Galsulfase is a variant of N-acetylgalactosamine 4-sulfatase, a polymorphic human enzyme. Galsulfase, a 56kD glycoprotein, is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell expression system. The recombinant protein has six asparagine-linked glycosylation sites, four of which carry a bis-mannose-6-phosphate manose7 oligosaccharide, for specific cellular recognition and uptake. Galsulfase is used for the treatment of mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome), an autosomal recessive disorder that results from the deficiency of N-acetylgalactosamine 4-sulfatase (or arylsulfatase B) activity. N-acetylgalactosamine 4-sulfatase is necessary for the breakdown of the glycosaminoglycans (GAGs) chondroitin 4-sulfate and dermatan sulfate, and without this enzyme cells are unable to excrete the GAG residues. Cellular accumulation of GAG residues disrupt normal cell function, and result in progressive cellular, tissue, and organ dysfunction. Prior to the development of galsulfase, specific drug therapy to treat MPS VI has not been available, and patients only received treatment for complications related to the disorder. Enzyme replacement therapy with galsulfase has been shown to increase the catabolism of and reduce the urinary excretion of GAGs. Three galsulfase clinical trials consisting of 54 severely debilitated MPS VI patients have been conducted. All galsulfase treated patients demonstrated improved walking (12-minute walking test) and stair-climbing (3-minute stair climb test) capacity compared to the placebo group. MPS VI affects approximately 1,100 individuals world wide; galsulfase has received orphan drug status for the treatment of this disorder. Galsulfase was approved by the FDA under the brand name Naglazyme(TM) on June 1, 2005.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Galsulfase should only be administered as an IV infusion.
-Administration can cause infusion related reactions. Premedication 30-60 minutes prior to the infusion with an antihistamine, with or without antipyretics, is recommended to decrease the incidence of infusion-related reactions. For severe infusion-related reactions, corticosteroids have been used. Carefully monitor the patient during the infusion; have appropriate supportive measures immediately available in the event of a serious allergic reaction.
-Galsulfase should not be diluted, or infused through the same intravenous line, with other drugs or dextrose solutions.
-Agitation can denature galsulfase, rendering it inactive. Always use caution to avoid excessive agitation. Do not shake vials or prepared product. Do not use filter needles to prepare the infusion.
IV infusion preparation:
-Determine the number of vials to be used per dose, based on the patient's weight. The dose is 1 mg/kg and each vial contains 5 mg/5 mL, therefore, each patient will receive 1 mL galsulfase per kg; round to the nearest 5 mL to allow for administration of whole vials.
-Allow the vials to reach room temperature before dilution; do not allow vials to remain at room temperature for more than 24 hours.
-Prior to withdrawing the solution, visually inspect each vial for particulate matter and discoloration; a few translucent particles may be present. The solution should be clear to slightly opalescent and colorless to pale yellow.
-The total infusion volume should be 250 mL. Therefore, from a 250 mL infusion bag of 0.9% NaCl, withdraw and discard a volume equal to that of the galsulfase solution to be added. For patients less than 20 kg who are susceptible to fluid overload, physicians may consider diluting galsulfase in 100 mL of 0.9% NaCl. If using a 100 mL bag, withdrawal of the equal volume of galsulfase solution is not necessary.
-Slowly withdraw galsulfase from the appropriate number of vials, then slowly add to the 0.9% NaCl bag. Gently rotate the infusion bag to ensure distribution of the solution; do not shake
-Diluted solutions should be administered immediately.
IV infusion administration:
-Administer over at least 4 hours. The initial infusion rate should be 6 mL/hr for the first hour. If well tolerated, increase the rate to 80 mL/hr for the remaining 3 hours; for patients receiving a 100 mL infusion, the infusion rate should be decreased so that the total infusion time is at least 4 hours. If infusion related reactions occur, the infusion time can be extended to up to 20 hours.
-Storage: If immediate use is not possible, diluted infusions can be stored in the refrigerator between 2-8 degrees C (36-46 degrees F). Storage after dilution should not exceed 48 hours from the time of preparation to the completion of administration.
