Drug: Elaprase

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 practice. The following serious adverse reactions are described below and elsewhere in the labeling:
  • Hypersensitivity Reactions Including Anaphylaxis [see WARNINGS AND PRECAUTIONS]
In clinical trials, the most common adverse reactions ( > 10%) following ELAPRASE treatment were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, corticosteroids or both prior to or during infusions. In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE-treated patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia. Clinical Trials in Patients 5 Years and Older A 53-week, double-blind, placebo-controlled clinical trial of ELAPRASE was conducted in 96 male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White, non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients: ELAPRASE 0.5 mg/kg once weekly, ELAPRASE 0.5 mg/kg every other week, or placebo. Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly treatment of ELAPRASE. Table 1 summarizes the adverse reactions that occurred in at least 9% of patients ( ≥ 3 patients) in the ELAPRASE 0.5 mg/kg once weekly group and with a higher incidence than in the placebo group. Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in At Least 9% of Patients in the ELAPRASE 0.5 mg/kg Once Weekly Group and with a Higher Incidence than in the Placebo Group (5 Years and Older)
System Organ Class
Adverse Reaction ELAPRASE (0.5 mg/kg weekly)
N=32
n (%) Placebo
N=32
n (%) Gastrointestinal disorder   Diarrhea 3 (9%) 1 (3%) Musculoskeletal and Connective Tissue Disorders   Musculoskeletal Pain 4 (13%) 1 (3%) Nervous system disorders   Headache 9 (28%) 8 (25%) Respiratory, thoracic and mediastinal disorders   Cough 3 (9%) 1 (3%) Skin and subcutaneous tissue disorders   Pruritus 8 (25%) 3 (9%)   Urticaria 5 (16%) 0 (0%) Additional adverse reactions that occurred in at least 9% of patients ( ≥ 3 patients) in the ELAPRASE 0.5 mg/kg every other week group and with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%). Extension Trial An open-label extension trial was conducted in patients who completed the placebo-controlled trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented to participate in the extension trial. All 94 patients received ELAPRASE 0.5 mg/kg once weekly for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial. In addition to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least 5% of patients ( ≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing (7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%). Clinical Trial in Patients 7 Years and Younger A 53-week, open-label, single-arm, safety trial of once weekly ELAPRASE 0.5 mg/kg treatment was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages 5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those observed in clinical trials in patients 5 years and older, with the most common adverse reactions following ELAPRASE treatment being hypersensitivity reactions (57%). A higher incidence of the following common hypersensitivity reactions were reported in this younger age group: pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions occurring in at least 10% of patients ( ≥ 3 patients) included: bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%). Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had missense mutations. Safety results demonstrated that patients with complete gene deletion, large gene rearrangement, nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity reactions and have serious adverse reactions following ELAPRASE administration, compared to patients with missense mutations. Table 2 summarizes these findings. Table 2: Impact of Antibody Status and Genetic Mutations on Occurrence of Serious Adverse Reactions and Hypersensitivity in Patients 7 Years and Younger Treated with ELAPRASE
  Total Anti-idursulfase antibodies (Ab) Anti-idursulfase neutralizing antibodies (Nab) Positive Negative Positive Negative Antibody Status Reported (patients) 28 19 9 15 13 Serious Adverse Reactions* (patients) 13 11 2 9 4 Hypersensitivity (patients) 16 12 4 10 6 Patients with genotype data 27 MUTATIONS Missense Mutation (n=12) Antibody status 12 3 9 1 11 Serious Adverse Reactions 2 0 2 0 2 Hypersensitivity Reactions 5 1 4 0 5 Complete Gene Deletion, Large Gene Rearrangement, Nonsense, Frameshift, Splice Site Mutations (n=15) Antibody Status 15 15 0 13 2 Serious Adverse Reactions 9 9 0 7 2 Hypersensitivity Reactions 11 11 0 10 1 * Serious adverse reactions included: bronchopneumonia/pneumonia, ear infection, and pyrexia. Immunogenicity Clinical Trials in Patients 5 Years and Older As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in patients 5 years and older, 63 of the 64 patients treated with ELAPRASE 0.5 mg/kg once weekly or placebo for 53 weeks, followed by ELAPRASE 0.5 mg/kg once weekly in the extension trial, had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive patients, 23 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative. Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response. Clinical Trial in Patients 7 Years and Younger In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb. All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure [see CLINICAL PHARMACOLOGY]. The immunogenicity data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. The observed incidence of positive antibody in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase 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 ELAPRASE. 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 post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two-to four-month period, up to several years after initiating ELAPRASE treatment [see WARNINGS AND PRECAUTIONS]. A seven year-old male patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after 4.5 years of treatment. Treatment has been withdrawn [see OVERDOSAGE]. Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia. Read the Elaprase (idursulfase solution) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

