ELOSULFASE ALFA: 5,024 Adverse Event Reports & Safety Profile

Elosulfase alfa is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. Human N-acetylgalactosamine-6-sulfatase (EC 3.1.6.4) is a hydrolytic lysosomal glycosaminoglycan-specific enzyme that hydrolyzes sulfate from either galactose-6-sulfate or N-acetyl-galactosamine-6-sulfate on the non-reducing ends of the glycosaminoglycans keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Elosulfase alfa is a soluble glycosylated dimeric protein with two oligosaccharide chains per monomer. Each monomeric peptide chain contains 496 amino acids and has an approximate molecular mass of 55 kDa (59 kDa including the oligosaccharides). One of the oligosaccharide chains contains bis-mannose-6-phosphate (bisM6P). bisM6P binds a receptor at the cell surface and the binding mediates cellular uptake of the protein to the lysosome. Elosulfase alfa has a specific activity of 2.6 to 6.0 units/mg. One activity unit is defined as the amount of the enzyme required to convert 1 micromole of sulfated monosaccharide substrate D-galactopyranoside-6-sulfate (Gal-6S) to de-sulfated-galactose (Gal) and free sulfate per minute at 37°C. VIMIZIM (elosulfase alfa) injection is a sterile, preservative-free, nonpyrogenic, clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion after dilution. Each single-dose vial contains 5 mL solution of 5 mg elosulfase alfa, 31.6 mg arginine hydrochloride, 34.5 mg monobasic sodium phosphate, 0.5 mg polysorbate 20, 8.2 mg sodium acetate, and 100 mg sorbitol in Water for Injection, USP with a pH between 5 to 5.8.

AND USAGE VIMIZIM (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). VIMIZIM is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). ( 1 )

AND ADMINISTRATION Administration of VIMIZIM should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) 2 mg per kg body weight administered once every week as an intravenous infusion over a minimum of 3.5 to 4.5 hours, based on infusion volume. ( 2.2 , 2.4 ) See the full prescribing information for administration modifications due to hypersensitivity reactions. ( 2.3 )

2.1 Important Administration Instructions Administration of VIMIZIM should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Initiate VIMIZIM in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . This product must be diluted prior to administration and administered using a low-protein binding infusion set equipped with a low-protein binding 0.2 micrometer (µm) in-line filter. Consider pre-medicating with antihistamines, with or without antipyretics, 30 to 60 minutes prior to the start of the infusion <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

2.2 Recommended Dosage The recommended dosage of VIMIZIM is 2 mg/kg administered intravenously over a minimum range of 3.5 to 4.5 hours (based on infusion volume) once every week.

2.3 Administration Modifications Due to Hypersensitivity Reaction In the event of a severe hypersensitivity reaction (e.g., anaphylaxis), discontinue the VIMIZIM infusion and immediately initiate appropriate medical treatment, including use of epinephrine. In the event of a mild to moderate hypersensitivity reaction, consider slowing or temporarily interrupting the infusion, or administering additional antihistamines, antipyretics, and/or corticosteroids <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

2.4 Preparation Instructions Use aseptic technique during preparation. Determine the number of VIMIZIM vials based on the patient&apos;s actual body weight in kg and the recommended dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Remove vials from the refrigerator. Select the appropriate size 0.9% Sodium Chloride Injection, USP infusion bag and calculate the infusion volume based on patient&apos;s actual body weight: For patients who weigh less than 25 kg, the final infusion volume should be 100 mL For patients who weigh 25 kg or more, the final infusion volume should be 250 mL. Withdraw and discard a volume of 0.9% Sodium Chloride Injection, USP from either the 100 mL or 250 mL infusion bag equal to the volume of VIMIZIM to be added. Withdraw the required volume of VIMIZIM from the vial(s) and add to the 0.9% Sodium Chloride Injection, USP infusion bag. Gently rotate the infusion bag to mix the diluted solution. Avoid vigorous shaking or agitation. Discard unused portion remaining in the vial(s). Visually inspect the solution for particulate matter and discoloration. The solution should be clear to slightly opalescent and colorless to pale yellow. The diluted VIMIZIM solution may contain proteinaceous particles in the form of translucent fibers which will be removed by the in-line filter during infusion. Discard if opaque particles are present or the solution is discolored.

2.5 Administration Instructions Use an infusion set equipped with a low-protein binding 0.2 micrometer (µm) in-line filter to administer VIMIZIM . Do not infuse with other products in the infusion tubing. Compatibility with other products has not been evaluated.

Table

1.

Intravenous Infusion

Rate for VIMIZIM Based on Patient Weight Patient Weight (kg) Infusion rate (mL/hour)

Initial

Rate (first 15 minutes)

Subsequent

Rate (next 15 minutes)

Subsequent Rate

Increments If tolerated, the infusion rate can be increased incrementally up to the maximum infusion rate.

Maximum Infusion Rate

Less than 25 kg 3 mL/hour 6 mL/hour 6 mL/hour every 15 minutes 36 mL/hour 25 kg or more 6 mL/hour 12 mL/hour 12 mL/hour every 15 minutes 72 mL/hour Table 2.

