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(vestronidase alfa-vjbk) Injection, for Intravenous Use
Anaphylaxis has occurred with MEPSEVII administration, as early as the first
dose [see WARNINGS AND PRECAUTIONS], therefore appropriate medical
support should be readily available when MEPSEVII is administered.
Closely observe patients during and for 60 minutes after MEPSEVII infusion
[seeDOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS].
Immediately discontinue the MEPSEVII infusion if the patient experiences
anaphylaxis [seeDOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS].
Vestronidase alfa-vjbk is a recombinant human lysosomal beta glucuronidase which is a purified
human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line.
Purified vestronidase alfa-vjbk exists as a homotetramer, with each monomer consisting of 629 amino
acids. The calculated isotope average molecular mass of each non-glycosylated peptide chain is
The amino acid sequence for vestronidase alfa-vjbk is the same as the amino acid sequence for
human beta-glucuronidase (GUS).
MEPSEVII (vestronidase alfa-vjbk) injection for intravenous infusion is a sterile, preservative-free,
non-pyrogenic, colorless to slightly yellow liquid supplied in a single-dose vial. Each mL of solution
contains vestronidase alfa-vjbk (2 mg), L-histidine (3.1 mg), polysorbate 20 (0.1 mg), sodium chloride
(7.88 mg) and sodium phosphate monobasic dihydrate (3.12 mg). The pH of the solution is 6.0.
Indications & Dosage
MEPSEVII is indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII
(MPS VII, Sly syndrome).
Limitations Of Use
The effect of MEPSEVII on the central nervous system manifestations of MPS VII has not been
DOSAGE AND ADMINISTRATION
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 Premedication].
The recommended dosage of MEPSEVII is 4 mg/kg administered by intravenous infusion every two
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 Administration Instructions].
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 Administration Instructions].
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].
Discontinue the infusion immediately if the patient experiences a severe systemic reaction,
including anaphylaxis [see WARNINGS AND PRECAUTIONS].
Prepare MEPSEVII according to the following steps using aseptic technique:
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):
Total dose (mg) = Patient’s weight (kg) x 4 mg/kg (recommended dose)
Total number of vials = Total dose (mg) divided by 10 mg/vial
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.
Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mL
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.
For a 1:1 dilution, prepare the solution at room temperature, as follows:
Select an empty infusion bag, sized upon the total volume of the final solution.
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.
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.
Slowly add MEPSEVII to the infusion bag using care to avoid agitation, ensuring liquid
to liquid contact without generating bubbles or turbulence.
Add 0.9% Sodium Chloride Injection, USP equal to the volume of MEPSEVII to the
Gently rock the infusion bag to ensure proper distribution of MEPSEVII. Do not shake
Administer MEPSEVII as follows:
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.
Use an infusion set equipped with an in-line, low-protein binding 0.2 micron filter to administer
the diluted MEPSEVII solution.
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.
Do not infuse with other products in the infusion tubing. Compatibility with other products has
not been evaluated.
Use MEPSEVII immediately after dilution and complete the infusion within 42 hours from the
time of dilution. Discard any unused product.
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
Table 1. Recommended Infusion Rate Schedule by Patient Weight for Administration of
MEPSEVII at Recommended Dose of 4 mg/kg
Drug and diluent
(infused over 4
for 1st Hour
Infusion Rate per
Dosage Forms And Strengths
Injection: 10 mg/5 mL (2 mg/mL) as a colorless to slightly yellow liquid in a single-dose vial.
Storage And Handling
MEPSEVII (vestronidase alfa-vjbk) injection is a colorless to slightly yellow liquid supplied as a carton
containing one 10 mg/5 mL (2 mg/mL) single-dose vial (NDC 69794-001-01).
Store under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light.
Manufactured by: Ultragenyx Pharmaceutical Inc. Novato, CA 94949. Revised: Nov 2017
Heart Disease: Causes of a Heart AttackSee Slideshow
Side Effects & Drug Interactions
The following serious adverse reactions are described below and elsewhere in the labeling:
Anaphylaxis [see WARNINGS AND PRECAUTIONS]
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 164 weeks.
Nineteen patients were younger than 18 years of age. Of these 23 patients, 20 patients were
evaluable for adverse reactions and 23 patients were evaluable for immunogenicity.
Adverse Reactions From The Randomized Start Trial
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].
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.
Table 2. Adverse Reactions in Patients with MPS VII in Study 301
n (Incidence Rate*)
n (Incidence Rate*)
Infusion site extravasation
Infusion site swelling
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
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.