Recommended Dose The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparation Instructions Prepare and use ELAPRASE according to the following steps using aseptic technique:
  1. Determine the total volume of ELAPRASE to be administered and the number of vials needed based on the patient's weight and the recommended dose of 0.5 mg/kg.
    Patient's weight (kg) × 0.5 mg per kg of ELAPRASE ÷ 2 mg per mL = Total mL of ELAPRASE
    Total mL of ELAPRASE ÷ 3 mL per vial = Total number of vials
    Round up to the next whole vial to determine the total number of vials needed. Remove the required number of vials from the refrigerator to allow them to reach room temperature.
  2. Before withdrawing the ELAPRASE solution from the vial, visually inspect each vial for particulate matter and discoloration. The ELAPRASE solution should be clear to slightly opalescent and colorless. Do not use if the solution is discolored or if there is particulate matter in the solution. Do not shake the ELAPRASE solution.
  3. Withdraw the calculated volume of ELAPRASE from the appropriate number of vials.
  4. Add the calculated volume of ELAPRASE solution to a 100 mL bag of 0.9% Sodium Chloride Injection, USP for intravenous infusion.
  5. Mix gently. Do not shake the solution.
Administration Instructions Administer the diluted ELAPRASE solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 micrometer (μm) in-line filter. The total volume of infusion should be administered over a period of 3 hours, which may be gradually reduced to 1 hour if no hypersensitivity reactions are observed. Patients may require longer infusion times if hypersensitivity reactions occur; however, infusion times should not exceed 8 hours. The initial infusion rate should be 8 mL per hour for the first 15 minutes. If the infusion is well tolerated, the rate of infusion may be increased by 8 mL per hour increments every 15 minutes. The infusion rate should not exceed 100 mL per hour. The infusion rate may be slowed, temporarily stopped, or discontinued for that visit in the event of hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]. ELAPRASE should not be infused with other products in the infusion tubing. Storage and Stability ELAPRASE does not contain 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 24 hours. Other than during infusion, do not store the diluted ELAPRASE solution at room temperature. Any unused product or waste material should be discarded and disposed of in accordance with local requirements.

Source: http://www.rxlist.com

No information provided. Last reviewed on RxList: 7/5/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older. In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older. The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age [see Use in Specific Populations].

Source: http://www.rxlist.com

None. Last reviewed on RxList: 7/5/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

One patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage for one and a half years, experienced two anaphylactic reactions over a 3-month period 4.5 years after initiating ELAPRASE treatment.

