NAGLAZYME

Galsufase is a variant form of the polymorphic human enzyme N-acetylgalactosamine 4-sulfatase of recombinant DNA origin.

Galsulfase is a glycoprotein with a molecular weight of approximately 56 kD.

The recombinant protein is comprised of 495 amino acids and contains six asparagine-linked glycosylation sites, four of which carry a bis mannose-6-phosphate manose7 oligosaccharide for specific cellular recognition.

Post-translational modification of

Cys53 produces the catalytic amino acid residue Ca-formylglycine, which is required for enzyme activity and is conserved in all members of the sulfatase enzyme family.

For the treatment of adults and children with Mucopolysaccharidosis VI.

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG.

VI (MPS VI, Maroteaux-Lamy syndrome) 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.

Galsulfase 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.

Week 1: 56-323 mL/kg and 59-2799 mL/kg by week 24.

minutes during the first week of treatment, 26 minutes by the 24th week.

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There is no experience with overdose of galsulfase.

Administration of

NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

The recommended dosage is 1 mg per kg of body weight administered once weekly as an intravenous infusion. 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.

NAGLAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.

Pretreatment with antihistamines with or without antipyretics is recommended to 60 minutes prior to the start of the infusion. 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.

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.

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.

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.

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.

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.

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.

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.

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.

Clinical studies with

NAGLAZYME were conducted in 56 patients, ages to 29 years, with the majority of these patients in the pediatric.

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 to 29 years old.

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.