Infusion-related reactions occurred in approximately 56% of patients receiving galsulfase in clinical trials, despite pretreatment with antihistamines. Severe infusion related symptoms included angioedema (facial edema, 11%), dyspnea (21%), respiratory distress, apnea, and urticaria. More common adverse reactions associated with infusion included fever, chills, rigors or shivering (21%), headache, rash (unspecified) (21%), and urticaria. Nausea and vomiting, hypertension (11%), retrosternal pain, abdominal pain (47%), malaise (11%), and arthralgia (42%), were also reported and may be associated with galsulfase infusion. Additional infusion-related reactions reported with post-marketing use of galsulfase included erythema, pallor, bradycardia, sinus tachycardia, hypoxia, cyanosis, tachypnea, and paresthesias. Onset of infusion related reactions did not occur in some patients until they had been receiving weekly infusions for over 1 year. No specific factors for the development of infusion related reactions have been found and, specifically, no association between the development of anti-galsulfase antibodies and infusion related reactions has been determined. If infusion related reactions occur, symptoms can be abated with temporary interruption or slowing of the infusion and the administration of additional antihistamines, antipyretics, and, occasionally, corticosteroids. If a severe infusion related reactions occur, immediately discontinue the infusion and administer appropriate treatment.
Galsulfase is used for the treatment of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), which is associated with corneal opacification and umbilical hernia. Increased corneal opacification and umbilical hernia were seen in 11% of patients receiving galsulfase in clinical trials, compared to no patients receiving placebo.
Other adverse reactions reported during clinical trials with galsulfase included: areflexia or hyporeflexia (11%), chest pain (unspecified) (16%), conjunctivitis (21%), cough, diarrhea, ear pain (otalgia, 42%) (possibly associated with otitis media), gastroenteritis (11%), nasal congestion (11%), pain (unspecified) (32%), pharyngitis (11%), hearing loss (impairment) (11%) and upper respiratory infection.
Galsulfase antibody formation, in the form of IgG antibodies, occurs in most patients within 4-8 weeks of galsulfase administration. In clinical studies, 98% of patients treated with galsulfase and evaluated for the presence of antibodies developed anti-glsulfase IgG antibodies. No association with anti-galsulfase antibody titers and infusion related reactions has been found. No association between antibody development and efficacy (i.e., decrease in urinary GAG concentrations) has been determined. Assessment of antibodies from one patient showed evidence of in vitro inhibition of galsulfase activity. Unfortunately, the antibody neutralizing effect of other IgG positive patients was not studied; comparison of antibody test results can be misleading due to possible differences in assay sensitivity and specificity. Further study is needed to determine if any clinical implications result with the develop of anti-galsulfase antibodies.
Immune-mediated reactions including membranous glomerulonephritis have been reported with galsulfase. One case of membranous nephropathy has been reported during post-marketing use of galsulfase. If immune-mediated reactions occur, consider discontinuation of galsulfase and initiate appropriates medical treatment. Consider the risks versus benefits of continuing treatment with galsulfase; patients who developed immune-mediated reactions have successfully continued receiving galsulfase under close supervision.
Anaphylactoid reactions, including anaphylactic shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension, have been reported during and up to 24 hours after galsulfase administration. Some reactions have been severe and life-threatening. If severe anaphylactic reactions occur, consider immediate infusion discontinuation, and institute appropriate medical treatment. Consider the risks and benefits of readministering galsulfase after an anaphylactic or severe allergic reaction. If the decision is made to readminister galsulfase after an anaphylactic reaction, have appropriate medical support measures including cardiopulmonary resuscitation equipment and epinephrine readily available.
Rare cases of thrombocytopenia have been reported during post-marketing use of galsulfase. Patients who developed thrombocytopenia have been successfully rechallenged and continued receiving galsulfase.
Cervical or spinal cord compression (SCC) with resultant myelopathy is a known and serious complication of mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). SCC is expected to occur in the natural progression of the disease in spite of treatment with galsulfase. Reports of new onset or worsening SCC requiring decompression surgery have been reported during post marketing surveillance of galsulfase. Patients with MPS VI should be monitored for signs and symptoms of cervical/spinal cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.
