Aldurazyme

Aldurazyme information, interactions and side effects, ALDURAZYME (laronidase) is a polymorphic variant of the human enzyme α-L-iduronidase 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 catalyzes the hydrolysis of terminal α-Liduronic 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.

ALDURAZYME, for IV infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME does not contain preservatives; vials are for single use only.

INDICATIONS

ALDURAZYME® (laronidase) is indicated for 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. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.

DOSAGE AND ADMINISTRATION

Recommended Dose

The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both.

Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only. Do not use the vial more than one time. 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. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting ALDURAZYME in a volume of 100 mL and administering at a decreased infusion rate.

Instructions 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 micrometer (μm) filter. There is no information on the compatibility of diluted ALDURAZYME with glass containers.

  1. Determine the number of vials to be diluted based on the patient’s weight and the recommended dose of 0.58 mg/kg, using the following equation:
    Patient’s weight (kg) x 1 mL/kg of ALDURAZYME = Total mL ALDURAZYME
    Total mL ALDURAZYME ÷ 5 mL per Vial = Total number of Vials.
  2. Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.
  3. 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 in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution.
  4. 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.
  5. 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.
  6. Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle.
  7. Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the solution.
  8. The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 μg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 μg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1 and 2.
  9. Administer the diluted ALDURAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 μm in-line filter.

Table 1: Incremental Rates for 100 mL ALDURAZYME® Infusion (For use with Patients Weighing 20 kg or Less)

 

Infusion Rate Criteria for Increasing Infusion Rate
2 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to…
4 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
8 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
16 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
32 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion.

 

Table 2: Incremental Rates for 250 mL ALDURAZYME® Infusion (For use with Patients Weighing Greater than 20 kg)

 

Infusion Rate Criteria for Increasing Infusion Rate
5 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to…
10 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
20 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
40 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to.
80 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion.

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° to 8°C (36° to 46°F) for up to 36 hours. 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.

ALDURAZYME must not be administered with other medicinal products in the same infusion. The compatibility of ALDURAZYME in solution with other products has not been evaluated.

HOW SUPPLIED

Dosage Forms And Strengths

ALDURAZYME is supplied as a sterile solution in 5 mL vials (2.9 mg per 5 mL).

Storage And Handling

ALDURAZYME is supplied as a sterile solution in single-use, clear Type I glass 5 mL vials, containing 2.9 mg laronidase per 5 mL solution. The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.

NDC 58468-0070-1, 5 mL vial

Refrigerate vials of ALDURAZYME at 2° to 8°C (36° to 46°F). Do not freeze or shake. Protect from light. Do not use ALDURAZYME after the expiration date on the vial. This product contains no preservatives.

SIDE EFFECTS

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 diseaserelated 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 and Older

A 26-week, double-blind, placebo-controlled clinical study (Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43 years old, 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 IV of ALDURAZYME 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 edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.

Table 3 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebocontrolled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.

Table 3: Summary of Adverse Reactions that Occurred in 2 Patients More in the ALDURAZYME® Group than in the Placebo Group in the 26-Week Placebo-controlled Study (Study 1)

 

MedDRA System Organ Class (SOC) MedDRA Preferred Term (N=22)
ALDURAZYME
n (%)
(N=23)
Placebo
n (%)
Blood and lymphatic system disorders
  Thrombocytopenia 2 (9) 0
Eye disorders
  Corneal opacity 2 (9) 0
General disorders and administration site conditions
  Chest pain 2 (9) 0
  Face edema 2 (9) 0
  Gravitational edema 2 (9) 0
  Injection site pain 2 (9) 0
  Injection site reaction 4 (18) 2 (9)
Hepatobiliary disorders
  Hyperbilirubinemia 2 (9) 0
Infections and infestations
  Abscess 2(9) 0
  Upper respiratory tract infection 7 (32) 4 (17)
Nervous system disorders
  Hyperreflexia 3 (14) 0
  Paresthesia 3 (14) 1 (4)
Skin and subcutaneous tissue disorders
  Rash 8 (36) 5 (22)
Vascular disorders
  Hypotension 2 (9) 0
  Poor venous access 3 (14) 0

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. 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.

Clinical Trials in Patients 6 Years and Younger

Study 3 was a 52-week, open-label, uncontrolled study of 20 MPS I patients, ages 6 months to 5 years old (at enrollment). Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks and up to 52 weeks. All patients were treated with antipyretics and antihistamines prior to the infusions.

The most commonly reported serious adverse events (regardless of relationship) reported with ALDURAZYME infusions in Study 3 were otitis media (20%), and central venous catheterization required for ALDURAZYME infusion (15%).

The nature and severity of infusion reactions were similar between the older and less severely affected patients in Studies 1 and 2, and the younger, more severely affected patients in Study 3. The most commonly reported adverse reactions in Study 3 were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥ 5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash.

Immunogenicity

In clinical trials, 99 of 102 patients (97%) treated with ALDURAZYME were positive for IgG antibodies to ALDURAZYME. No correlation was demonstrated between the presence of IgG anti-ALDURAZYME antibodies and therapeutic response (6 MWT and FVC) or the occurrence of allergic reactions. Potential for antibody neutralization of cellular uptake has not been assessed. No consistent association was demonstrated between the presence of antibodies that neutralize enzymatic activity and therapeutic response.

The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME using a specific enzyme-linked immunosorbent assay (ELISA) and confirmed by radioimmunoprecipitation (RIP). ALDURAZYME IgG antibodies were reported as titers. Drug specific antibody was detected in 42 of the 45 patients (93.3%) treated in Study 1 and Study 2. The mean time to seroconversion was 51 days in patients 6 years and older. In Study 3, all patients (100%) 5 years old or younger developed IgG antibodies against ALDURAZYME with a mean time to seroconversion of 26 days.

Nine patients in Study 1 and Study 2, collectively, who experienced severe infusion reactions were tested for ALDURAZYME-specific IgE antibodies and complement activation. IgE testing was performed by ELISA, and complement activation was measured by the Quidel Enzyme Immunoassay. One of the nine 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 openlabel clinical study of patients 5 years old or younger (Study 3) tested positive for IgE.

Other allergic reactions were also seen in patients receiving ALDURAZYME.

In the postmarketing 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 re-challenged. 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.

Postmarketing 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 postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock and laryngeal edema.

Adverse reactions resulting in death reported in the postmarketing 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 adverse reactions included fatigue, edema 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.

PRECAUTIONS

Anaphylaxis and Allergic Reactions

Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hours 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 beta-adrenergic agonists, epinephrine, and IV corticosteroids.

In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing 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 re-administer the product.

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 first ALDURAZYME infusion that resolved without intervention. The patient’s respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours 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.

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 pretreatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 Specific Populations

Pregnancy

Pregnancy Category B

A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and has revealed no evidence of impaired fertility or harm to the fetus due to ALDURAZYME. However, there are no adequate and well-controlled studies of ALDURAZYME in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry. For more information, visit www.MPSIregistry.com or call (800) 745-4447.

Nursing Mothers

It is not known whether the drug 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.

Nursing mothers with MPS I should be encouraged to enroll in the MPS I Registry.

Pediatric Use

The safety and effectiveness of ALDURAZYME was assessed in a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old, and was found to be similar to the safety and effectiveness of ALDURAZYME in pediatric patients 6 to 18 years, and adults.

Geriatric Use

Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.

OVERDOSE

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.

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