Source: http://www.rxlist.com

Dosage Forms And Strengths Injection: 6 mg/3 mL (2 mg/mL) in single-use vials Storage And Handling ELAPRASE is supplied as a sterile injection in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-off plastic cap. Each carton contains a single vial NDC 54092-700-01 Store ELAPRASE vials in the carton at 2°C to 8°C (36°F to 46°F) to protect from light. Do not freeze or shake. Do not use ELAPRASE after the expiration date on the vial. Manufactured by: Shire Human Genetic Therapies, Inc. 300 Shire Way Lexington, MA 02421. Phone # 1-866-888-0660. Revised: 06/2013Last reviewed on RxList: 7/5/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Hypersensitivity Reactions Including Anaphylaxis Serious hypersensitivity reactions, including anaphylaxis, have occurred during and up to 24 hours after infusion. Some of these reactions were life-threatening and included respiratory distress, hypoxia, hypotension, urticaria, and angioedema of the throat or tongue, regardless of duration of the course of treatment. If anaphylactic or other acute reactions occur, immediately discontinue the infusion of ELAPRASE and initiate appropriate medical treatment. When severe reactions have occurred during clinical trials, subsequent infusions were managed with antihistamine and/or corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early discontinuation of the ELAPRASE infusion [see ADVERSE REACTIONS]. In clinical trials with ELAPRASE, 16 of 108 (15%) patients experienced hypersensitivity reactions during 26 of 8,274 infusions (0.3%) that involved adverse events in at least two of the following three body systems: cutaneous, respiratory, or cardiovascular. Of these 16 patients, 11 experienced anaphylactic reactions during 19 of 8,274 infusions (0.2%) with symptoms of bronchospasm, cyanosis, dyspnea, erythema, edema (facial and peripheral), flushing, rash, respiratory distress, urticaria, vomiting, and wheezing. In postmarketing reports, patients receiving ELAPRASE experienced anaphylactic reactions up to several years after initiating treatment. Some patients were reported to have repeated anaphylactic events over a two-to four-month time period. Medical management included treatment with antihistamines, inhaled beta-adrenergic agonists, corticosteroids, oxygen, and vasopressors. Treatment was discontinued for some patients, while others continued treatment with premedication and a slower infusion rate. Due to the potential for severe reactions, appropriate medical support should be readily available when ELAPRASE is administered. Observe patients closely for an appropriate period of time after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. Risk of Hypersensitivity, Serious Adverse Reactions, and Antibody Development in Hunter Syndrome Patients with Severe Genetic Mutations In the clinical trial of Hunter syndrome patients aged 7 years and younger, patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and antiidursulfase antibody development than Hunter syndrome patients with missense mutations. Eleven of 15 (73%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and five of 12 (42%) patients with missense mutations experienced hypersensitivity reactions. Nine of 15 (60%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and two of 12 (17%) patients with missense mutations had serious adverse reactions. All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations developed anti-idursulfase (ELAPRASE) antibodies, compared to only 3 patients with missense mutations (Table 2). Thirteen patients with these mutations developed neutralizing antibodies, which interfere with ELAPRASE uptake into the cell or ELAPRASE enzyme activity, compared to only one patient with missense mutation [see ADVERSE REACTIONS and Use In Specific Populations]. Risk of Acute Respiratory Complications Patients with compromised respiratory function or acute febrile or respiratory illness at the time of ELAPRASE infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion. One patient with a tracheostomy, severe airway disease and acute febrile illness experienced respiratory distress, hypoxia, cyanosis, and seizure with a loss of consciousness during ELAPRASE infusion. Risk of Acute Cardiorespiratory Failure Caution should be exercised when administering ELAPRASE 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 ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient [see ADVERSE REACTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with ELAPRASE. ELAPRASE at intravenous doses up to 5 mg/kg administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats. Use In Specific Populations Pregnancy Pregnancy category C Teratogenicity studies have not been conducted with ELAPRASE. A pre-and postnatal development study in rats showed no evidence of adverse effects on pre-and postnatal development at intravenous doses up to 12.5 mg/kg, administered twice weekly (about 4 times the recommended human weekly dose of 0.5 mg/kg based on body surface area). There are no adequate and well-controlled studies 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. Nursing Mothers ELAPRASE was excreted in breast milk of lactating rats at a concentration higher (4 to 5-fold) than that of the plasma. It is not known whether ELAPRASE is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELAPRASE is administered to a nursing woman. Pediatric Use Clinical trials with ELAPRASE were conducted in 96 patients with Hunter syndrome, ages 5 to 31 years old, with the majority of the patients in the pediatric age group (median age 15 years old). In addition, an open-label, uncontrolled clinical trial was conducted in 28 patients with Hunter syndrome, ages 16 months to 7.5 years old. Patients 16 months to 5 years of age demonstrated reduction in spleen volume that was similar to that of adults and children 5 years and older. However, there are no data to support improvement in disease-related symptoms or long term clinical outcome in patients 16 months to 5 years of age. [see Clinical Studies]. The safety and effectiveness of ELAPRASE have not been established in pediatric patients less than 16 months of age. Geriatric Use Clinical studies of ELAPRASE did not include patients older than 31 years of age. It is not known whether older patients respond differently from younger patients. Last reviewed on RxList: 7/5/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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