Galsulfase (Monograph)

Drug class: Enzymes
Chemical name: Acetylgalactosamine 4-sulfatase (human CSL4S-342 cell)
Molecular formula: C₂₅₂₉H₃₈₄₃N₆₈₉O₇₁₆S₁₆
CAS number: 552858-79-4

Introduction

Galsulfase is a biosynthetic (recombinant DNA origin) form of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB), a lysosomal enzyme that catalyzes the hydrolysis of the sulfate ester from terminal N-acetylgalactosamine 4-sulfate residues of glycosaminoglycans (GAG) chondroitin 4-sulfate and dermatan sulfate.

Uses for Galsulfase

Mucopolysaccharidosis VI

Galsulfase is used as replacement therapy in patients with mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). Therapy with galsulfase improves endurance (as measured by increases in walking distance) in patients with MPS VI; effects of the drug on survival have not been established. Galsulfase is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.

MPS VI is an autosomal recessive lysosomal storage disorder characterized by a deficiency of N-acetylgalactosamine 4-sulfatase. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in accumulation of a glycosaminoglycan (GAG) substrate (dermatan sulfate) throughout the body, leading to widespread and progressive cellular, tissue, and organ dysfunction. Clinical manifestations include short stature, kyphosis, coarse facial features, dysostosis multiplex, joint stiffness, heart valve thickening, upper airway obstruction, hepatosplenomegaly, and corneal clouding. Most patients with MPS VI will die from disease-related complications between childhood and early adulthood; some patients with slowly advancing disease, however, maintain substantial levels of physical functioning into their 30s and may survive into their 50s or 60s.

Safety and efficacy of galsulfase were evaluated in a randomized, double-blind, placebo-controlled study in a limited number of patients 5–29 years of age with MPS VI. Galsulfase (1 mg/kg once weekly) was superior to placebo in improving walking capacity and also was associated with modest (but not statistically significant) improvements in stair-climbing capacity. At baseline, patients randomized to receive galsulfase or placebo were able to walk a mean distance of 227 or 381 meters, respectively, within 12 minutes; after 24 weeks of treatment, patients receiving galsulfase or placebo were able to walk an additional mean distance of 109 or 26 meters, respectively, within 12 minutes. In a 24-week open-label extension of this study, patients who continued to receive galsulfase experienced an additional 36-meter mean increase in 12-minute walking distance, while those switched from placebo to galsulfase experienced a 66-meter increase in 12-minute walking distance. Although galsulfase was superior to placebo in decreasing urinary GAG concentrations during the controlled study, no patient in the galsulfase group achieved normal urinary GAG concentrations during the 24-week treatment period.

Clinical Surveillance Program

The manufacturer has established a Clinical Surveillance Program to monitor the variability and progression of MPS VI, the long-term effects of galsulfase, and the effects of the drug on pregnancy and lactation. Patients, including pregnant and nursing women, should be encouraged to participate in this program. For more information on MPS VI or the Clinical Surveillance Program, visit [Web] or call 866-906-6100.

Galsulfase Dosage and Administration

Administration

Galsulfase is administered by IV infusion.

Galsulfase injection concentrate must be diluted prior to administration. (See Dilution under Dosage and Administration: Administration.) Solutions of galsulfase should be prepared using PVC containers and administered with a PVC infusion set equipped with an inline, low-protein-binding filter with a pore diameter of 0.2 µm.

Dilution

Prior to administration, galsulfase injection concentrate must be diluted in 0.9% sodium chloride injection to a final volume of 250 mL; in patients weighing 20 kg or less who are susceptible to fluid volume overload, clinicians may consider diluting the injection concentrate in a volume of 100 mL.

The appropriate number of galsulfase vials should be diluted based on the patient’s body weight and recommended dosage, and determined using the following equations:

Patient’s weight (kg) × 1 mL/kg of galsulfase = Total mL of galsulfase.

Total mL ÷ 5 mL/vial = Total vials, rounded to the nearest whole vial.

Galsulfase vials should be allowed to reach room temperature before dilution but should not be heated (e.g., in a microwave). Galsulfase injection concentrate should be inspected visually for particulate matter and discoloration prior to dilution and administration. The drug should be discarded if the concentrate is discolored or if particulate matter other than a few translucent particles is present.

Once the volume of galsulfase has been determined, an equal volume of 0.9% sodium chloride injection should be removed from the 250-mL infusion bag and discarded; this step is not necessary with the 100-mL infusion bag. The calculated volume of galsulfase injection concentrate should then be withdrawn from the appropriate number of vials and added slowly to the infusion bag, taking care to avoid agitation; a filter needle should not be used, since it may cause agitation, which may denature galsulfase and render the drug biologically inactive. The infusion bag should then be rotated gently to ensure proper distribution of galsulfase, taking care not to shake the diluted solution. Because galsulfase injection concentrate contains no preservative, partially used vials of undiluted drug should be discarded.

Galsulfase vials should be refrigerated at 2–8°C and should not be frozen or shaken; vials should not remain at room temperature longer than 24 hours prior to dilution. Galsulfase solutions should be used immediately after dilution; if not used immediately, diluted solutions may be stored under refrigeration (2–8°C) for a period not to exceed 48 hours from the time of preparation to completion of administration. Room temperature storage of diluted galsulfase solutions, other than during infusion, is not recommended.

Rate of Administration

Galsulfase infusion should be administered over no less than 4 hours. In patients receiving a total volume of 250 mL, the recommended initial infusion rate is 6 mL/hour for the first hour; if well tolerated, the rate may be increased to 80 mL/hour for the remaining 3 hours. In patients weighing 20 kg or less receiving galsulfase diluted in 100 mL of diluent, the infusion rate should be decreased so that the total infusion duration is no less than 4 hours (i.e., delivering 2.5% of the total volume in the first hour and 97.5% of the total volume over the next 3 hours). Compatibility with other drugs has not been evaluated; therefore, galsulfase must not be infused through the same IV tubing with other drugs.

