VIMIZIM

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-The solution should be clear to slightly opalescent and colorless to pale yellow when diluted. A diluted solution with slight flocculation (e.g., thin translucent fibers) is acceptable for administration.
Intravenous Administration
Prepare and administer this product under the supervision of a healthcare professional with the ability to manage medical emergencies.

Dilution
-Dilute the calculated dose in 0.9% NaCl to a final volume of 100 ml or 250 ml depending on the patient's weight:
-For patients weighing < 25 kg, the final volume should be 100 ml.
-For patients weighing >= 25 kg, the final volume should be 250 ml.

-Avoid agitation during preparation. Gently rotate the bag to ensure proper distribution. Do not shake the solution.
-Vials are for single-use only. Discard any unused product.
-Storage: Use immediately after dilution; vial does not contain preservatives. If immediate use is not possible, diluted product may be stored for up to 24 hours at 2-8 degrees C (36-46 degrees F) followed by up to 24 hours at 23-27 degrees C (73-81 degrees F). Administration should be completed within 48 hours from the time of dilution. Protect from light.

Intermittent IV Infusion
-Administer the diluted solution using a low-protein binding infusion set equipped with a low-protein binding 0.2 micrometer in-line filter.
-The rate of infusion depends on patient weight and tolerance:-For patients weighing < 25 kg: Begin the infusion at a rate of 3 ml/hr for the first 15 minutes, and then, if tolerated, the infusion rate may be increased to 6 ml/hr for the next 15 minutes. If this rate is tolerated, then the rate may be increased every 15 minutes in 6 ml/hr increments (Max: 36 ml/hr). The total volume of the infusion should be delivered over a minimum of 3.5 hours.
-For patients weighing >= 25 kg: Begin the infusion at a rate of 6 ml/hr for the first 15 minutes, and then, if tolerated, the infusion rate may be increased to 12 ml/hr for the next 15 minutes. If this rate is tolerated, then the rate may be increased every 15 minutes in 12 ml/hr increments (Max: 72 ml/hr). The total volume of the infusion should be delivered over a minimum of 4.5 hours.

-Slow, temporarily stop, or discontinue the infusion rate if a hypersensitivity reaction occurs.
-Do not infuse with other products in the infusion tubing. Compatibility with other products has not been evaluated.

Serious hypersensitivity reactions or anaphylaxis has occurred during elosulfase alfa administration; in premarketing clinical trials, 7.7% of patients experienced signs and symptoms consistent with anaphylaxis. Anaphylaxis occurred as late into treatment as the 47th infusion and included the following signs and symptoms: cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash (unspecified), dyspnea, chest discomfort, and gastrointestinal symptoms in conjunction with urticaria. Patients with acute febrile or respiratory illness may be at higher risk of complications from hypersensitivity reactions. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended for all patients. Personnel, medications, and equipment necessary to manage an acute hypersensitivity reaction should be readily available. Follow the recommended infusion rate schedule, and closely monitor patients during and for an appropriate period of time after administration. Cases of anaphylaxis have occurred as early as 30 minutes from the start of the infusion and up to 3 hours after infusion. Hypersensitivity reactions occurred in 18.7% of patients in clinical trials and have occurred as late as 6 days after an infusion. Depending on the severity of the hypersensitivity reaction, the infusion should be slowed or temporarily interrupted while antihistamines, antipyretics, and/or corticosteroids are administered for mild reactions. For severe reactions, the infusion should be stopped immediately and appropriate treatment initiated. The risks and benefits of re-administering elosulfase alfa should be considered after a severe reaction. Symptoms of hypersensitivity reactions that occurred in more than 2 patients in clinical trials include anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing. Counsel patients and/or caregivers about the signs and symptoms of hypersensitivity reactions, and instruct them to seek immediate medical attention if any such reactions occur.

Fever (33%) and chills (10.3%) were reported in pediatric and adult patients receiving elosulfase alfa during clinical trials. Fatigue was reported in 10.3% of patients, and headache was reported in 26% of patients.

Nausea (24%), vomiting (31%), and abdominal pain (21%) were among the most commonly reported adverse events in pediatric and adult patients treated with elosulfase alfa. Gastrointestinal symptoms have also occurred as part of a hypersensitivity reaction in some patients. Because these reactions can be life-threatening, carefully evaluate patients with gastrointestinal symptoms for the possibility of a hypersensitivity reaction.

Cervical or spinal cord compression (SCC) is a known and serious complication of Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). SCC may occur as part of the natural progression of the disease in spite of treatment with elosulfase alfa. In clinical trials, SCC was observed both in patients receiving elosulfase alfa and in patients receiving placebo. All patients with MPS IVA should be monitored for signs and symptoms of cervical/spinal cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.

In a clinical trial of elosulfase alfa, anti-drug antibody formation occurred in all patients receiving treatment by week 4; antibodies were sustained or increased for the duration of treatment. Because anti-drug antibodies developed in all patients receiving elosulfase alfa, no correlation of antibody development to treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could be determined. Additionally, at least once during the trial, all patients receiving elosulfase alfa tested positive for neutralizing antibodies capable of inhibiting the binding of drug to the mannose-6-phosphate receptor. Neutralizing antibody titers were not determined; therefore, the possibility of an association between neutralizing antibody titer and treatment effect is not known.

