ALDURAZYME: Package Insert and Label Information

ALDURAZYME- laronidase injection, solution, concentrate
Genzyme Corporation

WARNING: RISK OF ANAPHYLAXIS

  • Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME® infusions [see Warnings and Precautions (5.1)].
  • Appropriate medical support should be readily available when ALDURAZYME is administered [see Warnings and Precautions (5.1)].
  • Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions and require additional monitoring [see Warnings and Precautions (5.2, 5.3)].

1 INDICATIONS AND USAGE

ALDURAZYME ® is indicated for adult and pediatric 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.

Limitations of Use:

  • The risks and benefits of treating mildly affected patients with the Scheie form have not been established.

  • ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both [see Warnings and Precautions (5)].

Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single dose 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 [see Dosage and Administration (2.2)]. 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Adverse Reactions (6.3)].

2.2 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 micron 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) × 1 mL/kg of ALDURAZYME = Total number of mL of ALDURAZYME Total number of mL of 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/hour x 15 minutes (10 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
4 mL/hour x 15 minutes (20 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
8 mL/hour x 15 minutes (50 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
16 mL/hour x 15 minutes (100 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
32 mL/hour x ~3 hours (200 mcg/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/hour x 15 minutes (10 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
10 mL/hour x 15 minutes (20 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
20 mL/hour x 15 minutes (50 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
40 mL/hour x 15 minutes (100 mcg/kg/hr) Obtain vital signs, if stable then increase the rate to…
80 mL/hour x approximately 3 hours (200 mcg/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°C to 8°C (36°F 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.

3 DOSAGE FORMS AND STRENGTHS

Injection: 2.9 mg/5 mL (0.58 mg/mL) of laronidase as a colorless to pale yellow, clear to slightly opalescent solution in a single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis and Hypersensitivity Reactions

Anaphylaxis and serious hypersensitivity 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 serious hypersensitivity 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 intravenous corticosteroids [see Adverse Reactions (6)].

In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious hypersensitivity 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 hypersensitivity 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 hypersensitivity reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

5.2 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.

5.3 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 (6.3)].

5.4 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 [see Adverse Reactions (6.1, 6.3)].

6 ADVERSE REACTIONS

Serious and or clinically significant adverse reactions described elsewhere in labeling include:

6.1 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 hypersensitivity 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 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 intravenously 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 placebo-controlled 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)ALDURAZYMEn (%) (N=23)Placebon (%)
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 hypersensitivity reactions [see Warnings and Precautions (5)]. 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.

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