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.

1. 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.
   
   
2. 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.
   
   
3. 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.
   
   
4. 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.
   
   
5. 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.
   
   
6. Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME.  Do not shake the solution.
   
   
7. 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.

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.

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.

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. 

8.1 Pregnancy

Risk Summary

Available data from a pregnancy sub-study within the MPS VI Clinical Surveillance Program and case reports with NAGLAZYME use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, galsulfase administered intravenously to pregnant rats and rabbits during the period of organogenesis, showed no evidence of harm to the fetus at doses of about 0.5 and 0.97 times, respectively for rats and rabbits, the recommended human dose of 1 mg/kg based on body surface area (see Data).  

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.  All pregnancies have a background risk of birth defects, 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 embryo/fetal risk

Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse pregnancy outcomes for both mother and fetus.

Data

Human Data

Available data from a pregnancy sub-study within the MPS VI Clinical Surveillance Program and case reports with the use of NAGLAZYME during pregnancy have identified seventeen pregnancies. No major birth defects have been reported. Drug-associated adverse maternal and fetal outcomes have not been identified.

Animal Data

Reproduction studies have been performed with intravenous galsulfase during the period of organogenesis in pregnant rats at doses of galsulfase 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 pregnant  rabbits at  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 harm to the fetus due to galsulfase.  

8.2 Lactation

Risk Summary

There are no data on the presence of galsulfase in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAGLAZYME and any potential adverse effects on the breastfed infant from NAGLAZYME or from the underlying maternal condition.

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.

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.

12.2 Pharmacodynamics

The responsiveness of urinary GAG to dosage alterations of NAGLAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established.

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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of NAGLAZYME or of other galsulfase products.

In four clinical studies [see Clinical Studies (14)] of MPS VI patients 5 to 29 years of age, 53 of 54 (98%) NAGLAZYME-treated patients developed anti-galsulfase IgG antibodies (referred to as ADA) within 4 to 8 weeks of treatment.

In the placebo-controlled study, 19 of 19 (100%) NAGLAZYME-treated patients developed ADA. Neutralizing antibodies were detected in 4 of 16 (25%) patients who had samples available for neutralizing antibody assessments.

There was no identified clinically significant effect of ADA on infusion-associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. There is insufficient information to characterize the effects of ADA on pharmacokinetics of galsulfase.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with galsulfase.

Galsulfase at intravenous doses up to 3.0 mg/kg (about 0.5 times the recommended human dose of 1 mg/kg based on body surface area) was found to have no effect on the fertility and reproductive performance of male and female rats.

Hypersensitivity Reactions Including Anaphylaxis and Infusion Reactions

Advise the patient or caregiver that life-threatening hypersensitivity reactions, including anaphylaxis and infusion reactions, may occur with NAGLAZYME treatment.

Advise the patient or caregiver that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Inform the patient or caregiver of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and infusion reactions and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1, 5.5)].

Respiratory Adverse Reactions

Advise the patient or caregiver to report immediately to a healthcare provider if signs or symptoms of cardiac or respiratory decompensation occur during or following an infusion [see Warnings and Precautions (5.3, 5.4)]. Inform patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep to have these treatments readily available during infusion or extreme drowsiness/sleep induced by antihistamine use.