Mucopolysaccharidosis (MPS) Agents
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
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.
corneal opacification / Delayed / 11.0-11.0
hearing loss / Delayed / 11.0-11.0
cyanosis / Early / Incidence not known
angioedema / Rapid / Incidence not known
bradycardia / Rapid / Incidence not known
apnea / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
spinal cord compression / Delayed / Incidence not known
antibody formation / Delayed / 98.0-98.0
infusion-related reactions / Rapid / 56.0-56.0
dyspnea / Early / 21.0-21.0
conjunctivitis / Delayed / 21.0-21.0
chest pain (unspecified) / Early / 16.0-16.0
hypertension / Early / 11.0-11.0
sinus tachycardia / Rapid / Incidence not known
hypoxia / Early / Incidence not known
erythema / Early / Incidence not known
tachypnea / Early / Incidence not known
hypotension / Rapid / Incidence not known
thrombocytopenia / Delayed / Incidence not known
abdominal pain / Early / 47.0-47.0
arthralgia / Delayed / 42.0-42.0
otalgia / Early / 42.0-42.0
chills / Rapid / 21.0-21.0
rash / Early / 21.0-21.0
malaise / Early / 11.0-11.0
hyporeflexia / Delayed / 11.0-11.0
nasal congestion / Early / 11.0-11.0
pharyngitis / Delayed / 11.0-11.0
nausea / Early / Incidence not known
pallor / Early / Incidence not known
urticaria / Rapid / Incidence not known
headache / Early / Incidence not known
paresthesias / Delayed / Incidence not known
fever / Early / Incidence not known
shivering / Rapid / Incidence not known
vomiting / Early / Incidence not known
infection / Delayed / Incidence not known
cough / Delayed / Incidence not known
diarrhea / Early / Incidence not known
Common Brand Names
Recombinant form of the human enzyme N-acetylgalactosamine 4-sulfatase; allows for the breakdown of certain glycosaminoglycans (GAGs) in cellular lysosomes; approved for enzyme replacement therapy of Mucopolysaccharidosis VI.
Dosage And Indications
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.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
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.
Naglazyme Intravenous Inj Sol: 1mg, 1mL
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.
Safety and efficacy have not been established.
Mechanism Of Action
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.
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.
Pregnancy And Lactation
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.