Elosulfase alfa administration has been associated with serious hypersensitivity reactions or anaphylaxis. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended. Personnel, medications, and equipment necessary to manage an acute hypersensitivity reaction should be readily available. Follow the recommended infusion rate schedule, and closely monitor patients during and for an appropriate period of time after administration. Cases of anaphylaxis have occurred as early as 30 minutes from the start of the infusion and up to 3 hours after infusion. Hypersensitivity reactions have occurred as late as 6 days after an infusion. Counsel patients and caregivers about hypersensitivity reactions, and instruct them to seek immediate medical attention should any signs or symptoms occur. Patients with acute illness with fever or respiratory infection at the time of elosulfase alfa administration may be at increased risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to treatment with elosulfase alfa; administration of the infusion may need to be delayed.

Evaluate airway patency prior to initiation of elosulfase alfa therapy; sleep apnea is common in patients with (MPS IVA) Morquio A syndrome. Patients requiring oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments available during elosulfase alfa infusion in the event of an acute reaction or extreme drowsiness/sleep secondary to antihistamine use.

Description: Elosulfase alfa is a purified human enzyme for the treatment of patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). It is produced by recombinant technology in a Chinese hamster ovarian cell line and is administered as a weekly infusion. MPS IVA is an autosomal recessive lysosomal storage disorder that is caused by a mutation in the gene encoding N-acetylgalactosamine-6-sulfatase (GALNS), which leads to the absence or marked reduction of GALNS activity. Elosulfase alfa is intended to provide exogenous N-acetylgalactosamine-6-sulfatase. MPS IVA is a multisystem disorder that causes significant functional limitations and reduced quality of life, although the progression of symptoms is variable. Over time, patients have less endurance and more severe exercise and respiratory capacity limitations. Typically, patients appear unaffected at birth. For severely affected patients, symptoms occur within the first year of life, whereas other patients may not develop initial symptoms until later in childhood or adolescence. Prior to the availability of elosulfase alfa as an enzyme replacement therapy, treatment for MPS IVA primarily focused on pain management, treatment of infection and respiratory disease, and corrective orthopedic surgeries. In a 24-week, randomized, double-blind, placebo-controlled trial (n = 176, ages 5-57 years), a statistically significant improvement in the 6-minute walk test was noted in the treatment vs. the placebo group (primary endpoint); however, no difference was found in the rate of stair climbing (secondary endpoint). Patients receiving elosulfase alfa once weekly walked about 22.5 meters farther in 6 minutes compared with those who received placebo (p = 0.0174). Risk of anaphylaxis is a significant concern with elosulfase alfa. Premedication with antihistamines with or without antipyretics is recommended, and a careful infusion rate titration schedule must be observed. Patients should be monitored closely during and after the administration of the infusion. Elosulfase alfa is FDA-approved in children as young as 5 years of age.

For the treatment of mucopolysaccharidosis IVA (Morquio A syndrome):
NOTE: Elosulfase alfa has been designated as an orphan drug for this indication by the FDA.
Intravenous dosage:
Children >= 5 years and Adolescents: 2 mg/kg/dose IV administered once weekly. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
< 5 years: Safety and efficacy have not been established.
>= 5 years: 2 mg/kg/week IV.
-Adolescents
2 mg/kg/week IV.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder that is caused by a mutation in the gene encoding N-acetylgalactosamine-6-sulfatase (GALNS). Patients with MPS IVA have an absence or marked reduction of GALNS activity, which leads to the accumulation of the glycosaminoglycan (GAG) substrates keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Patients experience widespread tissue and organ damage, but the course of progression and severity is variable. Elosulfase alfa is intended to provide exogenous N-acetylgalactosamine-6-sulfatase. 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. Once inside the lysosomes, the catabolism of GAGs KS and C6S is thought to be increased.

NOTE: Because an animal model that recapitulates the human disease phenotype was not available, the activity of elosulfase alfa was evaluated using human primary chondrocytes from two MPS IVA patients. In this model, treatment with elosulfase alfa induced clearance of KS lysosomal storage from the chondrocytes.

Pharmacokinetics: Elosulfase alfa is administered via intravenous infusion. Elosulfase alpha pharmacokinetics were evaluated in 23 patients (ages 5-41 years) with Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) who received 2 mg/kg/dose IV weekly for 22 weeks. Doses were infused over approximately 4 hours. The following mean PK parameters were reported:

Week 0 Week 22
Cmax = 1.49 +/- 0.534 mcg/ml Cmax = 4.04 +/- 3.24 mcg/ml
Tmax = 172 +/- 75.3 min Tmax = 202 +/- 90.8 min
AUC = 238 +/- 100 mcg x min/ml AUC = 577 +/- 416 mcg x min/ml
Vd = 396 +/- 316 ml/kg Vd = 650 +/- 1842 ml/kg
CL = 10 +/- 3.73 ml/min/kg CL = 7.08 +/- 13 ml/min/kg
t1/2 = 7.52 +/- 5.48 min t1/2 = 35.9 +/- 21.5 min

Mean AUC and Cmax increased to 2.8- and 2.9-fold, respectively, at Week 22 compared to Week 0. Mean t1/2 increased from 7.5 min at Week 0 to 35.9 min at Week 22. These changes are likely related to the development of neutralizing antibodies in all patients receiving elosulfase alfa. Neutralizing antibody titers were not determined so the possibility of an association between neutralizing antibody titer and treatment efficacy is not known.


Affected cytochrome P450 enzymes: none