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Clinical Trials Experience
Because clinical trials are conducted under controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice. Assessment of adverse reactions is based on the exposure of 90 patients (45 male, 45 female) with late-onset Pompe disease, ages 10 to 70 years, to 20 mg/kg LUMIZYME (alglucosidase alfa) or placebo in a randomized, double-blind, placebo-controlled study designed to enroll patients age 8-70 years. The youngest LUMIZYME (alglucosidase alfa) -treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. All patients were na´ve to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received LUMIZYME (alglucosidase alfa) or placebo every other week for 78 weeks (18 months). The study population included 34 males and 26 females (N=60) in the LUMIZYME (alglucosidase alfa) group and 11 males and 19 females (N=30) in the placebo group. Two patients receiving LUMIZYME (alglucosidase alfa) discontinued the study due to anaphylactic reactions. A third patient in the LUMIZYME (alglucosidase alfa) group died during the study due to brain stem ischemia secondary to thrombosis of a basilar aneurysm, which was considered unrelated to treatment.
Serious adverse reactions reported with LUMIZYME (alglucosidase alfa) in the randomized, double-blind, placebo-controlled study included anaphylaxis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Anaphylactic reactions included: angioedema, throat tightness and chest pain/discomfort. One patient with a history of Wolff-Parkinson-White syndrome experienced a serious adverse reaction of supraventricular tachycardia. Other serious adverse events that occurred in a higher incidence in LUMIZYME (alglucosidase alfa) treated patients compared to placebo included coronary artery disease, intervertebral disc protrusion, pneumonia, gastroenteritis, and dehydration.
The most common adverse reactions observed were infusion reactions. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in LUMIZYME (alglucosidase alfa) treated patients at an incidence of ≥ 5% compared to placebo in the controlled study included anaphylaxis, urticaria, diarrhea, vomiting, dyspnea, pruritus, rash/erythema, pharyngolaryngeal pain, neck pain, hypoacusis, flushing/feeling hot, pain in extremity, fall and chest discomfort. Additional infusion reactions observed in other clinical trials and expanded access programs with LUMIZYME (alglucosidase alfa) included respiratory distress, cough, livedo reticularis, agitation, irritability, retching, rigors, tremor and increased lacrimation.
If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion or allergic reactions occur, immediate discontinuation of the administration of LUMIZYME (alglucosidase alfa) should be considered, and appropriate medical treatment should be initiated [see WARNINGS AND PRECAUTIONS]. Severe infusion reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylactic reactions, epinephrine was administered. Patients who have experienced infusion reactions should be treated with caution when they are re-administered LUMIZYME (alglucosidase alfa) .
Delayed onset infusion reactions have also been observed with LUMIZYME (alglucosidase alfa) infusion. Delayed onset infusion reactions, defined as adverse reactions that occurred within 48 hours after completion of LUMIZYME (alglucosidase alfa) infusion, occurred in LUMIZYME (alglucosidase alfa) treated patients at an incidence of ≥ 3% compared to placebo treated patients in a controlled trial. Symptoms included urticaria, dizziness, procedural pain, pharyngolaryngeal pain, malaise, muscle spasms, musculoskeletal pain, musculoskeletal weakness, musculoskeletal stiffness, neck pain, insomnia, and epistaxis. Patients should be counseled about the possibility of delayed onset infusion reactions and given proper follow up instructions.
Table 2 enumerates adverse reactions that occurred in LUMIZYME (alglucosidase alfa) treated patients at an incidence of ≥ 5% compared to placebo treated patients during the randomized, double-blind, placebo-controlled study. Reported adverse reactions have been classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology System Organ Class and Preferred Term.
Table 2: Summary of Adverse Reactions Occurring in LUMIZYME (alglucosidase alfa)
Treated Patients at an Incidence ≥ 5% Compared to Placebo Treated Patients
|System Organ Class||Preferred Term||LUMIZYME (alglucosidase alfa)
|Blood and lymphatic system disorders||Lymphadenopathy||5 (8.3)||0 (0)|
|Ear and labyrinth disorders||Hypoacusis||20 (33.3)||7 (23.3)|
|Vertigo||4 (6.7)||0 (0)|
|Ear discomfort or pain||7 (11.7)||2 (6.7)|
|Eye disorders||Vision blurred||3 (5)||0 (0)|
|Gastrointestinal disorders||Constipation||6 (10)||0 (0)|
|Dyspepsia||5 (8.3)||0 (0)|
|Vomiting||13 (21.7)||3 (10)|
|General disorders and administration site conditions||Chest discomfort or pain||10 (16.7)||2 (6.7)|
|Infusion site reactions||8 (13.3)||0 (0)|
|Malaise||3 (5)||0 (0)|
|Edema, peripheral||10 (16.7)||3 (10)|
|Pain||5 (8.3)||1 (3.3)|
|Immune system disorders||Anaphylaxis||4 (6.7)||0 (0)|
|Infections and infestations||Gastroenteritis||6 (10)||1 (3.3)|
|Respiratory tract infection||3 (5)||0 (0)|
|Upper respiratory tract infection||11 (18.3)||3 (10)|
|Injury, poisoning and procedural complications||Procedural pain||9 (15)||3 (10)|
|Metabolism and nutrition disorders||Hypokalemia||3 (5)||0 (0)|
|Musculoskeletal and connective tissue disorders||Muscle twitching||5 (8.3)||1 (3.3)|
|Musculoskeletal pain||22 (36.7)||9 (30)|
|Musculoskeletal stiffness or tightness||9 (15)||2 (6.7)|
|Nervous system disorders||Somnolence||3 (5)||0 (0)|
|Tremor||4 (6.7)||0 (0)|
|Renal and urinary disorders||Nephrolithiasis||3 (5)||0 (0)|
|Respiratory, thoracic and mediastinal disorders||Dyspnea, exertional||4 (6.7)||0 (0)|
|Epistaxis||3 (5)||0 (0)|
|Skin and subcutaneous tissue disorders||Hyperhidrosis||5 (8.3)||0 (0)|
|Pruritis||6 (10)||1 (3.3)|
|Urticaria||6 (10)||0 (0)|
As with all therapeutic proteins, there is potential for immunogenicity. The data reflect the percentage of patients whose tests results were considered positive for antibodies to alglucosidase alfa using an enzyme-linked immunosorbent assay (ELISA) and confirmed by a radioimmunoprecipitation (RIP) assay for alglucosidase alfa-specific IgG antibodies. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including inhibitory 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 alglucosidase alfa with the incidence of antibodies to other products may be misleading.
