laronidase (Rx)

>10%

Development of anti-laronidase antibodies (91% in one study) - clinical significance unknown

Rash (36%)

Injection site reaction (18%)

Poor venous access (14%)

Hyperreflexia (14%)

Paresthesia (14%)

Chills (20%; children 6 months to 5 years)

Otitis media (20%; children 6 months to 5 years)

Upper respiratory tract infection (32%)

Infusion reactions (49%)

• Rash (13%)
• Flushing (11%)
• Pyrexia (11%)
• Headache (9%)
• Abdominal pain or discomfort (9%)
• Nausea (7%)
• Diarrhea (7%)
• Feeling hot or cold (7%)
• Vomiting (4%)
• Pruritus (4%)
• Arthralgia (4%)
• Urticaria (4%)

1-10%

Thrombocytopenia (9%)

Corneal opacity (9%)

Chest pain (9%)

Face edema (9%)

Gravitational edema (9%)

Injection site pain (9%)

Hyperbilirubinemia (9%)

Hypotension (9%)

< 1%

Anaphylactic shock

Laryngeal edema

Fatigue

Peripheral edema

Erythema

Cyanosis

Angioedema

Contraindications

Hypersensitivity

Cautions

Consider registration in the MPS I Registry, www.MPSIregistry.com or 1-800-745-4447

Consider delaying treatment in patients with acute febrile/respiratory illness; may increase risk of infusion related reactions; premedication with antihistamines and antipyretics recommended; decrease infusion rate temporarily; manage reactions by administering additional antipyretics and antihistamines

Use caution in patients with fluid overloads or in conditions where fluid restriction is indicated; exacerbation of such conditions may occur during infusions

Not indicated for CNS manifestations of the disorder

Use caution in patients with sleep apnea; apnea treatment options should be readily available during infusion or with use of sedating antihistamines including supplemental oxygen and CPAP

Pregnancy

An MPS I Registry has been established and pregnant women with MPS I should be encouraged to enroll; for more information, visit www.registrynxt.com or call 1-800-745-4447 ext. 15500

Available data from published case reports and postmarketing experience in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal studies

• No evidence of fetal harm observed in rats when laronidase was administered during organogenesis at doses up to 6.2 times the recommended human dose

Clinical considerations

• Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse pregnancy outcomes for both mother and fetus

Lactation

Data are not available on the presence of laronidase in human milk or the effects on milk production

No adverse effects have been reported in breastfed infants in a few postmarketing cases of laronidase use in lactating women

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant alpha-L-iduronidase, an enzyme (deficient in mucopolysaccharidosis I) involved in the breakdown of glycosaminoglycans within lysosomes; walking capacity and pulmonary function improves in patients treated with this recombinant product

Absorption

Peak plasma concentration: 1.2-1.7 mcg/mL

AUC: 4.5-6.9 mcg•hr/mL

Onset: 3-6 wk (initial effect); 26 wk (max effect)

Distribution

Vd: 0.24-0.6 L/kg

Elimination

Half-life: 1.5-3.6 hr

Plasma clearance: 1.7-2.7 mL/min/kg

IV Incompatibilities

Do not mix with other drugs in same infusion solution

IV Preparation

Dilute commercially available injection concentrate in NS containing 0.1% human albumin prior to administration

Pretreatment with antipyretics &/or antihistamines is recommended 60 min before start of laronidase infusions

Prepare solutions using PVC containers

Vial calculation

• Appropriate number of laronidase vials should be diluted based on body weight and dose determined using the equations listed below
• Patient's weight (kg) x 1 mL/kg of laronidase = Total # mL of laronidase
• Total # mL/5 mL per vial = Total # of vials, rounded up to the nearest whole vial

Prepare infusion bag of NS containing human albumin 0.1% based on total infusion volume

Prior to addition of albumin to the infusion bag, remov & discard an amount of NS equal to volume of albumin

For a total infusion volume of 100 mL, add 2 or 0.4 mL of human albumin 5% or 25%; for a total infusion volume of 250 mL, add 5 or 1 mL of albumin 5% or 25%

Gently rotate to ensure proper distribution of albumin

Prior to addition of calculated volume of laronidase to infusion bag, remove & discard an equal volume of NS containing albumin 0.1%

Calculated volume of laronidase injection concentrate should be withdrawn slowly from appropriate number of vials & added slowly to infusion bag, followed by gentle rotation for even distribution; do not use filter needle since it may cause agitation & denature laronidase

IV Administration

Premedicate with antipyretics &/or antihistamines 1 hr before infusion

Infuse over 3-4 hr (see infusion rate schedule below)

Peds: <20 kg: give a total volume of 100 mL; >20 kg: give a total volume of 250 mL

Administer with PVC infusion set equipped with an inline, low-protein-binding filter with a pore diameter of 0.2 microns

Infusion rates for body Weight <20 kg

• 2 mL/h for 15 min (10 mcg/kg/hr); if vital signs stable increase rate to
• 4 mL/h for 15 min (20 mcg/kg/hr); if vital sign stable, increase rate to
• 8 mL/h for 15 min (50 mcg/kg/hr); if vital sign stable, increase rate to
• 16 mL/h for 15 min (100 mcg/kg/hr); if vital sign stable, increase rate to
• 32 mL/h for 3 hr (200 mcg/kg/hr); continue at this rate for the remainder of the infusion

Infusion rates for body weight >20 kg

• 5 mL/h for 15 min (10 mcg/kg/hr); if vital signs stable increase rate to
• 10 mL/h for 15 min (20 mcg/kg/hr); if vital sign stable, increase rate to
• 20 mL/h for 15 min (50 mcg/kg/hr); if vital sign stable, increase rate to
• 40 mL/h for 15 min (100 mcg/kg/hr); if vital sign stable, increase rate to
• 80 mL/h for 3 hr (200 mcg/kg/hr); continue at this rate for the remainder of the infusion

Storage

Store at 2-8°C

Protect from freezing

Do not shake