VIMIZIM- elosulfase alfa injection, solution, concentrate
BioMarin Pharmaceutical Inc.
WARNING: RISK OF ANAPHYLAXIS
Life-threatening anaphylactic reactions have occurred in some patients during Vimizim infusions. Anaphylaxis, presenting as 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, have been reported to occur during Vimizim infusions, regardless of duration of the course of treatment. Closely observe patients during and after Vimizim administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring [see Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6)].
1 INDICATIONS AND USAGE
Vimizim (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dose is 2 mg per kg given intravenously over a minimum range of 3.5 to 4.5 hours, based on infusion volume, once every week. Pre-treatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion [see Warnings and Precautions ( 5.1)].
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2.2 Preparation Instructions
Important Information: This product should be prepared and administered under the supervision of a healthcare professional with the ability to manage medical emergencies.
Determine the number of vials to be diluted based on the individual patient's weight and the recommended dose of 2 mg/kg.
Dilute the calculated dose to a final volume of 100 mL or 250 mL using 0.9% Sodium Chloride Injection, USP.
The final volume is based on the patient's weight as follows:
� For patients who weigh less than 25 kg, the final volume should be 100 mL;
� For patients who weigh 25 kg or more, the final volume should be 250 mL.
The solution should be clear to slightly opalescent and colorless to pale yellow when diluted. Do not use if the solution is discolored or if there is particulate matter in the solution. Note that a diluted solution with slight flocculation (e.g., thin translucent fibers) is acceptable for administration.
Avoid agitation during preparation. Gently rotate the bag to ensure proper distribution. Do not shake the solution.
2.3 Administration Instructions
Administer the diluted solution to patients using a low-protein binding infusion set equipped with a low-protein binding 0.2 micrometer (�m) in-line filter.
Note: The safety and effectiveness of Vimizim have not been established in pediatric patients less than 5 years of age [see Use in Specific Populations (8.4)].
For patients who weigh less than 25 kg: initial infusion rate should be 3 mL per hour for the first 15 minutes and, if tolerated, increased to 6 mL per hour for the next 15 minutes. If this rate is tolerated, then the rate may be increased every 15 minutes in 6 mL per hour increments, not to exceed 36 mL per hour. The total volume of the infusion should be delivered over a minimum of 3.5 hours.
For patients who weigh 25 kg or more: initial infusion rate should be 6 mL per hour for the first 15 minutes and, if tolerated, the infusion rate may be increased to 12 mL per hour for the next 15 minutes. If this rate is tolerated, then the rate may be increased every 15 minutes in 12 mL per hour increments, not to exceed 72 mL per hour. The total volume of the infusion should be delivered over a minimum of 4.5 hours.
The infusion rate may be slowed, temporarily stopped, or discontinued for that visit in the event of hypersensitivity reactions [see Warnings and Precautions (5.1)]. Do not infuse with other products in the infusion tubing. Compatibility with other products has not been evaluated.
2.4 Storage and Stability
Vimizim does not contain preservatives; therefore the product should be used immediately after dilution. If immediate use is not possible, the diluted product may be stored for up to 24 hours at 2�C to 8�C (36�F to 46�F) followed by up to 24 hours at 23�C to 27�C (73�F to 81�F). Administration of Vimizim should be completed within 48 hours from the time of dilution. Vials are for single-use only. Discard any unused product. Do not freeze or shake. Protect from light.
3 DOSAGE FORMS AND STRENGTHS
Injection: 5 mg/5 mL (1 mg/mL) in single-use vials.
DESCRIPTION
Vimizim is a formulation of elosulfase alfa, which 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 is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride for Injection, USP prior to administration. Vimizim is supplied in clear Type 1 glass 5 mL vials. Each vial provides 5 mg elosulfase alfa, 31.6 mg L-arginine hydrochloride, 0.5 mg polysorbate 20, 13.6 mg sodium acetate trihydrate, 34.5 mg sodium phosphate monobasic monohydrate, and 100 mg sorbitol in a 5 mL extractable solution with a pH between 5.0 to 5.8. Vimizim does not contain preservatives. Each vial is for single use only.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N -acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Vimizim is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.
In the absence of an animal disease model that recapitulates the human disease phenotype, elosulfase alfa pharmacological activity was evaluated using human primary chondrocytes from two MPS IVA patients. Treatment of MPS IVA chondrocytes with elosulfase alfa induced clearance of KS lysosomal storage from the chondrocytes.
HOW SUPPLIED/STORAGE AND HANDLING
Vimizim is supplied as a concentrated solution for infusion (1 mg per mL) requiring dilution. One vial of 5 mL contains 5 mg Vimizim.
NDC 68135-100-01, 5 mL vial
Store Vimizim under refrigeration at 2�C to 8�C (36�F to 46�F). Do not freeze or shake. Protect from light.
Diluted Vimizim should be used immediately. If immediate use is not possible, diluted Vimizim may be stored for up to 24 hours at 2�C to 8�C (36�F to 46�F) followed by up to 24 hours at 23�C to 27�C (73�F to 81�F) during administration.