In the randomized, double-blind, placebo-controlled study, all patients with available samples treated with LUMIZYME (N=59, 100%) developed IgG antibodies to alglucosidase alfa. All patients who developed IgG antibodies did so within the first 3 months of exposure (median time to seroconversion was 4 weeks). There was no apparent association between mean or peak IgG antibody titers and the occurrence of adverse reactions.
Patients who developed IgG antibodies to alglucosidase alfa were also evaluated for inhibition of enzyme activity or cellular uptake of enzyme in in vitro assays. None of the 59 evaluable patients tested positive for inhibition of enzyme activity. Antibody titers for cellular uptake inhibition were present in 18 of 59 patients (31%) by Week 78. All other patients tested negative for inhibition of cellular uptake. Patients who were positive for uptake inhibition tended to have higher IgG titers than patients who tested negative for uptake inhibition. Among the 32 patients with evaluable pharmacokinetic (PK) samples, 5 patients tested positive for uptake inhibition at times corresponding to PK sampling times as compared to other patients. The clearance values for 4 of these 5 patients were approximately 1.2- to 1.8-fold greater in the presence (Week 52) as compared to in the absence of inhibitory antibodies (Week 0) [see CLINICAL PHARMACOLOGY].
Patients in the clinical studies or in the postmarketing setting have undergone testing for alglucosidase alfa-specific IgE antibodies. Testing was performed in patients who experienced moderate to severe or recurrent infusion reactions, for which mast-cell activation was suspected.
Ten patients in the randomized, double-blind, placebo-controlled study underwent testing for alglucosidase alfa-specific IgE antibodies. Two of 10 patients evaluated tested positive for alglucosidase alfa-specific IgE-binding antibodies, both of whom experienced anaphylactic reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. One patient who developed IgE antibodies discontinued the study following anaphylaxis.
A small number of LUMIZYME (alglucosidase alfa) treated patients in the postmarketing setting who were evaluated tested positive for presence of alglucosidase alfa-specific IgE antibodies. Some of these patients experienced anaphylaxis [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Some patients who tested positive for alglucosidase alfa-specific IgE antibodies were successfully rechallenged with LUMIZYME (alglucosidase alfa) using a slower infusion rate at lower initial doses and have continued to receive treatment under close clinical supervision [see WARNINGS AND PRECAUTIONS].
Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions [see WARNINGS AND PRECAUTIONS]. Therefore, these patients should be monitored more closely during administration of LUMIZYME (alglucosidase alfa) .
The following adverse reactions have been identified during post approval use of LUMIZYME (alglucosidase alfa) . 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 LUMIZYME (alglucosidase alfa) , deaths, and serious adverse reactions have been reported, including anaphylaxis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Adverse events resulting in death reported in the postmarketing setting with LUMIZYME (alglucosidase alfa) treatment included cardiorespiratory arrest, respiratory failure, hemothorax, pneumothorax, cardiac failure, sepsis, aortic dissection, cerebrovascular accident, and skin necrosis. The most frequently reported serious adverse reactions were infusion reactions. In addition to the infusion reactions reported in clinical trials, the following serious adverse events have been reported in at least 2 patients: dyspnea, respiratory failure, bronchospasm, stridor, decreased oxygen saturation/hypoxia, pharyngeal edema, chest discomfort, chest pain, hypotension, hypertension, erythema, flushing, lung infection, tachycardia, cyanosis, and hypersensitivity. One case of hyperparathyroidism has been reported.
Systemic and cutaneous immune mediated reactions, including necrotizing skin lesions have been reported in postmarketing safety experience with alglucosidase alfa [see WARNINGS AND PRECAUTIONS].
Read the Lumizyme (alglucosidase alfa) Side Effects Center for a complete guide to possible side effects
Interference with Other Drugs
No drug interaction or in vitro metabolism studies were performed.
Last reviewed on RxList: 6/18/2010
This monograph has been modified to include the generic and brand name in many instances.
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