ALDURAZYME
Generic: LARONIDASE
Basic Information
Manufacturer
Genzyme Corporation
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
a80ac249-cae4-41f3-88bb-344088b20e60
Indications & Usage
1 INDICATIONS AND USAGE ALDURAZYME ® is indicated for the treatment of: adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and patients with the Scheie form of MPS I who have moderate to severe symptoms.
ALDURAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for the treatment of patients with the Scheie form of MPS I who have moderate to severe symptoms.
( 1 ) Limitations of Use: The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
( 1 ) ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.
( 1 ) Limitations of Use The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established.
The effect of ALDURAZYME on central nervous system manifestations of the disorder has not been determined.
ALDURAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for the treatment of patients with the Scheie form of MPS I who have moderate to severe symptoms.
( 1 ) Limitations of Use: The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
( 1 ) ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.
( 1 ) Limitations of Use The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established.
The effect of ALDURAZYME on central nervous system manifestations of the disorder has not been determined.
Adverse Reactions
6 ADVERSE REACTIONS Serious and or clinically significant adverse reactions described elsewhere in labeling include: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Acute Respiratory Complications Associated with Administration [see Warnings and Precautions (5.2) ] Acute Cardiorespiratory Failure [see Warnings and Precautions (5.3) ] Infusion-Associated Reactions [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥10%) in patients: 6 months of age and older are: infusion reactions (pyrexia, chills, blood pressure increased, tachycardia, and oxygen saturation decreased).
( 6.1 ) 6 years and older are: rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing, and poor venous access.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
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.
Serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and hypersensitivity reactions.
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.
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 common adverse reactions reported in patients who received ALDURAZYME 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 2 enumerates adverse reactions and selected laboratory abnormalities that occurred during the 26-week placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.
Table 2: Adverse Reactions that Occurred in at Least 2 Patients More in the ALDURAZYME Group than in the Placebo Group Among Adult and Pediatric Patients with MPS I in Study 1 ALDURAZYME N=22 n (%) Placebo N=23 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 hypersensitivity reactions [see Warnings and Precautions (5) ] .
One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgG and IgE binding antibodies and complement activation.
The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME.
The most common adverse reactions reported in patients who received ALDURAZYME were 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 nature and severity of infusion reactions were similar between the older and less severely affected patients (Studies 1 and 2) and the younger, more severely affected patients (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.
6.2 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 [see Warnings and Precautions (5.1) ] 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 underlying disease [see Warnings and Precautions (5.3) ].
Additional adverse reactions included fatigue, peripheral edema, 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.
Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Including Anaphylaxis In the MPS I Registry and other postmarketing setting, laronidase-specific IgE and/or IgG antibodies appeared to be associated with anaphylaxis and suspected hypersensitivity reactions in ALDURAZYME-treated patients [see Clinical Pharmacology (12.6) ].
( 6.1 ) 6 years and older are: rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing, and poor venous access.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
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.
Serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and hypersensitivity reactions.
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.
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 common adverse reactions reported in patients who received ALDURAZYME 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 2 enumerates adverse reactions and selected laboratory abnormalities that occurred during the 26-week placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.
Table 2: Adverse Reactions that Occurred in at Least 2 Patients More in the ALDURAZYME Group than in the Placebo Group Among Adult and Pediatric Patients with MPS I in Study 1 ALDURAZYME N=22 n (%) Placebo N=23 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 hypersensitivity reactions [see Warnings and Precautions (5) ] .
One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgG and IgE binding antibodies and complement activation.
The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME.
The most common adverse reactions reported in patients who received ALDURAZYME were 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 nature and severity of infusion reactions were similar between the older and less severely affected patients (Studies 1 and 2) and the younger, more severely affected patients (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.
6.2 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 [see Warnings and Precautions (5.1) ] 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 underlying disease [see Warnings and Precautions (5.3) ].
Additional adverse reactions included fatigue, peripheral edema, 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.
Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Including Anaphylaxis In the MPS I Registry and other postmarketing setting, laronidase-specific IgE and/or IgG antibodies appeared to be associated with anaphylaxis and suspected hypersensitivity reactions in ALDURAZYME-treated patients [see Clinical Pharmacology (12.6) ].