Version May 2024
Patients treated with laronidase have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during laronidase administration. If a severe hypersensitivity reaction (eg, anaphylaxis) occurs, discontinue laronidase immediately and initiate appropriate medical treatment. In patients with severe hypersensitivity reactions, a desensitization procedure to laronidase may be considered.
Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions and require additional monitoring.
Note: Premedicate with antipyretic and/or antihistamines 1 hour prior to start of infusion.
Mucopolysaccharidosis (MPS) I (Hurler syndrome, Hurler-Scheie, and Scheie phenotypes):
Note: Enzyme replacement therapy with laronidase is typically initial therapy in Hurler-Scheie and Scheie phenotypes with initiation of treatment as early as possible to maximize long-term benefits (Al-Sannaa 2015; de Ru 2011; Horovitz 2016; Martins 2009); patients with severe Hurler syndrome at risk for neuro-cognitive impairment may be candidates for hematopoietic stem cell transplant (HSCT) with possible peri-transplant laronidase therapy; further studies needed (Parini 2017).
Weekly dosing: Infants >3 months, Children, and Adolescents: IV: 0.58 mg/kg/dose once weekly; dose should be rounded up to the nearest whole vial; Note: In FDA-approval trials, the youngest patient to receive laronidase was 6 months of age (Wraith 2007); however, sibling case-reports evaluating early laronidase therapy includes patients as young 3 to 4 months of age (Al-Sannaa 2015; Gabrielli 2010; Laraway 2013).
Every-2-week dosing; Limited data available; role in management not defined; some experts suggest regimen for patients with compliance challenges (Martins 2009); however, most data has been as maintenance therapy after 1 year of weekly dosing (Horovitz 2016; Kyosen 2019):
Children ≥4 years and Adolescents: IV: 1.2 mg/kg/dose every other week (Giugliani 2009; Horovitz 2016; Kyosen 2019). In a trial describing use in 20 patients (median [range] age at time of extended-interval dosing for phenotype: Hurler: 6 years [3.9 to 6.2 years]; Hurler-Scheie: 12.3 years [4 to 25 years]; Scheie: 18.7 years [8 to 25 years]), data showed that patients switched to every-2-week dosing maintained existent improvement in clinical signs and laboratory parameters and no patient exhibited deterioration; therapy was reported to be well-tolerated; the range of duration of therapy reported was 1 to 9 years (Horovitz 2016).
There are no dosing adjustments provided in the manufacturer's labeling.
There are no dosing adjustments provided in the manufacturer's labeling.
(For additional information see "Laronidase: Drug information")
Dosage guidance:
Safety: Appropriate medical monitoring and support measures, including CPR equipment, should be readily available during administration.
Clinical considerations: Consider premedication with antihistamines with or without antipyretic 1 hour prior to start of infusion.
MPS I (Hurler syndrome, Hurler-Scheie, and Scheie forms): IV: 0.58 mg/kg once weekly; dose should be rounded up to the nearest whole vial.
Missed dose: If ≥1 dose is missed, restart treatment as soon as possible, keeping the 1-week interval between infusions thereafter.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults and pediatrics.
>10%:
Cardiovascular: Flushing
Dermatologic: Skin rash
Hypersensitivity: Infusion-related reaction
Immunologic: Antibody development (including neutralizing antibodies)
Local: Injection-site reaction (including pain at injection site)
Nervous system: Chills, hyperreflexia, paresthesia
Respiratory: Upper respiratory tract infection
Miscellaneous: Fever
1% to 10%:
Cardiovascular: Chest pain, edema (gravitational), hypotension, increased blood pressure, tachycardia
Dermatologic: Pallor, pruritus
Hematologic & oncologic: Thrombocytopenia
Hepatic: Hyperbilirubinemia
Hypersensitivity: Facial edema, severe hypersensitivity reaction (including anaphylactic shock, anaphylaxis)
Infection: Abscess
Nervous system: Tremor
Ophthalmic: Corneal opacity
Respiratory: Oxygen saturation decreased, rales, respiratory distress, wheezing
Frequency not defined: Hypersensitivity: Angioedema
Postmarketing:
Cardiovascular: Acute cardiorespiratory failure, peripheral edema
Dermatologic: Erythema of skin
Nervous system: Fatigue
Respiratory: Cyanosis, laryngeal edema
There are no contraindications listed within the manufacturer’s US labeling.
