2.1 Recommended Dosage

MEPSEVII should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Premedication is recommended 30 to 60 minutes prior to the start of the infusion [see Dosage and Administration (2.2)].

The recommended dosage of MEPSEVII is 4 mg/kg administered by intravenous infusion every two weeks.

Administer the infusion over approximately 4 hours. Infuse the first 2.5% of the total volume over the first hour. After the first hour, increase the infusion rate as tolerated in order to complete infusion over the following 3 hours according to the recommended rate guidelines in Table 1 [see Dosage and Administration (2.4)].

2.2  Premedication

• Administration of a non-sedating antihistamine with or without an anti-pyretic medication is recommended 30 to 60 minutes prior to the start of the infusion for patient comfort.
  
• Follow the instructions in Table 1 for the rate of MEPSEVII infusion [see Dosage and Administration (2.4)].
  
• Observe patients closely during the infusion and following the infusion for a minimum of 60 minutes for the development of anaphylaxis [see Warnings and Precautions (5.1)].
  
• Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis [see Warnings and Precautions (5.1)].

2.3 Preparation Instructions

Prepare MEPSEVII according to the following steps using aseptic technique:

1. Determine the number of vials to be diluted based on the patient's actual weight and the recommended dose of 4 mg/kg, using the following calculations (a-b):

      a. Total dose (mg) = Patient's weight (kg) x 4 mg/kg (recommended dose)

      b. Total number of vials = Total dose (mg) divided by 10 mg/vial

2. Round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat, microwave or shake vials.

      a. Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mL concentration

3. The final solution will be a 1:1 dilution of MEPSEVII with 0.9% Sodium Chloride Injection, USP. More than 1:1 dilution may be used if the patient can tolerate additional infusion volume, taking into consideration cardiac function and fluid status.

4. For a 1:1 dilution, prepare the solution at room temperature, as follows:

      a. Select an empty infusion bag, sized upon the total volume of the final solution.  

      b. Prior to withdrawing MEPSEVII from the vial, visually inspect the solution for particulate matter and discoloration. Because this is a protein solution, slight flocculation (thin translucent fibers) may occur. The MEPSEVII solution should be colorless to slightly yellow. Discard if the solution is discolored or if there is particulate matter in the solution.

      c. Slowly withdraw the volume of the calculated MEPSEVII dose from the appropriate number of vials (step 2a) using caution to avoid excessive agitation and any air or frothing. Use a sufficiently large needle (18 gauge) to minimize bubbles in the solution.

      d. Slowly add MEPSEVII to the infusion bag using care to avoid agitation, ensuring liquid to liquid contact without generating bubbles or turbulence.

      e. Add 0.9% Sodium Chloride Injection, USP equal to the volume of MEPSEVII to the infusion bag.

      f. Gently rock the infusion bag to ensure proper distribution of MEPSEVII. Do not shake the solution. 

2.4 Administration Instructions

Administer MEPSEVII as follows: 

1. The rate of infusion: In the first hour infuse 2.5% of the total volume, and infuse the remaining volume over the subsequent three hours (see Table 1). Account for any dead space in the lines to ensure 2.5% of the total infusion volume is delivered into the patient's bloodstream during the first hour of infusion.
   
2. Use an infusion set equipped with an in-line, low-protein binding 0.2 micron filter to administer the diluted MEPSEVII solution.
   
3. Do not flush the line containing MEPSEVII to avoid a rapid bolus of infused enzyme. Due to the low infusion rate, additional saline may be added through a separate line (piggyback or Y tube) to maintain sufficient intravenous flow to prevent clotting or line blockage.
   
4. Do not infuse with other products in the infusion tubing. Compatibility with other products has not been evaluated. 
   
5. Use MEPSEVII immediately after dilution and complete the infusion within 42 hours from the time of dilution. Discard any unused product.

Stability

If immediate use is not possible, the diluted solution may be stored up to 36 hours under refrigeration at 2°C to 8°C (36°F to 46°F) followed by up to 6 hours at room temperature up to a maximum of 25°C (77°F).

