Can Laronidase cause malaise?

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) ].

WARNINGS AND PRECAUTIONS Risk of Acute Respiratory Complications: Patients with acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Consider delaying ALDURAZYME infusion. Sleep apnea is common in MPS I patients. Consider evaluating airway patency prior to initiation of treatment with ALDURAZYME. Appropriate respiratory support should be available during infusion. ( 5.2 ) Risk of Acute Cardiorespiratory Failure: Patients susceptible to fluid overload may be at increased risk for serious exacerbation of their cardiac or respiratory status during infusions. Consider a decreased total infusion volume and infusion rate when administering ALDURAZYME to these patients. Appropriate medical monitoring and support measures should be available during infusion. ( 2.2 , 5.3 ) Infusion Reactions: If severe IARs occur, discontinue ALDURAZYME and initiate appropriate medical treatment. ( 5.4 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported 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. 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. Prior to ALDURAZYME administration, consider premedicating patients with antihistamines, with or without antipyretics, 60 minutes before the start of infusion. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during ALDURAZYME administration. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue ALDURAZYME immediately and initiate appropriate medical treatment. Exercise caution 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) ]. Consider the risks and benefits of re-administering ALDURAZYME following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to ALDURAZYME may be considered. If the decision is made to readminister ALDURAZYME, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended rate. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3) ]. 5.2 Acute Respiratory Complications Associated with Administration 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. 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. Sleep apnea is common in MPS I patients. Consider evaluating airway patency 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 Acute Cardiorespiratory Failure In postmarketing experience, reports of acute cardiorespiratory failure have been reported with ALDURAZYME treatment [see Adverse Reactions (6.2) ] . 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 may be at increased risk of serious exacerbation of their cardiac or respiratory status during infusions. Consider a decreased total infusion volume and infusion rate when administering ALDURAZYME to these patients [see Dosage and Administration (2.2) ]. Appropriate medical monitoring and support 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. 5.4 Infusion-Associated Reactions ALDURAZYME may cause infusion-associated reactions (IARs). Prior to ALDURAZYME administration, consider pre-medicating with antihistamines, with or without antipyretics, 60 minutes before the start of infusion to reduce the risk of IARs. However, IARs may still occur in patients after receiving pre-medication. If a severe IAR occurs, discontinue ALDURAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering ALDURAZYME following a severe IAR. Patients may be re-challenged using slower infusion rates. Once a patient tolerates the infusion, the infusion rate may be increased to reach the recommended infusion rate. If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3) , and Adverse Reactions (6.1 , 6.2) ] .