see Patient Counseling Information (17.2)]. 8.4 Pediatric Use Clinical studies with NAGLAZYME were conducted in 56 patients, ages 5 to 29 years, with the majority of these patients in the pediatric age group [see Clinical Studies (14)]. In addition, an open-label study was conducted in four infants (3 months to 12.7 months) treated with 1 mg/kg (n = 2) or 2 mg/kg (n = 2) of NAGLAZYME. Safety results in infants were consistent with results observed in patients 5 to 29 years old [see Adverse Reactions (6)]. 8.5 Geriatric Use Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients.