Aldurazyme

Aldurazyme

Manufacturer:

Genzyme

Distributor:

DKSH
Full Prescribing Info
Contents
Laronidase.
Description
Each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5 mL from each vial provides laronidase 2.9 mg.
It also contains the following excipients: Sodium chloride 43.9 mg, sodium phosphate monobasic monohydrate 63.5 mg, sodium phosphate dibasic heptahydrate 10.7 mg, polysorbate 80 0.05 mg. Aldurazyme does not contain preservatives.
Aldurazyme (laronidase) is a polymorphic variant of the human enzyme α-Liduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate.
Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. Aldurazyme has a specific activity of approximately 172 U/mg.
Action
Pharmacology: Mechanism of Action: Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue and organ dysfunction.
The rationale of Aldurazyme therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. Aldurazyme uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.
Because many proteins in the blood are restricted from entry into the central nervous system (CNS) by the blood brain barrier, effects of intravenously administered Aldurazyme on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of Aldurazyme to cross the blood brain barrier has not been evaluated in animal models or in clinical trials.
Pharmacodynamics: The pharmacodynamic effect of Aldurazyme was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of Aldurazyme is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established (see Clinical Studies as follows).
Clinical Studies: The safety and efficacy of Aldurazyme were assessed in 3 clinical studies.
Clinical Studies in Patients ≥6 years: Study 1 was a randomized, double-blind, placebo-controlled study in 45 patients 6-43 years with MPS I, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I. All patients had a baseline percent predicted forced vital capacity (FVC) ≤77%. Patients received Aldurazyme at 0.58 mg/kg of body weight once weekly or placebo once weekly for 26 weeks. All patients were treated with antipyretics and antihistamines prior to each infusion.
The primary efficacy outcome assessments were percent predicted FVC and distance walked in 6 min (6-min walk test). After 26 weeks, patients treated with Aldurazyme showed improvement in percent predicted FVC and in 6-min walk test compared to placebo-treated patients (see Table 1).

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Evaluations of bioactivity were changes in liver size and urinary GAG levels. Liver size and urinary GAG levels decreased in patients treated with Aldurazyme compared to patients treated with placebo. No patient in the group receiving Aldurazyme reached the normal range for urinary GAG levels during this 6-month study.
Study 2 was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed study 1. Patients received Aldurazyme at 0.58 mg/kg body weight once weekly. For patients treated with Aldurazyme, the mean increase in 6-min walk test distance was maintained for an additional 182 weeks through completion of study 2.
At the end of study 2, the decrease in the mean urinary GAG was similar to the decrease in urinary GAG reported in Aldurazyme treated patients at the end of study 1. The relationship of urinary GAG to other measures of clinical response has not been established.
The efficacy of Aldurazyme was also assessed in a 26-week phase 4 open-label dose optimization study of 32 patients evaluated with 4 dosing regimens: 0.58 mg/kg (100 U/kg) weekly, 1.2 mg/kg (200 U//kg) weekly, 1.2 mg/kg (200 U/kg) every 2 weeks or 1.8 mg/kg (300 U/kg) every 2 weeks. The phase 4 dose optimization study results were generally similar to the results of the phase 3 double-blind study. Reductions in urinary GAG level and liver volume were similar between all 4 groups; however, there is no evidence that the long term clinical efficacy of these dose regimens is equivalent.
Pharmacokinetics: The pharmacokinetics of laronidase were evaluated in ≥6 year old patient (N=10-12) with MPS I who received 0.58 mg/kg of body weight once weekly of Aldurazyme as a 4-hr infusion in the placebo-controlled clinical study (study 1). After the 1st, 12th and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2-1.7 mcg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC) ranged from 4.5-6.9 mcg·hr/mL. The mean volume of distribution (Vz) ranged from 0.24-0.6 L/kg. Mean plasma clearance (CL) ranged from 1.7-2.7 mL/min/kg, and the mean elimination half-life (t½) ranged from 1.5-3.6 hrs.
Most patients who received once-weekly infusions of Aldurazyme in study 1 developed antibodies to laronidase by week 12. Between weeks 1 and 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.
The pharmacokinetics of Aldurazyme have not been established in patients ≤6 years.
Indications/Uses
Patients with Hurler and Hurler-Scheie forms of mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
Aldurazyme has been shown to improve pulmonary function and walking capacity. It has not been evaluated for effects on the CNS manifestations of the disorder.
Dosage/Direction for Use
Recommended Dose: 0.58 mg/kg of body weight administered once weekly as an IV infusion. Pre-treatment is recommended 60 min prior to the start of the infusion, and may include antihistamines, antipyretics or both (see Warnings).
Patients with a Body Weight of ≤20 kg: Infuse a total volume of 100 mL.
Patients with a Body Weight ≥20 kg: Infuse a total volume of 250 mL.
Patients with Underlying Cardiac or Respiratory Compromise and Weighing up to 30 kg: May consider diluting Aldurazyme in a volume of 100 mL and administering at a decreased infusion rate (see Precautions and Adverse Reactions).
All dosage should be delivered over approximately 3-4 hrs. The initial infusion rate of 10 mcg/kg/hr may be incrementally increased every 15 min during the 1st hr, as tolerated, until a maximum infusion rate of 200 mcg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hrs) (see Tables 2 and 3).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Administration: The concentrated solution for infusion must be diluted with 0.9% sodium chloride injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient's body weight.
Instruction for Use: Prepare and use Aldurazyme according to the following steps. Use aseptic techniques. Prepare Aldurazyme using low protein-binding containers and administer with a low protein-binding infusion set equipped with an in-line, low protein-binding 0.2 mcg filter. There is no information on the compatibility of diluted Aldurazyme with glass containers. Determine the number of vials to be diluted based on the individual patient's weight and the recommended dose of 0.58 mg/kg: [Patient's weight (kg) x 1 mL/kg of Aldurazyme = total number of mL of Aldurazyme, then total number of mL of Aldurazyme ÷ 5 mL/vial = total number of vials].
Round up to the nearest whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.
Before withdrawing the Aldurazyme from the vial, visually inspect each vial for particulate matter and discoloration. The Aldurazyme solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present. Do not use if solution is discolored or if there is particulate matter in the solution.
Withdraw and discard a volume of the 0.9% sodium chloride injection, USP, from the infusion bag, equal to the volume of Aldurazyme concentrate to be added.
Slowly withdraw the calculated volume of Aldurazyme from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature Aldurazyme, rendering it biologically inactive.
Slowly add the Aldurazyme solution to the 0.9% sodium chloride injection, using care to avoid agitation of the solutions. Do not use a filter needle.
Gently rotate the infusion bag to ensure proper distribution of Aldurazyme. Do not shake the solution.
Overdosage
There have been no reports of overdose with Aldurazyme. In clinical studies, a small number of patients received doses up to 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week. Adverse events reported in patients receiving 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week were similar to the adverse events reported by patients treated with 0.58 mg/kg body weight once weekly.
Contraindications
There are no known contraindications to the use of Aldurazyme.
Warnings
Life-threatening anaphylactic reactions have been observed in some patients during Aldurazyme infusions. Therefore, appropriate medical support should be readily available when Aldurazyme is administered. Patients with compromised respiratory function of acute respiratory disease may be at risk of serious acute exacerbation of the respiratory compromise due to infusion reactions and require additional monitoring.
Special Precautions