Minimum Infusion

Time for VIMIZIM Based on Patient Weight Patient Weight (kg)

Minimum Infusion

Time (hours) Less than 25 kg 3.5 hours 25 kg or more 4.5 hours

2.6 Storage of the Diluted Solution If the diluted VIMIZIM solution is not used immediately: Store the diluted solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature between 23°C to 27°C (73°F to 81°F) for up to 24 hours. Diluted VIMIZIM solution must be used within 48 hours, inclusive of total infusion time. Discard if not used within 48 hours. Do not freeze or shake.

None. None. ( 4 )

REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] . Risk of Acute Respiratory Complications [see Warnings and Precautions (5.2) ] . Spinal or Cervical Cord Compression [see Warnings and Precautions (5.3) ] . Most common adverse reactions (≥10%) are: pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin at 1-866-906-6100 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 practice. A 24-week, randomized, double-blind, placebo-controlled clinical trial of VIMIZIM was conducted in 176 patients with MPS IVA, ages 5 to 57 years old. Approximately half of the patients (49%) were male. Of the 176 patients, 65% were White, 23% Asian, 3% Black, and 10% Other race. The majority of patients (78%) were non-Hispanic. Patients were randomized to three treatment groups: VIMIZIM 2 mg/kg once per week (n=58), VIMIZIM 2 mg/kg once every other week (n=59), or placebo (n=59). All patients were treated with antihistamines prior to each infusion.

Table

3 summarizes the most common adverse reactions that occurred in the placebo-controlled trial with an incidence of ≥ 10% in patients treated with VIMIZIM 2 mg/kg once per week and with a higher incidence than in the placebo-treated patients.

Table

3: Adverse Reactions That Occurred in the Placebo-Controlled Trial in At Least 10% of Patients in the VIMIZIM 2 mg/kg Once Per Week Group and with a Higher Incidence than in the Placebo Group Adverse Reaction VIMIZIM 2 mg/kg once per week Placebo N= 58 n (%) N= 59 n (%)

Pyrexia

19 (33%) 8 (14%)

Vomiting

18 (31%) 4 (7%)

Headache

15 (26%) 9 (15%)

Nausea

14 (24%) 4 (7%) Abdominal pain 12 (21%) 1 (2%)

Chills

6 (10%) 1 (2%)

Fatigue

6 (10%) 2 (3%)

Extension

Trial An open-label extension trial was conducted in 173 patients who completed the placebo-controlled trial [see Clinical Studies (14) ] . No new adverse reactions were reported.

6.2 Immunogenicity As with all therapeutic proteins, including VIMIZIM, there is potential for immunogenicity. The detection 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 in other studies or to other elosulfase alfa products may be misleading. All patients treated with VIMIZIM 2 mg/kg once per week in the placebo-controlled trial developed anti-drug antibodies by Week 4. Anti-drug antibody titers were sustained or increased for the duration of VIMIZIM treatment. Because all patients developed anti-drug antibodies, associations between antibody titers and reductions in treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could not be determined. All patients treated with VIMIZIM 2 mg/kg once per week tested positive for neutralizing antibodies capable of inhibiting the drug from binding to the mannose-6-phosphate receptor at least once during the trial. Binding to this receptor is required for VIMIZIM to be taken into cells where it is active. Neutralizing antibody titers were not determined in the patients. Therefore, the possibility of an association between neutralizing antibody titer and treatment effect cannot be assessed.

AND PRECAUTIONS Risk of Acute Respiratory Complications: Patients with acute febrile or respiratory illness 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 VIMIZIM and consider delaying the VIMIZIM infusion. ( 5.2 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including VIMIZIM. In premarketing clinical trials, 18 of 235 (7.7%) patients treated with VIMIZIM experienced signs and symptoms consistent with anaphylaxis.

These

18 patients experienced 26 anaphylactic reactions during infusion with signs and symptoms including cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (e.g., nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria. These cases of anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion. Anaphylaxis occurred as late into treatment as the 47 th infusion. In clinical trials with VIMIZIM, 44 of 235 (18.7%) patients experienced hypersensitivity reactions, including anaphylaxis. Hypersensitivity reactions have occurred as early as 30 minutes from the start of infusion but as late as six days after infusion. Frequent symptoms of hypersensitivity reactions (occurring in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of VIMIZIM should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate VIMIZIM in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Observe patients closely for an appropriate period of time after administration of VIMIZIM, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials. Because of the potential for hypersensitivity reactions, administer antihistamines with or without antipyretics prior to infusion. Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporarily interrupting the infusion, and/or administering additional antihistamines, antipyretics, and/or corticosteroids for mild to moderate reactions. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue VIMIZIM and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. Consider the risks and benefits of re-administering VIMIZIM following a severe reaction.

5.2 Risk of Acute Respiratory Complications Patients with acute febrile or respiratory illness at the time of VIMIZIM infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient&apos;s clinical status prior to administration of VIMIZIM and consider delaying the VIMIZIM infusion. Sleep apnea is common in MPS IVA patients. Evaluation of airway patency should be considered prior to initiation of treatment with VIMIZIM. 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 acute reaction, or extreme drowsiness/sleep induced by antihistamine use.

5.3 Spinal or Cervical Cord Compression Spinal or cervical cord compression (SCC) is a known and serious complication of MPS IVA and may occur as part of the natural history of the disease. In clinical trials, SCC was observed both in patients receiving VIMIZIM and patients receiving placebo. Patients with MPS IVA should be monitored for signs and symptoms of SCC (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.