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    Mucopolysaccharidosis (MPS) Agents

    DEA CLASS

    Rx

    DESCRIPTION

    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.

    COMMON BRAND NAMES

    Naglazyme

    HOW SUPPLIED

    Naglazyme Intravenous Inj Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    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.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    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.

    STORAGE

    Naglazyme:
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Hamster protein hypersensitivity

    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.

    Respiratory infection

    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.

    Sleep apnea

    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.

    Children, infants, neonates

    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.

    Geriatric

    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.

    Pregnancy

    Galsulfase is classified as FDA pregnancy risk category B. Well-controlled studies in pregnant women are lacking; however, animal data in two species suggests low risk. 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. A Clinical Surveillance Program has been established and is available for pregnant women who receive the drug. 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 in the US using the toll free number (800-983-4587).

    Breast-feeding

    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.

    Spinal cord compression

    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.

    ADVERSE REACTIONS

    Severe

    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

    Moderate

    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

    Mild

    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 (unspecified) / 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

    DRUG INTERACTIONS

    Chloroquine: (Minor) Theoretically, there is a possible drug interaction between galsulfase and medications which may impact lysosomal efficacy. Both chloroquine and hydroxychloroquine are weak bases that accumulate in acidic lysosomes because of ion trapping. The subsequent elevation of lysosomal pH results in lysosomal enzyme inhibition. Although these drugs have been clinically shown to interact with other MPS treatments, it is unknown if they will have any effect on the efficacy of galsulfase.
    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.
    Hydroxychloroquine: (Minor) Theoretically, there is a possible drug interaction between galsulfase and medications which may impact lysosomal efficacy. Both chloroquine and hydroxychloroquine are weak bases that accumulate in acidic lysosomes because of ion trapping. The subsequent elevation of lysosomal pH results in lysosomal enzyme inhibition. Although these drugs have been clinically shown to interact with other MPS treatments, it is unknown if they will have any effect on the efficacy of galsulfase.

    PREGNANCY AND LACTATION

    Pregnancy

    Galsulfase is classified as FDA pregnancy risk category B. Well-controlled studies in pregnant women are lacking; however, animal data in two species suggests low risk. 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. A Clinical Surveillance Program has been established and is available for pregnant women who receive the drug. 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 in the US using the toll free number (800-983-4587).

    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.

    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.

    PHARMACOKINETICS

    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.

    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.