Anaphylaxis and Allergic Reactions: Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hrs after Aldurazyme infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia and urticaria. If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of Aldurazyme and initiate appropriate medical treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled β-adrenergic agonists, epinephrine, IV corticosteroids (see Adverse Reactions).
In clinical studies and post-marketing safety experience with Aldurazyme, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, preexisting upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when Aldurazyme is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.
The risks and benefits of re-administering Aldurazyme following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to readminister Aldurazyme.
Acute Respiratory Complications Associated with Administration: Patients with an acute febrile or respiratory illness at the time of Aldurazyme infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient's clinical status prior to administration of Aldurazyme and consider delaying Aldurazyme infusion. One patient with acute bronchitis and hypoxia experienced increased tachypnea during the 1st Aldurazyme infusion that resolved without intervention. The patient's respiratory symptoms returned within 30 min of completing the infusion and responded to bronchodilator therapy. Approximately 6 hrs after the infusion, the patient experienced coughing, then respiratory arrest and died.
Sleep apnea is common in MPS I patients. Evaluation of airway patency should be considered prior to initiation of treatment with Aldurazyme. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.
Risk of Acute Cardiorespiratory Failure: Caution should be exercised when administering Aldurazyme to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during Aldurazyme infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient (see Adverse Reactions).
Infusion Reactions: Because of the potential for infusion reactions, patients should receive antipyretics and/or antihistamines prior to infusion. If an infusion reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms (see Adverse Reactions).
Information for Patients: Patients should be counseled that allergic reactions may occur during Aldurazyme treatment, including life-threatening anaphylaxis. Premedication and reduction of infusion rate may alleviate those allergic reactions associated with the infusion. The appropriate length of post-infusion monitoring is to be determined based on the individual patient's clinical status and infusion history.
Patients should be advised to report any adverse reactions experienced while on Aldurazyme treatment.
The full benefits of Aldurazyme may not be evident for several months to years of treatment. To maintain treatment benefit, Aldurazyme should be administered on a weekly basis as indicated.
Patients should be informed that a registry for MPS I patients has been established in order to better understand the MPS I disease and to tract clinical outcomes of patients with MPS I over time. Patients should be encouraged to participate and advised that their participation is voluntary may involve long-term follow-up.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Studies to assess the mutagenic and carcinogenic potential of laronidase have not been conducted.
Laronidase at IV doses up to 3.6 mg/kg (6.2 times the human dose) was found to have no effect on the fertility and reproductive performance of male and female rats.
Use in pregnancy & Lactation: Pregnancy Category B.
A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Aldurazyme. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Aldurazyme should be used during pregnancy only if clearly needed.
Pregnant women with MPS 1 should be encouraged to enroll in the MPS 1 registry.
Nursing Mothers: It is not known whether Aldurazyme is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aldurazyme is administered to a nursing woman.
Use in children: Patients <5 years were not included in the clinical studies because of inability to comply with efficacy outcome assessments. It is not known if children <5 years respond differently from older children.
Use in the elderly: Clinical studies of Aldurazyme did not include patients ≥65 years. It is not known whether they respond differently from younger patients.
Use In Pregnancy & Lactation
Pregnancy Category B.
A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Aldurazyme. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Aldurazyme should be used during pregnancy only if clearly needed.
Pregnant women with MPS 1 should be encouraged to enroll in the MPS 1 registry.
Nursing Mothers: It is not known whether Aldurazyme is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aldurazyme is administered to a nursing woman.
Adverse Reactions
                  Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most serious adverse reactions reported with Aldurazyme treatment during clinical trials were anaphylactic and allergic reactions. Most adverse reactions reported in clinical trials were considered disease-related and unrelated to study drug. The most common adverse reactions were infusion reactions. The frequency of infusion reactions decreased over time with continued use of Aldurazyme, and the majority of reactions were classified as being mild to moderate in severity. Most infusion reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, antipyretics or both.
Clinical Trials in Patients ≥6 years: A 26-week, double-blind, placebo-controlled clinical study (study 1) of Aldurazyme was conducted in 45 patients 6-43 years with MPS I, gender evenly distributed (N=23 females and 22 males). Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie and 7 Scheie. Patients were randomized to receive either 0.58 mg/kg Aldurazyme IV per week for 26 weeks or placebo. All patients were treated with antipyretics and antihistamines prior to the infusions. Infusion reactions were reported in 32% (7 of 22) of Aldurazyme treated patients. The most commonly reported infusion reactions regardless of treatment group were flushing, pyrexia, headache and rash. Flushing occurred in 5 patients (23%) receiving Aldurazyme; the other reactions were less frequent. Less common infusion reactions included angioedema (including face oedema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.
Table 4 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebo-controlled study (study 1) that were reported in at least 2 patients more in the Aldurazyme group than in the placebo group (see Table 4).