5.1  Anaphylaxis

Anaphylaxis to MEPSEVII was reported in 2 of 20 patients in the clinical program [see Adverse Reactions (6.1)]. These reactions occurred during MEPSEVII infusion and were observed as early as the first dose of MEPSEVII for one patient. Manifestations included respiratory distress, cyanosis, decreased oxygen saturation, and hypotension. The two patients with anaphylaxis to MEPSEVII during the clinical trials had one occurrence each and tolerated subsequent infusions of MEPSEVII, without recurrence.

Anaphylaxis can be life-threatening. MEPSEVII should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Patients should be observed for 60 minutes after MEPSEVII administration. If severe systemic reactions occur, including anaphylaxis, immediately discontinue the MEPSEVII infusion and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Consider the risks and benefits of re-administering MEPSEVII following anaphylaxis.

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.

The MEPSEVII clinical program included 23 patients aged 5 months to 25 years who received treatment with MEPSEVII at doses up to 4 mg/kg once every two weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.

Table 2 summarizes the adverse reactions that occurred in Study 301, a randomized start trial in 12 patients with MPS VII between the ages of 8 and 25 years [see Clinical Studies (14)].

Adverse reactions in Table 2 occurred in one or more patients treated with MEPSEVII at a dosage of 4 mg/kg at a higher patient frequency than placebo. Adverse reaction incidence rates are presented in the table below to account for the different duration of exposure to active treatment vs. placebo.

n = number of reactions

*Adverse reaction incidence rates calculated per 8.3 patient years for exposure to MEPSEVII, and 2.7 years of exposure for placebo

Febrile Convulsion

One patient receiving a dose of 4 mg/kg experienced a febrile convulsion during MEPSEVII treatment at Week 66. The infusion was stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the adverse reaction resolved. The patient subsequently was re-challenged without recurrence and continued on treatment.

6.2 Immunogenicity

As with all therapeutic proteins, 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 the studies described below with the incidence of antibodies in other studies to other vestronidase alfa products may be misleading.

Immunogenicity data were available from 23 patients who received MEPSEVII for up to 187 weeks of treatment. Eighteen out of 23 (78%) patients developed anti-vestronidase alfa-vjbk antibodies (ADA). Ten of the 18 (55.6%) ADA-positive patients were tested positive for neutralizing antibodies (NAb). There is no correlation between ADA titer and NAb development.

Six treatment-naïve patients had pre-existing ADA titers at baseline. ADAs were detected in five of these six patients post-treatment. The post-treatment ADA titers were the same as or below the baseline ADA titer values in two patients, but one of these two patients was positive for NAb. ADA titer values after treatment increased 64-fold, 128-fold, and 364-fold, respectively, in the other three patients.

The presence of ADA titer did not appear to affect reduction in urinary glycosaminoglycans (uGAGs).

8.1  Pregnancy

Risk Summary

There are no available data on MEPSEVII use in pregnant women to determine a drug-associated risk of adverse developmental outcomes. In embryofetal development studies, vestronidase alfa-vjbk administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no adverse developmental outcomes at doses up to 1.6 and 10 times, respectively for rats and rabbits, the exposure at the recommended human dose. In a pre- and post-natal development study in rats, an increased number of stillbirths were observed at exposures less than the recommended human dose (see Data). The clinical relevance of these animal findings is uncertain.

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.

Data

Animal Data

In embryofetal development studies, vestronidase alfa-vjbk administered intravenously to pregnant rats (once a week) and rabbits (once every 3 days) during the period of organogenesis showed no adverse developmental outcomes at doses up to 20 mg/kg. The 20 mg/kg dose in rats and rabbits provides approximately 1.6 and 10 times the human exposure (AUC) of 57.9 hr*mcg/mL at the 4 mg/kg dose administered once every other week, respectively.

