Laronidase 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. Serious hypersensitivity reactions, including anaphylaxis and infusion-related reactions, can occur. Patients susceptible to fluid volume overload or with compromised cardiac or respiratory function may be at risk for serious acute cardiorespiratory failure. Consider premedication with antihistamines with or without antipyretics; resuscitative equipment should be readily available during administration. Infusion reactions were the most common adverse reactions in patients 6 months to 5 years. In patients 6 years and older, the most common adverse reactions were rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing, and poor venous access.
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.
-Laronidase is a colorless to pale yellow, clear to slightly opalescent solution. Some translucency may be present in the solution. Discard if visible particulate matter is present.
-If 1 or more doses of laronidase are missed, restart treatment as soon as possible, maintaining the 1-week interval between infusions. Do NOT double a dose to compensate for a missed dose.
Intravenous Administration
-For intravenous (IV) infusion only; do not administer as an IV bolus injection.
-Do not infuse laronidase with other medications; compatibility has not been evaluated.
-Consider premedication with antipyretics and/or antihistamines 1 hour prior to beginning each infusion.
Dilution
-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.
-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 50 mL (patients weighing 2 kg to less than 4 kg), 100 mL (patients weighing 4 kg to 20 kg), 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 and decreased infusion rate 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. Do NOT store at room temperature. The solution must be infused within 8 hours after removal from the refrigerator, inclusive of the total infusion time, or discarded.
Intermittent IV Infusion
-Use an infusion set equipped with an in-line, low-protein binding (0.2 micron) filter to administer.
-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 (2 to 3 hours). Incremental infusion rate steps and volumes by patient weight may be found in the laronidase package labeling.
-If a severe infusion-related or hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment.-Consider the risks and benefits of readministering laronidase after severe hypersensitivity reactions (including anaphylaxis).
-Some patients have been rechallenged using slower infusion rates. A desensitization procedure may also be considered. If readministration occurs, ensure the patient tolerates the infusion before rate is increased to the approved recommended dosage.
-If a mild-to-moderate infusion-related or hypersensitivity reaction occurs, temporarily hold the infusion for 15 to 30 minutes or slow the infusion rate by 25% to 50% and initiate appropriate medical treatment.-If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider reinitiating the infusion within 7 to 14 days, up to 25% to 50% of the rate at which the reaction occurred with appropriate premedication.
-If symptoms subside after holding the infusion, resume the infusion at 25% to 50% reduced rate as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete the infusion at the reduced rate as tolerated.
-Starting with the next infusion, increase the infusion rate by increments of 25% as tolerated until the recommended infusion rate is reached. Closely monitor the patient.
-At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection at the same infusion rate used for the last part of the infusion.
-After infusion, immediately dispose of any unused product.
A double-blind, placebo-controlled trial consisting of 45 patients with MPS I (n = 22 laronidase, n = 23 placebo) receiving laronidase 0.58 mg/kg/dose 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 to 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 reactions reported in those patients treated with laronidase (n = 22) in clinical trials included chest pain (unspecified) (9% laronidase vs. 0% placebo), poor venous access (14% vs. 0%), hypotension (9% vs. 0%), and edema (9% vs. 0%). Peripheral edema, erythema, cyanosis, and fatigue have also been reported during postmarketing surveillance.
Respiratory-infection related adverse reactions reported in those patients treated with laronidase (n = 22) included upper respiratory tract infection which occurred in 7 (32%) patients receiving laronidase and 4 (17%) patients receiving placebo. Abscess was reported in 9% of patients. One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first laronidase infusion that resolved without intervention. The patient's respiratory symptoms returned within 30 minutes after completing the infusion and responded to bronchodilatory therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.
Serious hypersensitivity reactions or anaphylaxis has been reported with laronidase therapy. Some reactions were life-threatening and included cardiorespiratory arrest, respiratory failure, cardiac failure, pneumonia, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airway disorder, hypoxia, laryngeal edema, hypotension, bradycardia, and urticaria. In clinical studies and during postmarketing surveillance, approximately 1% of patients experienced severe or serious hypersensitivity reactions. Recurrent reactions may occur, and patients who have experienced anaphylactic reactions may require prolonged observation. 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). One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both laronidase-specific IgG and IgE binding antibodies and complement activation. Slowing the rate of infusion or temporarily stopping the infusion may ameliorate most infusion-related adverse reactions with laronidase.