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All 45 patients who completed the placebo-controlled study (study 1) continued treatment in an open-label, uncontrolled extension study (study 2). All patients received Aldurazyme 0.58 mg/kg of body weight once weekly for up to 182 weeks. The most serious adverse reactions reported with Aldurazyme infusions in study 2 were anaphylactic and allergic reactions (see Warnings and Precautions). The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with Aldurazyme. The most commonly reported infusion reactions included rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%) and injection site reaction (9%). Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%) and urticaria (4%). Additional common adverse reactions included back pain and musculoskeletal pain.
Immunogenicity: In clinical trials, 99-102 patients (97%) treated with Aldurazyme were positive for immunoglobulin G (IgG) antibodies to Aldurazyme. The clinical significance of antibodies to Aldurazyme, including the potential for product neutralization, is not known. Potential for antibody neutralization of cellular uptake has not been assessed.
The data reflect the percentage of patients whose test results were considered positive for antibodies to Aldurazyme using an enzyme-linked immunosorbent assay (ELISA) for Aldurazyme-specific IgG binding antibodies reported as titers (57 patients) or optical density units per microliter (OD/microliter) (42 patients), and confirmed by radio-immunoprecipitation (RIP). The relationship of Aldurazyme antibody concentration in titer units and OD/microliter units has not been established.
Nine (9) patients in study 1 and study 2, collectively, who experienced severe infusion reactions were tested for Aldurazyme-specific immunoglobulin E (IgE) antibodies and complement activation. IgE testing was performed by enzyme-linked immunosorbent assay (ELISA), and complement activation was measured by the Quidel Enzyme Immunoassay. One of the 9 patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both Aldurazyme-specific IgE binding antibodies and complement activation. None of the patients in the open-label clinical study of patients ≤5 years (study 3) tested positive for IgE.
Other allergic reactions were also seen in patients receiving Aldurazyme (see Adverse Reactions).
In the post-marketing setting, approximately 1% of patients experienced severe or serious infusion allergic reactions and tested positive for IgE. Of these IgE-positive patients, some have discontinued treatment, but some have been successfully rechallenged. The clinical significance of IgE antibodies has not been established.
As with all the therapeutic proteins, there is potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Aldurazyme with the incidence of antibodies to other products may be misleading.
Post-marketing Experience: The following adverse reactions have been identified during post approval use of Aldurazyme. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In post-marketing experience with Aldurazyme, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock and laryngeal oedema.
Adverse reactions resulting in death reported in the post-marketing setting with Aldurazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure and pneumonia. These events have been reported in MPS I patients with significant underlying disease.
Additional common adverse reactions included fatigue, oedema peripheral, erythema and cyanosis.
There have been a small number of reports of extravasation in patients treated with Aldurazyme. There have been no reports of tissue necrosis associated with extravasation.
Drug Interactions
No formal drug interaction studies have been conducted.
Incompatibilities: Aldurazyme must not be mixed with other medicinal products in the same infusion.
The compatibility of Aldurazyme in solution with other products has not been evaluated.
Caution For Usage
Aldurazyme does not contain any preservatives, therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°-8°C (36°-46°F) for up to 36 hrs. Other than during infusion, room temperature storage of diluted solution is not recommended.
Any unused product or waste material should be discarded and disposed of in accordance with local requirements.
Storage
Store under refrigeration at 2-8°C (36-46°F). Do not freeze or shake. Protect from light.
ATC Classification
A16AB05 - laronidase ; Belongs to the class of enzymes. Used in the treatment of alimentary tract and metabolism problems.
Presentation/Packing
Soln for infusion 2.9 mg/5 mL (sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution in single-use vial) x 1's.
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