In a pre- and post-natal developmental study in rats, vestronidase alfa-vjbk was administered every 3 days from gestation day 7 through lactation day 20 at doses of 2 mg/kg, 6 mg/kg, and 20 mg/kg. Mortality and adverse clinical signs were observed in the maternal animals at the 20 mg/kg dose (1.6 times the human exposure (AUC) at the recommended human dose of 4 mg/kg). Subsequently, the 20 mg/kg dose was reduced to 12 mg/kg. Maternal toxicity with mortality in one animal was also observed at the 6 mg/kg dose (0.17 times the AUC at the recommended human dose of 4 mg/kg). At the 2 mg/kg dose (0.01 times the AUC at the recommended human dose of 4 mg/kg), no adverse effects were observed in the maternal animals; however, there was a statistically significant decrease in the number of live births and subsequent increase in the number of stillbirths at this dose.

8.2  Lactation

Risk Summary 

There are no data on the presence of vestronidase alfa-vjbk in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MEPSEVII and any potential adverse effects on the breastfed infant from vestronidase alfa-vjbk or from the underlying maternal condition.

8.4  Pediatric Use

The safety and effectiveness of MEPSEVII have been established in pediatric patients less than 18 years of age [see Adverse Reactions (6),Clinical Studies (14)].

8.5  Geriatric Use

Clinical trials of MEPSEVII did not include any patients aged 65 and over. It is not known whether elderly patients respond differently from younger patients.

12.1        Mechanism of Action

Mucopolysaccharidosis VII (MPS VII or Sly syndrome) is a lysosomal disorder characterized by the deficiency of GUS that results in GAG accumulation in cells throughout the body leading to multisystem tissue and organ damage.

Vestronidase alfa-vjbk is a recombinant form of human GUS and is intended to provide exogenous GUS enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to cell surface receptors, leading to cellular uptake of the enzyme, targeting to lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.

12.2       Pharmacodynamics

In clinical studies, MEPSEVII treatment resulted in sustained reduction of urinary excretion of GAGs during long-term treatment [see Clinical Studies (14)].

12.3  Pharmacokinetics

The pharmacokinetics of vestronidase alfa-vjbk were evaluated in a total of 23 MPS VII patients including 19 pediatric patients and 4 adults. Serum exposures of vestronidase alfa-vjbk appeared to increase approximately proportionally from 1 mg/kg (0.25 times the approved recommended dosage) to 2 mg/kg (0.5 times the approved recommended dosage), and 4 mg/kg (the recommended dosage). After repeated dosing of 4 mg/kg every other week, the mean ± standard deviation of maximal concentration (Cmax) was 17.3 ± 9.6 mcg/mL (range: 4.7 to 35.7 mcg/mL); and the mean ± standard deviation of area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) was 50.9 ± 32.2 mcg*hr/mL (range: 17.4 to 153 mcg*hr/mL).

Vestronidase alfa-vjbk concentrations in pediatric patients less than 5 years of age were similar to the concentrations in older children and adults.

Distribution

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total volume of distribution (Vss) was 251 ± 140 mL/kg (range: 97 to 598 mL/kg).

Elimination

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 83.6 ± 43.2 mL/hr/kg (range: 38.3 to 184mL/hr/kg); the mean ± standard deviation of the elimination half-life (t1/2) was 2.33 ± 0.75 hours (range: 0.86 to 3.03 hours). The inter-subject variability (coefficient of variation) in total clearance (CL) was 52%.

Metabolism

Vestronidase alfa-vjbk is a recombinant human enzyme and is therefore eliminated by proteolytic degradation into small peptides and amino acids.

Excretion

No excretion studies have been conducted in humans. Vestronidase alfa-vjbk is not expected to be eliminated through renal or fecal excretion.

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate the mutagenic potential have not been performed with vestronidase alfa-vjbk.

Vestronidase alfa-vjbk at intravenous doses up to 20 mg/kg administered weekly to rats prior to mating and after mating on gestation days 6, 9, 12, 15 and 18 (females), [approximately up to 4.5 times (male rats) and 1.6 times (female rats) the human AUC0-t of 3440 mcg*min/mL at the 4 mg/kg dose administered once every other week] was found to have no adverse effect on fertility and reproductive performance of male and female rats.