Laronidase (BM-101, recombinant human alpha-L-iduronidase) is an enzyme replacement therapy for the treatment of mucopolysaccharidosis I (MPS I), a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-L-iduronidase. The lack of the enzyme causes glycosaminoglycans (GAG) to build up in cells; the manifestations can include growth and developmental delay, enlargement of spleen and liver, skeletal deformity, cardiac and pulmonary impairment, vision or hearing loss, and mental dysfunction. The drug is indicated for enzyme replacement in patients with the Hurler and Hurler-Scheie forms of MPS I, and for Scheie patients with moderate to severe symptoms. In a randomized, double-blinded, placebo-controlled study (n = 45), at 26 weeks, laronidase treatment statistically improved pulmonary function (FVC) by a mean of 5.6 percentage points (median 3; p =0.009); the 6-minute walk test distance, a measure of endurance, also improved by a mean of 38.1 meters (p =0.066). An open-label study reported similar results. The drug has also been shown to biochemically reduce the excess carbohydrates that are stored in the organs of patients with MPS I; however, the clinical significance of this carbohydrate reduction at the biochemical level is not certain. Laronidase has not been evaluated to see if it improves the CNS manifestations (i.e., hydrocephalus, developmental delay) of the disorder. Laronidase is the first drug treatment for MPS I; bone marrow transplantation being the only other viable option. Via a drug registry, the manufacturer will obtain long-term information related to the natural history of MPS I and the safety and efficacy of laronidase. Patients are encouraged to learn more about the registry by visiting www.registrynxt.com or by calling 1-800-745-4447 (ext. 15500) in the US. The manufacturer also offers CareConnectPSS (https://www.careconnectpss.com/), a program and service network designed to support people living with MPS I and their caregivers.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-For intravenous (IV) infusion only; do not administer as an IV bolus injection.
-DO not mix laronidase infusion with other medications; compatibility has not been evaluated.
-Premedicate with antipyretics and/or antihistamines 1 hour prior to beginning each infusion.

Dilution
-Use aseptic technique.
-Determine the number of laronidase vials to be diluted based on patient's weight. Round up to the nearest whole vial. Allow vials to reach room temperature prior to dilution; do not heat or microwave vials.
-Visually inspect each vial prior to dilution. The undiluted solution should be clear to slightly opalescent and colorless to pale yellow. A few translucent particles may be present. Do not use if the solution is discolored or contains opaque particulate matter.
-Prepare laronidase infusions using only low-protein binding containers. There is no information on glass compatibility.
-Dilute with 0.9% Sodium Chloride Injection to a total volume of 100 mL (patients weighing 20 kg or less) or 250 mL (patients weighing more than 20 kg). For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, a total volume of 100 mL may be utilized.
-Prior to the addition of laronidase, remove and discard a volume equal to the volume of laronidase to be added to the bag. Using a needle without a filter, slowly withdraw the calculated volume of laronidase from the appropriate number of vials and add to 0.9% Sodium Chloride Injection; use caution to avoid excess agitation. After the addition of laronidase, gently rotate the infusion bag to ensure proper distribution; do not shake.
-Storage: If immediate use is not possible once the infusion is prepared, the infusion bag may be stored under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for no longer than 36 hours. Discard any partially used vials of laronidase.

Intermittent IV Infusion
-Administer laronidase using only low-protein binding containers and infusion sets. The infusion set should be equipped with an in-line, low-protein binding (0.2 micron) filter. There is no information on glass compatibility.
-Administer the diluted IV infusion solution immediately via slow IV infusion over 3 to 4 hours.
-The initial infusion rate of 10 mcg/kg/hour may be increased incrementally every 15 minutes over the first hour, as tolerated and if vital signs are stable, to a maximum rate of 200 mcg/kg/hour. The maximum rate is then maintained for the duration of the infusion. Pump infusion rates may be found in the laronidase package labeling.
-After infusion, immediately dispose of any unused product due to lack of preservative.