Canadian labeling: Severe hypersensitivity to laronidase or any component of the formulation
Concerns related to adverse effects:
• Hypersensitivity/anaphylactoid reactions: Hypersensitivity reactions, which may include airway obstruction, bradycardia, bronchospasm, hypotension, hypoxia, respiratory distress/failure, stridor, tachypnea, and urticaria, may be severe and tend to occur during or within 3 hours after administration. In the case of anaphylaxis, caution should be used if epinephrine is being considered; many patients with MPS I have pre-existing heart disease.
• Infusion reactions: Infusion reactions may occur; use caution and consider delaying treatment in patients with acute febrile/respiratory illness; may result in increased risk for infusion-related reactions. Pretreatment with antipyretics and antihistamines is recommended.
Disease-related concerns:
• Fluid overload: Use with caution in patients at risk for fluid overload or in conditions where fluid restriction is indicated (eg, acute underlying respiratory illness, compromised cardiac and/or respiratory function); conditions may be exacerbated during infusion. Extended observation may be necessary for some patients.
• MPS I: Appropriate use: Has not been studied in patients with mild symptoms of the Scheie form of MPS I. Not indicated for the CNS manifestations of the disorder.
• Sleep apnea: Use with caution in patients with sleep apnea; evaluate patients prior to initiation of therapy. Apnea treatment options should be readily available (eg, CPAP or supplemental oxygen) during infusion or with use of sedating antihistamines.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Registry: A patient registry has been established and all patients are encouraged to participate. Registry information may be obtained at www.registrynxt.com or by calling 1-800-745-4447.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Aldurazyme: 2.9 mg/5 mL (5 mL) [contains polysorbate 80]
No
Solution (Aldurazyme Intravenous)
2.9 mg/5 mL (per mL): $256.93
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Aldurazyme: 2.9 mg/5 mL (5 mL) [contains polysorbate 80]
Parenteral: IV infusion: Antipyretics and/or antihistamines should be administered 60 minutes prior to infusion. Laronidase must be diluted prior to administration.
Administer IV using an infusion set with low protein-binding 0.2 micrometer in-line filter. Total infusion volume and rates are based on body weight (see following table); deliver infusion over ~3 to 4 hours. For weekly administration, initiate infusion at 10 mcg/kg/hour for 15 minutes; if tolerated, the infusion rate may be incrementally increased every 15 minutes during the first hour; increase to a maximum infusion rate of 200 mcg/kg/hour which is maintained for the remainder of the infusion (approximately 3 hours). Higher doses may be administered every 2 weeks and infused over a total of 4 hours (Giugliani 2009; Kyosen 2019). If an infusion-related reaction occurs, decrease the rate of infusion, temporarily discontinue the infusion, and/or administer additional antipyretics/antihistamines.