Roughly 96% (70 of 73) of patients developed laronidase-specific IgG antibody formation within 2 months after starting laronidase treatment. Anti-drug antibody (ADA) titers peaked at approximately 4 months and generally declined over time. The 3 patients who did not develop ADA were patients with Hurler-Scheie forms of mucopolysaccharidosis I (MPS I). Higher ADA titers were observed in patients with Hurler forms of MPS I. Neutralizing antibodies that inhibited cellular uptake of laronidase were detected in 38 of 70 (54%) patients who developed ADA. Neutralizing antibodies that inhibited laronidase enzyme activity were detected in 1 of 70 (1.4%) patients who developed ADA. In some laronidase-treated patients who developed ADA, the plasma clearance of laronidase at week 12 was higher than that at week 1, and patients with higher ADA titers had higher clearance. At week 26, clearance of laronidase was similar to that at week 1. In the MPS I registry and other postmarketing settings, laronidase-specific IgE and/or IgG antibodies appeared to be associated with anaphylaxis and suspected hypersensitivity reactions in laronidase-treated patients. In studies, 9 laronidase-treated patients who experienced severe infusion-associated reactions were tested for laronidase-specific IgE antibodies. Only 1 of the 9 patients tested positive for laronidase-specific IgE antibodies. In the MPS I registry, laronidase-specific IgE and IgG antibodies were evaluated in 10 patients who had suspected hypersensitivity reactions. Of these 10 patients, 9 tested positive for laronidase-specific IgE and/or IgG antibodies and 1 patient tested negative for both IgE and IgG antibodies. During postmarketing surveillance, 5 laronidase-treated patients experienced anaphylaxis and had ADA results available within 7 days of event onset. Of these 5 patients, 3 patients tested positive for laronidase-specific IgE and/or IgG antibodies and in the other 2 patients, IgE antibodies were not detected and IgG antibody results were not reported.
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 (9% laronidase vs. 0% placebo), corneal opacification (9% vs. 0%) and hyperbilirubinemia (9% vs. 0%). Extravasation has also been reported with postmarketing use of laronidase; there have been no reports of tissue necrosis.
Serious hypersensitivity reactions or anaphylaxis have occurred in patients during or up to 3 hours after laronidase infusions. Some reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airway disorder, hypoxia, hypotension, bradycardia, and urticaria. Consider premedication with antihistamines with or without antipyretics 60 minutes prior to the infusion. Administration requires a specialized care setting where cardiopulmonary resuscitation equipment is readily available. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Use epinephrine with caution due to the increased prevalence of coronary artery disease in Mucopolysaccharidosis I (MPS I) patients. Consider the risks and benefits of readministration after a severe reaction. Some patients have been rechallenged using slower infusion rates. A desensitization procedure may also be considered. If readministration occurs, ensure the patient tolerates the infusion before the rate is increased to the recommended dosage. If a mild-to-moderate hypersensitivity reaction occurs, temporarily hold or slow the infusion rate and initiate appropriate medical treatment.
Available data from the Mucopolysaccharidosis I (MPS I) registry pregnancy sub-registry, published case reports, and the global pharmacovigilance database with laronidase use in more than 30 pregnant patients have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Individualize continued MPS I treatment during pregnancy to the pregnant patient. Animal studies in rats at doses 6.2 times the human dose have not revealed evidence of impaired fertility or harm to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to laronidase; information about the registry can be obtained at 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. No adverse effects have been reported in breastfed infants during postmarketing surveillance. 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. Breastfeeding patients 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.
Severe infusion-related reactions have occurred in patients treated with laronidase. Infusion-related reactions may occur during or within a few hours after infusion and are more likely to occur with higher infusion rates. Consider premedication with antihistamines with or without antipyretics 60 minutes prior to infusion. Patients with an acute febrile or respiratory illness at the time of infusion may be at greater risk for infusion reactions. Carefully consider the patient's clinical status prior to laronidase administration and consider delaying laronidase infusion. If a severe infusion-related reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of readministration after a severe reaction. Some patients have been rechallenged using slower infusion rates. Once the patient tolerates the infusion, increase the rate to the recommended rate. If a mild-to-moderate infusion-related reaction occurs, temporarily hold or slow the infusion rate.
Patients susceptible to fluid volume overload or those with acute underlying respiratory illness or compromised cardiac and/or respiratory function (e.g., heart failure, respiratory insufficiency) may be at increased risk of serious exacerbation of their cardiac or respiratory status during infusions. Consider a decreased total infusion volume and infusion rate when administering laronidase to these patients. Monitor vitals frequently in patients with acute underlying respiratory illness or compromised cardiac or respiratory function who require fluid restriction. Some patients may require prolonged observation. Consider delaying laronidase infusion in patients with an acute febrile or respiratory illness at the time of infusion as these patients may be at greater risk of infusion reactions.
Evaluate airway patency prior to initiation of laronidase therapy; sleep apnea is common in patients with Mucopolysaccharidosis I (MPS I). Patients requiring oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments available during laronidase infusion in the event of an acute reaction or extreme drowsiness/sleep secondary to antihistamine use.
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: 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
0.58 mg/kg/dose IV once weekly.
-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 alpha-L-iduronidase and is used in mucopolysaccharidosis I (MPS 1), rare autosomal recessive storage disorders. MPS I disorders are caused by the deficiency of alpha-L-iduronidase, a lysosomal hydrolase required for catabolism of the glycosaminoglycan (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.
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.