General Dosage

Dosage of galsulfase is expressed in mg of protein content. The specific activity of galsulfase is 70 units per mg of protein.

The recommended dosage of galsulfase for the treatment of mucopolysaccharidosis VI (MPS VI) in adults and children 5 years of age and older is 1 mg/kg given by IV infusion once weekly.

Premedication

To minimize the risk of infusion-related reactions associated with galsulfase, premedication with antihistamines, with or without antipyretics, is recommended 30–60 minutes before initiation of each galsulfase infusion.

Management of Toxicity

If infusion reactions occur, the manufacturer recommends reducing the infusion rate (i.e., extending the infusion duration up to 20 hours) or interrupting therapy and initiating treatment with additional antihistamines, antipyretics, and, occasionally, corticosteroids. If severe infusion reactions occur, the infusion should be discontinued, and appropriate treatment initiated. (See Infusion Reactions under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

No special population dosage recommendations at this time.

Cautions for Galsulfase

Contraindications

No known contraindications.

Warnings/Precautions

Warnings

Infusion Reactions

Infusion reactions, sometimes severe, have been reported in 30 of 55 patients receiving galsulfase despite pretreatment with antihistamines. The most common manifestations of infusion reactions include fever, chills/rigors, headache, rash, and mild to moderate urticaria of the face and neck. Severe manifestations include angioedema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria. Other manifestations (e.g., nausea, vomiting, elevated blood pressure, retrosternal pain, abdominal pain, malaise, joint pain) also have been reported. Initial infusion reactions were observed as late as week 55 of treatment.

In clinical studies, manifestations of infusion reactions were ameliorated by slowing the infusion rate or interrupting therapy and initiating treatment with additional antihistamines, antipyretics, and, occasionally, corticosteroids. For subsequent infusions, patients received galsulfase at a slower infusion rate and received additional prophylactic antihistamines; patients who previously experienced severe infusion reactions also received prophylactic corticosteroids. Despite these measures, 13 of 30 patients experienced additional infusion reactions.

If severe infusion reactions occur, the infusion should be discontinued immediately, and appropriate treatment initiated. The risks and benefits of readministering galsulfase following a severe infusion reaction should be considered.

General Precautions

Immunogenicity

In clinical studies, 98% (53/54) of patients receiving galsulfase developed anti-galsulfase IgG antibodies. Antibody development typically appeared approximately 4–8 weeks following initiation of treatment. Five patients with high antibody titers experienced differences in pharmacokinetic parameters (increased and decreased galsulfase area under the plasma-concentration time curve [AUC]) during the 24-week treatment period. When analyzed for neutralizing activity, one patient’s antibodies indicated in vitro inhibition of galsulfase activity. Because of small sample size, the clinical importance of neutralizing antibodies is not known. Antibody levels did not correlate with adverse events (e.g., infusion reactions), urinary glycosaminoglycan (GAG) concentrations, or endurance parameters.

Sleep Apnea

Because sleep apnea is common in patients with mucopolysaccharidosis VI (MPS VI), pretreatment with antihistamines 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 antihistamine-induced extreme drowsiness/sleepiness.

Concomitant Diseases

Clinicians should consider delaying galsulfase infusions in patients who present with an acute febrile or respiratory illness.

Specific Populations

Pregnancy

Category B. (See Clinical Surveillance Program under Uses: Mucopolysaccharidosis VI.)

Lactation

Not known whether galsulfase is distributed into milk. Use with caution in nursing women. (See Clinical Surveillance Program under Uses: Mucopolysaccharidosis VI.)

Pediatric Use

Safety and efficacy not established in children younger than 5 years of age.

Geriatric Use

Clinical studies of galsulfase did not include patients older than 29 years of age. It is not known whether geriatric patients (65 years of age and older) respond differently than younger patients.

Common Adverse Effects

The most common adverse effects reported during clinical studies of galsulfase include headache, fever, arthralgia, vomiting, upper respiratory tract infections, abdominal pain, diarrhea, ear pain, cough, and otitis media. Other adverse effects reported in more than 10% of patients receiving galsulfase in the 6-month placebo-controlled study include pain, conjunctivitis, dyspnea, rigors, chest pain, pharyngitis, areflexia, increased corneal opacification, facial edema, gastroenteritis, hypertension, malaise, nasal congestion, and umbilical hernia.

Drug Interactions

No formal drug interaction studies have been performed.

Description

Galsulfase is a biosynthetic (recombinant DNA origin) form of N-acetylgalactosamine 4-sulfatase, a lysosomal enzyme that catalyzes the hydrolysis of the sulfate ester from terminal N-acetylgalactosamine 4-sulfate residues of glycosaminoglycan (GAG) chondroitin 4-sulfate and dermatan sulfate. In patients with MPS VI, galsulfase provides an exogenous source of N-acetylgalactosamine 4-sulfatase for uptake into lysosomes and catabolism of glycosaminoglycans.

Advice to Patients

Importance of clinicians informing patients that a Clinical Surveillance Program has been established to monitor the variability and progression of mucopolysaccharidosis VI (MPS VI), long-term effects of galsulfase, and effects of the drug on pregnancy and lactation. Importance of encouraging patient participation and of advising patients that participation is voluntary and may involve long-term follow-up. (See Clinical Surveillance Program under Uses: Mucopolysaccharidosis VI.)

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.