Galsulfase should be used cautiously in patients with hamster protein hypersensitivity (i.e., Chinese hamster ovary cell hypersensitivity), galsulfase hypersensitivity, or hypersensitivity to other components of the product due to increased risk of severe allergic reactions.
Patients with mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) are at increased risk of infection possibly due to associated cytoplasmic inclusion in polymorphonuclear leukocytes, disease related cranial and other skeletal abnormalities, or decreased pulmonary function. Patients receiving galsulfase have experienced infection related adverse reactions. To avoid complications associated with these infections, it is recommended to delay galsulfase administration to patients with an acute febrile or respiratory infection until the infection has resolved.
Drowsiness associated with antihistamine use, for pretreatment of galsulfase infusion related reactions, can increase the risk of apneic episodes associated with sleep apnea, a common complication seen in MPS VI patients. Evaluation of airway patency should be considered prior to galsulfase administration and patients using supplemental oxygen or continuous positive airway pressure during sleep should have these treatments readily available. Severe infusion related reactions can occur with galsulfase (see Adverse Reactions), thus all patients should receive prophylaxis with an antihistamine with or without antipyretics. Some patients may develop an infusion reaction despite prophylaxis; stopping the infusion and administering additional antihistamines, antipyretics, and occasionally corticosteroids allows for most patients to receive the entire infusion. Subsequent infusions can be managed by slowing the infusion rate, treatment with additional antihistamines, and possibly prophylactic corticosteroids. Even despite these additional measures, 43% of patient have experienced additional infusion related reactions. The risks and benefits of readministering galsulfase after a severe infusion related reaction should be considered.
Patients between the ages of 5-29 years of age (mostly pediatric) were included in clinical studies of galsulfase. The safety and efficacy of galsulfase in neonates, infants and children less than 5 years old have not been established. It is unknown how patients less than 5 years old will react to galsulfase therapy, use cautiously if administering to these patients.
Due to the shortened life span associated with MPS VI, clinical studies did not include patients older than 29 years of age. It is not known if geriatric patients will respond differently to galsulfase compared to younger patients.
There are no available data on galsulfase use during pregnancy to inform a drug-associated risk of pregnancy-related outcomes. Well-controlled studies in pregnant women are lacking; however, animal reproduction studies in rats and rabbits found no effects on embryo-fetal development when galsulfase was given during the period of organogenesis. It is unknown whether galsulfase crosses the human placenta, its molecular weight (about 56,000) and brief half-life suggests minimal if any exposure to the embryo or fetus. Because Maroteaux-Lamy syndrome is a debilitating chronic disease, galsulfase should not be withheld because of pregnancy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to galsulfase; information about the registry can be obtained at clinicaltrials.gov/ct/show/NCT00214773?order=2.
It is unknown whether galsulfase is excreted in breast milk, however its molecular weight (about 56,000) and brief half-life suggests minimal if any exposure to the nursing infant. In addition, as a glycoprotein, any drug excreted in the milk would most likely be digested in the infant's GI tract. The manufacturer recommends that galsulfase should be used with caution in women who are breast-feeding. A Clinical Surveillance Program is available for lactating women who receive galsulfase. Participation is voluntary and involves long term follow up. Information regarding the program may be obtained by visiting the manufacturer's web site or by calling the US toll free number (800-983-4587). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Cervical or spinal cord compression (SCC) with resultant myelopathy is a known and serious complication of mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). SCC is expected to occur in the natural progression of the disease in spite of treatment with galsulfase. Reports of new onset or worsening SCC requiring decompression surgery have been reported during post marketing surveillance of galsulfase. Patients with MPS VI should be monitored for signs and symptoms of cervical/spinal cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.
For the treatment of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome):
NOTE: Galsulfase has been designated as an orphan drug for this indication by the FDA.