A double-blind, placebo-controlled trial consisting of 45 patients with MPS I (n=22 laronidase, n=23 placebo) and utilizing a laronidase dose of 0.58 mg/kg was conducted over a 26 week period. Patient age ranged from 6 to 43 years. An open-label extension was continued for up to 182 weeks. An additional open-label study was conducted in 20 pediatric patients aged 6 months-5 years. The below adverse drug reaction (ADR) rates may not reflect anticipated rates in practice due to small sample sizes, and widely varying study conditions. The following adverse events occurred in at least 2 patients more in the laronidase group vs. the placebo group. Adverse events in the controlled trial were similar in nature and severity to those that occurred in the open-label study.

Cardiovascular-related adverse events reported in those patients treated with laronidase (n=22) in clinical trials included chest pain (unspecified) (n=2 patients in the laronidase group vs. n=0 in the placebo group), poor venous access (n=3 vs. 0), hypotension (n=2 vs. 0) and edema (n=2 vs. 0). Peripheral edema and fatigue have also been reported during post marketing surveillance.

Respiratory-infection related adverse events reported in those patients treated with laronidase (n=22) included upper respiratory tract infection which occurred in 7 (32%) patients taking laronidase and 4 (17%) patients taking placebo. Otitis media occurred in 20% of pediatric patients aged 6 months-5 years receiving laronidase in clinical trials.

Serious hypersensitivity reactions or anaphylaxis has been reported with laronidase therapy. Hypersensitivity type reactions, including infusion-related reactions and anaphylaxis, were the most commonly reported adverse events during laronidase clinical trials. Additionally, during postmarketing surveillance, severe and serious infusion-related reactions, including life-threatening reactions, have been reported. In a placebo-controlled clinical trial, the common ADRs requiring treatment were infusion-related reactions (e.g., flushing, fever, headache, and rash), which occurred in roughly 7 of 22 patients (32%) receiving laronidase. Infusion-related reactions occurring more often in patients receiving laronidase than placebo included rash (36% vs. 22%), injection site reaction (18% vs. 9%), injection site pain (9% vs. 0%), face edema (angioedema) (9% vs. 0%), and hypotension (9% vs. 0%). Flushing occurred in 23% of patients receiving laronidase. Most infusion-related reactions were mild to moderate in severity. The frequency of infusion-related reactions decreased over time. Less common infusion-related reactions included feeling hot, hyperhidrosis, sinus tachycardia, vomiting, back pain, cough, bronchospasm, dyspnea, urticaria, and pruritus. Infusion-related reactions occurred in 35% to 49% of adult and pediatric patients in open-label studies. Reactions included chills (20%), rash (5% or more), flushing (11%), pyrexia (11% to 30%), hypertension (10%), sinus tachycardia (10%), decreased oxygen saturation (10%), headache (9%), abdominal pain or discomfort (9%), injection site reaction (9%), nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4% or more), arthralgia (4%), urticaria (4%), back pain, and musculoskeletal pain. Reactions occurring in at least 5% of pediatric patients included pallor, tremor, respiratory distress, wheezing, and crepitations (pulmonary). Additionally, anaphylactic reactions, such as respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, laryngeal edema, and urticaria, have also been reported. Severe or serious allergic reactions occurred in approximately 1% of patients in clinical trials and postmarketing reports. One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both laronidase-specific IgE binding antibodies and complement activation. Slowing the rate of infusion, temporarily stopping the infusion, and/or treating with additional antipyretics and/or antihistamines may ameliorate most infusion-related adverse events with laronidase. To help prevent infusion-related events, a slower infusion and/or additional prophylactic antipyretics and/or antihistamines may be helpful from the outset. As hypersensitivity reactions may be life-threatening, have appropriate medical support readily available when laronidase is administered. Recurrent reactions may occur, and patients who have experienced anaphylactic reactions may require prolonged observation. Consider the risks versus benefit of readministering laronidase in patients who have experienced anaphylactic or severe allergic reactions. Patients with compromised respiratory function or acute respiratory disease may be at higher risk of life-threatening complications from infusion reactions. These patients may require additional monitoring. Also, consider delaying the infusion in patients with concomitant acute respiratory and/or febrile illness.

