|warnings=* 5.1 Anaphylaxis and Allergic Reactions
[see BOXED WARNING ]
====Precautions====
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 [see ADVERSE REACTIONS (6)].
* Description
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.
<!--Adverse Reactions-->
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.
<!--Clinical Trials Experience-->
5.2 Acute Respiratory Complications Associated with Administration
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
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.
=====Body as a Whole=====
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 pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms
<!--Adverse Reactions-->
=====Cardiovascular=====
<!--Clinical Trials Experience-->
|clinicalTrials=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 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.
=====Digestive=====
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.
[[File:Laronidase Adv.png|none|400px]]
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 (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
=====Endocrine=====
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), pruritis, and rash.
6.2 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.
=====Hematologic and Lymphatic=====
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 radio-immunoprecipitation (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 [see CLINICAL STUDIES (14) for the Study populations].
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 open-label 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 [see ADVERSE REACTIONS (6)].
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.
=====Metabolic and Nutritional=====
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=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 BOXED WARNING and WARNINGS AND PRECAUTIONS (5)] and laryngeal edema.
=====Musculoskeletal=====
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.
|drugInteractions=
<!--Use in Specific Populations-->
|FDAPregCat=B
|useInPregnancyFDA=* 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.
=====Neurologic=====
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
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInNursing=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.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
Nursing mothers with MPS I should be encouraged to enroll in the MPS I Registry
|useInPed=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
|useInGeri=Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
Line 220:
Line 162:
<!--Administration and Monitoring-->
<!--Administration and Monitoring-->
|administration=* Oral
|administration=* Intravenous
|monitoring=* 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.
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|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.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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Black Box Warning
WARNING:
See full prescribing information for complete Boxed Warning.
RISK OF ANAPHYLAXIS:
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 or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.
Overview
Laronidase is a Enzyme that is FDA approved for the treatment of Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pyrexia, chills, blood pressure increased, tachycardia, and oxygen saturation decreased, rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing,.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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
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 [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 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 [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) and 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 micrometer (µm) 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 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 number mL of ALDURAZYME
Total number mL of ALDURAZYME ÷ 5 mL per Vial = Total number of Vials.
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.
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.
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, USP 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.
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.
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
Mucopolysaccharidosis, Type I (Hurler and Hurler-Scheie forms)
Dosage
(6 months or older) 0.58 mg/kg of body weight as an IV infusion once a week; pretreat 60 minutes before infusion with antihistamines and/or antipyretics
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in pediatric patients.
Contraindications
None
Warnings
WARNING:
See full prescribing information for complete Boxed Warning.
RISK OF ANAPHYLAXIS:
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 or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.
5.1 Anaphylaxis and Allergic Reactions
[see BOXED WARNING ]
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 [see ADVERSE REACTIONS (6)].
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.
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 pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms
Adverse Reactions
Clinical Trials Experience
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 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 placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.
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 (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), pruritis, and rash.
6.2 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 radio-immunoprecipitation (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 [see CLINICAL STUDIES (14) for the Study populations].
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 open-label 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 [see ADVERSE REACTIONS (6)].
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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5)] 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.
Drug Interactions
There is limited information regarding Laronidase Drug Interactions in the drug label.
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
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Laronidase in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Laronidase during labor and delivery.
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
Geriatic Use
Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Laronidase with respect to specific gender populations.
Race
There is no FDA guidance on the use of Laronidase with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Laronidase in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Laronidase in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Laronidase in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Laronidase in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
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.
IV Compatibility
There is limited information regarding IV Compatibility of Laronidase in the drug label.
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.
Pharmacology
There is limited information regarding Laronidase Pharmacology in the drug label.