NOTE: When to start treatment and the optimal duration of therapy is unknown. In clinical trials, galsulfase was given to severely debilitated MPS VI patients with clinical signs and symptoms of disease.
Intravenous dosage:
Adults, Adolescents, and Children >= 5 years old: 1 mg/kg IV infused over no less than 4 hours once per week. Administer at a rate of 6 mL/hour for the first hour. For patients receiving a 250 mL infusion: if the infusion is well tolerated, the rate can be increased to 80 mL/hour for the remaining 3 hours. For patients receiving a 100 mL infusion : if the infusion is well tolerated, the rate can be increased so that the remaining volume of the infusion is administered over 3 hours. If an infusion related reaction occurs, the infusion time can be extended to up to 20 hours.
Children < 5 years old and Infants: Safety and efficacy have not been established.
Maximum Dosage Limits:
-Adults
No maximum dosage information is available.
-Elderly
No maximum dosage information is available.
-Adolescents
No maximum dosage information is available.
-Children
>= 5 years old: No maximum dosage information is available.
< 5 years old: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Gentamicin: (Minor) There is a possible drug interaction between galsulfase and medications which may impact lysosomal efficacy. Gentamicin slightly increases the intralysosomal pH of proximal tubular cells and decreases the activity of the lysosomal proteinases, cathepsin B and L, which are proteolytic activators of other lysosomal enzymes. Because similar interactions have occurred between gentamicin and other therapies used for a similar disease, the effectiveness of galsulfase therapy should be monitored during coadministration.
Galsulfase is taken up into cellular lysosomes through the binding of manose-6 phosphate-terminated oligosaccharide chains of galsulfase to specific cellular mannosephosphate receptors. Once incorporated into cellular lysosomes, it increases the catabolism of glycosaminoglycans (GAGs). Galsulfase replaces the enzyme N-acetylgalactosamine 4-sulfatase, which is a lysosomal hydrolase that catalyses the cleavage of the sulfate ester from terminal N-acetylgalactosamine 4-sulfatase residues of the GAGs chondroitin 4-sulfate and dermatan sulfate. The accumulation of dermatan sulfate throughout the body results in the manifestations of the disease mucopolysaccharidosis VI; galsulfase is administered to promote catabolism, and prevent further accumulation, of dermatan sulfate and relieve the symptoms of this disease.
Galsulfase is administered via intravenous infusion. Following 24 weeks of treatment in patients with mucopolysaccharidosis VI, at a dose of 1 mg/kg per week, specific pharmacokinetic parameters of galsulfase were reported: median clearance was 3.7 mL/kg/min (range 1.1-55.9 mL/kg/min); and median half life was 26 minutes (range 8-40 minutes). Urinary glycosaminoglycan (GAG) concentrations decreased over 24 weeks of treatment, although normal urinary GAG concentrations were not achieved. It appears that reduction of urinary GAG is dose dependent. Another study has shown that reductions in urinary GAG concentrations have been maintained for over 2.5 years; it has been suggested that urinary GAG levels below 100 mg/mg creatinine are associated with improved mortality.
It is unclear if the development of anti-galsulfase antibodies affects the efficacy of galsulfase. The assessment of antibodies from one patient showed evidence of in vitro inhibition of galsulfase activity. Unfortunately, other patients' antibodies were not tested for neutralizing effect. However, the comparison of antibody test results may be misleading due to possible differences in assay sensitivity and specificity.
-Route-Specific Pharmacokinetics
Intravenous Route
Following 24 weeks of treatment in patients with mucopolysaccharidosis VI, at a dose of 1 mg/kg per week, specific pharmacokinetic parameters of galsulfase were reported: median peak plasma concentration was 1.5 mcg/mL (range 0.2-5.5 mcg/mL) and median AUC was 4.3 h x mcg/mL (range 1-3.5 h x mcg/mL).
Overall, 98% of patients who received galsulfase in clinical trials developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment. After 24 weeks of treatment, high antibody titers were associated with a decrease in galsulfase plasma AUC in 4 patients and an increase in galsulfase plasma AUC in 1 patient.