Laronidase

Dosage Forms

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 mouse (murine) and/or hamster protein, polysorbate 80]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

Infants and Children 6 months to 5 years: V_d: 0.12-0.56 L/kg

Children ≥6 years and Adults: V_d: 0.24-0.6 L/kg

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.

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

Use: Labeled Indications

Mucopolysaccharidosis I (Hurler syndrome, Hurler-Scheie, and Scheie forms): Treatment of Hurler and Hurler-Scheie forms of mucopolysaccharidosis I (MPS I); treatment of Scheie form of MPS I in patients with moderate to severe symptoms

Contraindications

There are no contraindications listed within the manufacturer’s US labeling.

Canadian labeling: Severe hypersensitivity to laronidase or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Premedicate with antipyretic and/or antihistamines 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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Premedicate with antipyretic and/or antihistamines 1 hour prior to start of infusion.

Mucopolysaccharidosis I (Hurler syndrome, Hurler-Scheie, and Scheie forms): Infants ≥6 months, Children, and Adolescents: IV: 0.58 mg/kg/dose once weekly; dose should be rounded up to the nearest whole vial

Reconstitution

Determine the number of vials to dilute by calculating the required dose and rounding up to the nearest whole vial. Allow vials to come to room temperature prior to admixture. Do not use if the solution is discolored or contains particulate matter. Prepare the infusion using a low protein-binding container (there is no compatibility information of diluted laronidase in glass containers). Total volume of infusion is determined by body weight. For patients weighing ≤20 kg (or weighing up to 30 kg and with cardiac or respiratory compromise), dilute the required dose in 100 mL NS; for patients weighing >20 kg, dilute required dose in 250 mL NS. Remove and discard a volume of NS from the infusion bag equal to the volume of the calculated dose of laronidase. Slowly withdraw from vial(s) and slowly add laronidase to the NS; avoid excessive agitation; do not use filter needle. Gently rotate infusion bag to mix (do not shake).

Administration

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 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). Vital signs should be monitored every 15 minutes, if stable; in case of infusion-related reaction in any patient, decrease the rate of infusion, temporarily discontinue the infusion, and/or administer additional antipyretics/antihistamines. 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.

Storage

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.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Unless otherwise noted, adverse reactions were reported in patients ≥6 years of age.

>10%:

Cardiovascular: Flushing (11% to 23%), venous irritation (poor venous access: 14%)

Central nervous system: Chills (infants and children 6 months to 5 years: 20%), hyperreflexia (14%), paresthesia (14%)

Dermatologic: Skin rash (13% to 36%; infants and children 6 months to 5 years: ≥5%)

Immunologic: Antibody development (93% to 97%; infants and children 6 months to 5 years: 100%)

Local: Injection site reaction (18%)

Otic: Otitis media (infants and children 6 months to 5 years: 20%)

Respiratory: Upper respiratory tract infection (32%)

Miscellaneous: Infusion-related reaction (32% to 49%; may be severe; infants and children 6 months to 5 years: 35%), fever (11%; infants and children 6 months to 5 years: 30%)

1% to 10%:

Cardiovascular: Hypertension (infants and children 6 months to 5 years: 10%), oxygen saturation decreased (infants and children 6 months to 5 years: 10%), tachycardia (infants and children 6 months to 5 years: 10%), chest pain (9%), edema (9%), facial edema (9%), hypotension (9%), hot and cold flashes (7%)

Central nervous system: Headache (9%)

Dermatologic: Pallor (infants and children 6 months to 5 years: ≥5%), pruritus (4%), urticaria (4%), hyperhidrosis

Gastrointestinal: Abdominal pain (≤9%), abdominal distress (≤9%), diarrhea (7%), vomiting (4%)

Hematologic & oncologic: Thrombocytopenia (9%)

Hepatic: Hyperbilirubinemia (9%)

Hypersensitivity: Severe hypersensitivity (1%)

Local: Abscess at injection site (9%), pain at injection site (9%)

Neuromuscular & skeletal: Tremor (infants and children 6 months to 5 years: ≥5%), arthralgia (4%), back pain, musculoskeletal pain

Ophthalmic: Corneal opacity (9%)

Respiratory: Rales (infants and children 6 months to 5 years: ≥5%), respiratory distress (infants and children 6 months to 5 years: ≥5%), wheezing (infants and children 6 months to 5 years: ≥5%), bronchospasm, cough, dyspnea

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, cardiac failure, cyanosis, erythema, fatigue, laryngeal edema, peripheral edema, pneumonia, respiratory failure

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Anaphylactic reactions have been observed during infusion, immediate treatment for hypersensitivity reactions should be available during administration. Additional monitoring may be required in patients with compromised respiratory function or acute respiratory disease; may be at increased risk for acute exacerbation of respiratory symptoms due to infusion reaction. 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. Immediately discontinue infusion if severe reactions occur; medical support should be available during administration. Risks and benefits should be carefully considered prior to readministration following a severe hypersensitivity reaction. Patients who initially experience severe reactions may require prolonged monitoring. 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. Decrease infusion rate, temporarily discontinue infusion, and/or administer additional antipyretics and antihistamines to manage infusion reactions.

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.

Monitoring Parameters

Vital signs, FVC, height, weight, range of motion, serum antibodies to alpha-L-iduronidase, urine levels of glycosaminoglycans (GAG), change in liver size

Pregnancy

Pregnancy Risk Factor

B

Pregnancy Considerations

Information related to the use of laronidase in pregnancy is limited (Anbu 2006; Castorina 2015).

Pregnant patients are encouraged to enroll in the MPS I registry (800-745-4447 or www.registrynxt.com).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience flushing, warm sensation, cold sensation, common cold symptoms, abdominal pain, nausea, or diarrhea. Have patient report immediately to prescriber severe headache, pale skin, tremors, twitching, chest pain, fast heartbeat, slow heartbeat, shortness of breath, severe dizziness, passing out, chills, burning or numbness feeling, fast breathing, bruising, bleeding, edema, vision changes, or severe injection site irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.