|
Patient Weight |
Total Infusion Volume |
Volume Based Infusion Rate |
|---|---|---|
|
aGiugliani 2009; Kyosen 2019; manufacturer's labeling | ||
|
≤20 kg |
100 mL NS |
2 mL/hour x 15 minutes |
|
4 mL/hour x 15 minutes | ||
|
8 mL/hour x 15 minutes | ||
|
16 mL/hour x 15 minutes | ||
|
32 mL/hour x ~3 hours | ||
|
>20 kg |
250 mL NS |
5 mL/hour x 15 minutes |
|
10 mL/hour x 15 minutes | ||
|
20 mL/hour x 15 minutes | ||
|
40 mL/hour x 15 minutes | ||
|
80 mL/hour x ~3 hours | ||
|
Note: For patients up to 30 kg with cardiac or respiratory compromise, a total infusion volume of 100 mL NS and slower infusion rate may be considered. | ||
IV: Administer using an infusion set with low protein-binding and 0.2 micrometer in-line filter. Antipyretics and/or antihistamines should be administered 60 minutes prior to infusion. Volume and infusion rate are based on actual body weight; deliver infusion over ~3 to 4 hours. An initial 10 mcg/kg/hour infusion rate may be incrementally increased every 15 minutes during the first hour if tolerated (see below); increase to a maximum infusion rate of 200 mcg/kg/hour which is maintained for the remainder of the infusion (~3 hours). After administration, flush infusion line with NS at the same infusion rate as was last used for administration. Vital signs should be monitored every 15 minutes, if stable. Manufacturer provides the following infusion rate information for patients receiving usual preparation:
≤20 kg: Total infusion volume: 100 mL.
2 mL/hour for 15 minutes.
4 mL/hour for 15 minutes.
8 mL/hour for 15 minutes.
16 mL/hour for 15 minutes.
32 mL/hour for remainder of infusion (~3 hours).
>20 kg: Total infusion volume: 250 mL.
5 mL/hour for 15 minutes.
10 mL/hour for 15 minutes.
20 mL/hour for 15 minutes.
40 mL/hour for 15 minutes.
80 mL/hour for remainder of infusion (~3 hours).
Note: A total infusion volume of 100 mL NS and slower infusion rate may be considered for patients with cardiac or respiratory compromise who weigh up to 30 kg.
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Do not shake. Following dilution in NS, solution for infusion should be used immediately; however, if not used immediately, diluted solutions should be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 36 hours; administer infusion, including infusion time, within 8 hours after removal from the refrigerator. Discard any unused portion.
Treatment of patients with Hurler and Hurler-Scheie forms of mucopolysaccharidosis I (MPS I), and patients with the Scheie form who have moderate to severe symptoms (FDA approved in pediatric patients [age not specified] and adults).
None known.
There are no known significant interactions.
Information related to the use of laronidase in pregnancy is limited (Anbu 2006; Castorina 2015).
Pregnant patients are encouraged to enroll in the mucopolysaccharidosis I registry (1-800-745-4447, extension 15500 or www.registrynxt.com).
Signs of infusion reactions, vital signs, forced vital capacity (FVC), growth parameters (height/weight), range of motion, serum antibodies to α-L-iduronidase, urine levels of glycosaminoglycans (GAG), change in liver size.
Laronidase is a recombinant (replacement) form of alpha-L-iduronidase derived from Chinese hamster cells. Alpha-L-iduronidase is an enzyme needed to break down endogenous glycosaminoglycans (GAGs) within lysosomes. A deficiency of alpha-L-iduronidase leads to an accumulation of GAGs, causing cellular, tissue, and organ dysfunction as seen in MPS I. Improved pulmonary function and walking capacity have been demonstrated with the administration of laronidase to patients with Hurler, Hurler-Scheie, or Scheie (with moderate-to-severe symptoms) forms of MPS.
Distribution:
Infants and Children 6 months to 5 years: Vd: 0.12-0.56 L/kg
Children ≥6 years and Adults: Vd: 0.24-0.6 L/kg
Half-life elimination:
Infants and Children 6 months to 5 years: 0.3-1.9 hours
Children ≥6 years and Adults: 1.5-3.6 hours
Excretion:
Infants and Children 6 months to 5 years: Clearance: 2.2-7.7 mL/minute/kg
Children ≥6 years and Adults: Clearance: 1.7-2.7 mL/minute/kg; during the first 12 weeks of therapy the clearance of laronidase increases proportionally to the amount of antibodies a given patient develops against the enzyme. However, with long-term use (≥26 weeks) antibody titers have no effect on laronidase clearance.
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