Roughly 97% (99 of 102) of patients have developed laronidase-specific IgG antibody formation to the product by week 12. The clinical significance of these antibodies to laronidase is not known, including the potential for product neutralization. Between weeks 1 and 12 increases in plasma clearance of laronidase were observed in some patients and appeared to be proportional to the antibody titer. At week 26, clearance of laronidase was similar to that at week 1, despite continued presence or increased titers of antibodies. Approximately 1% of patients have experienced severe or serious allergic reactions and tested positive for laronidase-specific IgE antibodies. Some of these patients have been successfully rechallenged. The relationship between the presence of anti-laronidase antibodies and clinical efficacy outcomes is unknown. The data reflect the percentage of patients whose test results were positive for antibodies to laronidase in specific assays and are highly dependent on the sensitivity and specificity of these assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to laronidase with the incidence of antibodies to other products may be misleading.

Central nervous system reactions to laronidase were infrequent but sample sizes were small. In the laronidase group, hyperreflexia and paresthesias occurred in 3 patients each vs. zero patients with hyperreflexia and 1 patient with paresthesias in the placebo group.

Other reported ADRs to laronidase included: thrombocytopenia (n=2 in laronidase group vs. 0 with placebo), corneal opacification (n=2 in laronidase group vs. 0 with placebo) and hyperbilirubinemia (n=2 in laronidase group vs. 0 with placebo). Corneal opacification is an expected component of MPS I and may not necessarily be a drug-induced effect. Extravasation has also been reported with post-marketing use of laronidase; there have been no reports of tissue necrosis.

Serious hypersensitivity reactions or anaphylaxis has occurred during or for up to 3 hours after infusions of laronidase. Patients with pre-existing pulmonary disease such as upper airway obstruction or compromised respiratory function, or an acute illness at the time of the infusion may be at increased risk for infusion-related reactions. All patients should receive antipyretics and/or antihistamines 60 minutes prior to the infusion. If an infusion reaction occurs, either decrease the infusion rate, temporarily stop the infusion and/or administer additional pre-treatment medications to help lessen the effect. If severe hypersensitivity or an anaphylactic reaction occurs, immediately stop the laronidase infusion and initiate appropriate resuscitative measures. Use epinephrine with caution due to the increased prevalence of coronary artery disease in MPS I patients. Laronidase should be used with extreme caution and close monitoring, if at all, in any patient who has exhibited prior laronidase hypersensitivity. Administer laronidase in a facility with adequate and size appropriate resuscitative equipment. Personnel should be trained in the use of this equipment for patients who have life-threatening symptoms.

There are no adequate and well-controlled studies of laronidase use in human pregnancy, and its ability to cause fetal harm or affect reproductive capacity is unknown. Animal studies in rats at doses 6.2 times the human dose have not revealed evidence of impaired fertility or harm to the fetus; however, animal studies are not always predictive of human response. Use laronidase during pregnancy only if clearly needed. Pregnant women with mucopolysaccharidosis I (MPS I) are encouraged to enroll in the MPS I registry by visiting www.registrynxt.com or by calling 1-800-745-4447 (ext. 15500).

Data are limited regarding the use of laronidase during breast-feeding, and its excretion in human milk is unknown. Use caution when administering laronidase to lactating women. 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, health care providers are encouraged to report the adverse effect to the FDA. Nursing women with mucopolysaccharidosis I (MPS I) are encouraged to enroll in the MPS I registry by visiting www.registrynxt.com or by calling 1-800-745-4447 (ext. 15500).

Safety and efficacy of laronidase in neonates and infants less than 6 months of age have not been established.

Laronidase has not been studied in geriatric patients 65 years of age and older. It is not known if they will respond to laronidase differently than younger adults.

