Vimizim

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.

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.

Administration Instructions

Administer the diluted solution to patients using a low-protein binding infusion set equipped with a low-protein binding 0.2 micrometer (µm) 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 ].

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 ]. Do not infuse with other products in the infusion tubing.  Compatibility with other products has not been evaluated.

  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.

Pregnancy

Pregnancy Exposure Registry

There is a Morquio A Registry that collects data on pregnant women with MPS IVA who are treated with Vimizim.  Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment.

Risk Summary

Available data from published case reports and postmarketing experience with Vimizim use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no effects on embryo-fetal development were observed in rats given daily administration of elosulfase alfa up to 33 times the human steady-state AUC (area under the concentration-time curve) at the recommended human weekly dose premating and through the period of organogenesis. No effects on embryo-fetal development were observed in rabbits given daily administration of elosulfase alfa at doses up to 8 times the human steady-state AUC at the recommended weekly dose during organogenesis, which produced maternal toxicity. A dose-dependent increase in stillbirths was observed when elosulfase alfa was administered daily in rats during organogenesis through lactation at doses 5 times the human steady-state AUC at the recommended human weekly dose. An increase in pup mortality was observed at doses producing maternal toxicity.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse outcomes for both mother and fetus.

Data

Animal Data

All reproductive studies with rats included pre-treatment with diphenhydramine to prevent or minimize hypersensitivity reactions.  The effects of elosulfase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone.  Daily intravenous administration of up to 20 mg/kg elosulfase alfa in rats (33 times the human steady-state AUC at the recommended weekly dose of 2 mg/kg) during a 15-day pre-mating period, mating, and the period of organogenesis, produced no maternal toxicity or effects on embryo-fetal development.  Daily intravenous administration of up to 10 mg/kg in rabbits (8 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis had no effects on embryo-fetal development.  However, maternal toxicity (gross changes in liver) was observed in rabbits given doses of 1 mg/kg/day and higher (0.1 times the human steady-state AUC at the recommended weekly dose).  Elosulfase alfa produced an increase in the percentage of stillbirths when administered daily to rats at intravenous doses of 6 mg/kg and higher (5 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis through lactation.  Daily intravenous administration of 20 mg/kg (33 times the human steady-state AUC at the recommended weekly dose) produced maternal toxicity and an increase in mortality of offspring during the lactation period.  This study lacked a full evaluation of neurodevelopmental milestones; however, no effects of elosulfase alfa were noted in tests for learning and memory.

Lactation

Risk Summary

There are no data on the presence of elosulfase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. Elosulfase alfa is present in milk from treated rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Vimizim and any potential adverse effects on the breastfed infant from Vimizim or from the underlying maternal condition.

There is a Morquio A Registry that also collects data on breastfeeding women with MPS IVA who are treated with Vimizim. Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment.

Data

Animal Data

Elosulfase alfa was detected in 1 of 5 milk samples from rat dams administered 6 mg/kg/day elosulfase alfa and 4 of 5 milk samples from dams administered 20 mg/kg/day elosulfase alfa. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

Pediatric Use

Safety and effectiveness of Vimizim have been established in pediatric patients 5 years of age and older.  Use of Vimizim in patients 5 years of age and older is supported by an adequate and well-controlled trial in pediatric and adult patients. Clinical trials with Vimizim were conducted in 176 patients (median age 12 years, range 5 to 57 years old) with the majority of patients in the pediatric age group (53% aged 5 to 11 years, 27% aged 12 to 17 years) [see Clinical Studies ].  Safety and effectiveness in pediatric patients below 5 years of age have not been established.

Geriatric Use

Clinical studies of Vimizim did not include any patients aged 65 and over. It is not known whether they respond differently from younger patients.