For the treatment of the Hurler and Hurler-Scheie forms of mucopolysaccharidosis I (MPS I) and for treatment of the Scheie form of MPS I (moderate to severe symptoms only):
NOTE: Laronidase has been designated as an orphan drug for this indication by the FDA.
Intravenous dosage:
Adults: 0.58 mg/kg/dose IV infused over 3 to 4 hours once weekly. The initial infusion rate is 10 mcg/kg/hour and may be increased incrementally every 15 minutes during the first hour of infusion to the maximum infusion rate of 200 mcg/kg/hour. Pretreatment with antipyretics and/or antihistamines is recommended 60 minutes prior to the start of each infusion. Laronidase has been administered once weekly for up to 182 weeks in clinical trials.
Infants, Children, and Adolescents 6 months to 17 years: 0.58 mg/kg/dose IV infused over 3 to 4 hours once weekly. The initial infusion rate is 10 mcg/kg/hour and may be increased incrementally every 15 minutes during the first hour of infusion to the maximum infusion rate of 200 mcg/kg/hour. Pretreatment with antipyretics and/or antihistamines is recommended 60 minutes prior to the start of each infusion. Laronidase has been administered once weekly for up to 182 weeks in clinical trials.

Maximum Dosage Limits:
-Adults
0.58 mg/kg/dose IV once weekly.
-Geriatric
Maximum dosage information is not available.
-Adolescents
0.58 mg/kg/dose IV once weekly.
-Children
0.58 mg/kg/dose IV once weekly.
-Infants
>= 6 months: 0.58 mg/kg/dose IV once weekly.
< 6 months: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

There are no drug interactions associated with Laronidase products.

Laronidase is an exogenous enzyme replacement for a-L-iduronidase and is used in mucopolysaccharidosis I (MPS 1), rare autosomal recessive storage disorders. MPS I disorders are caused by the deficiency of a-L-iduronidase, a lysosomal hydrolase required for catabolism of the glycosaminoglycans (GAG) substrates dermatan sulfate and heparan sulfate. Accumulation of these substrates lead to widespread cellular, tissue and organ dysfunction. Laronidase uptake into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors. Clinically, the patient may notice improvement in breathing and endurance as a result of enzyme replacement. The drug has been shown to biochemically reduce the excess carbohydrates that are stored in the organs of patients with MPS I; however, the clinical significance of this carbohydrate reduction at the biochemical level is not certain. Laronidase has not been evaluated to see if it improves the central nervous system manifestations of the disorder.

Laronidase is administered as an intravenous infusion. It is not known if laronidase will cross into the CNS or breast milk. In patients 6 years and older, the mean volume of distribution ranged from 0.24 to 0.6 L/kg, mean plasma clearance ranged from 1.7 to 2.7 mL/minute/kg, and the elimination half-life ranged from 1.5 to 3.6 hours. In patients 6 months to 5 years, the mean volume of distribution ranged from 0.12 to 0.56 L/kg, mean plasma clearance ranged from 2.2 to 7.7 mL/minute/kg, and the elimination half-life ranged from 0.3 to 1.9 hours.


-Route-Specific Pharmacokinetics
Intravenous Route
The pharmacokinetics of laronidase were evaluated in a study including patients 6 years and older (n = 10 to 12) with MPS I who received a 4-hour infusion of 0.58 mg/kg once per week. Mean maximum plasma concentrations (Cmax) were evaluated at weeks 1, 12, and 26 and ranged from 1.2 to 1.7 mcg/mL. The mean AUC ranged from 4.5 to 6.9 mcg x hour/mL. The majority of patients receiving weekly infusions developed antibodies to laronidase by week 12 of therapy. Between weeks 1 to 12, increases in the plasma clearance of laronidase were observed in some patients and appeared to be proportional to the antibody titer. At week 26, plasma clearance of laronidase was comparable to that at week 1, in spite of the continued and, in some cases, increased titers of antibodies. In a separate study, the pharmacokinetics of laronidase were evaluated in patients 6 months to 5 years (n = 7 to 9) who received a 4-hour infusion of 0.58 mg/kg once per week. After the 26th weekly infusion, maximum plasma concentrations (Cmax) ranged from 0.6 to 1.6 mcg/mL. The mean AUC ranged from 1.3 to 4.4 mcg x hour/mL.


-Special Populations
Geriatric
The pharmacokinetics of laronidase have not been studied in the elderly.