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 to vestronidase alfa-vjbk with the incidence of antibodies to other products may be
Immunogenicity data were available from 23 patients. Eighteen out of 23 patients (78%) developed
anti-vestronidase alfa-vjbk antibodies (ADA). Ten of the 18 (55.6%) ADA-positive patients developed
neutralizing antibodies (NAb) on at least one occasion. There is no correlation between ADA titer and
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 in two patients and 364-fold in the third patient.
The presence of ADA titer does not appear to affect reduction in the pharmacodynamic marker,
urinary glycosaminoglycans (uGAGs), as assessed in clinical trials.
No Information Provided
Warnings & Precautions
Included as part of the "PRECAUTIONS" Section
Anaphylaxis to MEPSEVII was reported in 2 of 20 patients in the clinical program [see ADVERSE REACTIONS]. 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,
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.
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.
Use In Specific Populations
There are no available data on MEPSEVII use in pregnant women to determine a drug-associated
risk of adverse developmental outcomes. In animal reproduction studies, vestronidase alfa-vjbk
administered intravenously to pregnant rats and rabbits during the period of organogenesis showed
no maternal toxicity or adverse developmental outcomes at doses causing maternal serum exposures
(AUC) up to 1.6 and 10 times, respectively for rats and rabbits, the exposure at the recommended
human dose (see Data).
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.
In animal reproduction 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.
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.
The safety and effectiveness of MEPSEVII have been established in pediatric patients less than 18
years of age [see ADVERSE REACTIONS , Clinical Studies].
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.
Overdosage & Contraindications
No Information Provided
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
In all patients evaluated, MEPSEVII treatment resulted in reduction of urinary excretion of GAGs
including chondroitin sulfate and dermatan sulfate, which was sustained with continued treatment.
The pharmacokinetics of vestronidase alfa-vjbk were evaluated in a total of 19 MPS VII patients
including 15 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 20.0 ± 8.1 mcg/mL (range: 6.6 to 34.9 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 3440 ± 1430 mcg*min/mL (range: 1130 to 5820 mcg*min/mL).
Vestronidase alfa-vjbk concentrations in pediatric patients less than 5 years of age were similar to the
concentrations in older children and adults.
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 260 ± 130 mL/kg (range: 97 to 598 mL/kg).
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard
deviation of the total clearance (CL) was 1.3 ± 0.7 mL/min/kg (range: 0.6 to 3.3 mL/min/kg); the mean
± standard deviation of the elimination half-life (t1/2) was 155 ± 37 minutes (range: 51 to 213 minutes).
The inter- and intra-subject variability (coefficient of variation) in total clearance (CL) was 59% and
Vestronidase alfa-vjbk is a recombinant human enzyme and is therefore eliminated by proteolytic
degradation into small peptides and amino acids.
No excretion studies have been conducted in humans. Vestronidase alfa-vjbk is not expected to be
eliminated through renal or fecal excretion.
The clinical program for MEPSEVII included 23 patients with MPS VII, 17 of whom were evaluable for
efficacy, 20 for safety, and 23 for immunogenicity. Patients were enrolled in clinical trials and
expanded access protocols receiving treatment at doses up to 4 mg/kg once every two weeks for up
to 164 weeks. The patients ranged in age from 5 months to 25 years. Sixteen patients were younger
than 18 years of age.
Studies 301 And 202
Study UX003-CL301 (referred to as Study 301, NCT02230566) was a randomized start trial of
MEPSEVII 4 mg/kg every two weeks in patients with MPS VII. Twelve patients were randomized to
one of four placebo durations before crossing over to active treatment. Three patients received
MEPSEVII immediately for a duration of 48 weeks, 3 patients received placebo for 8 weeks then
MEPSEVII for 40 weeks, 3 patients received placebo for 16 weeks then MEPSEVII for 32 weeks, and
3 patients received placebo for 24 weeks then MEPSEVII for 24 weeks. Of the 12 patients enrolled in
the trial, 4 were male and 8 were female and ranged in age from 8 to 25 years (median 14 years).
Nine patients were younger than 18 years of age. The majority of the patients were white (75%), with
50% of Hispanic or Latino ethnicity. Patients who were enrolled in Study 301 were eligible to roll over
to Study UX003-CL202 (referred to as Study 202, NCT02432144), an open-label extension trial in
which patients received additional doses of MEPSEVII at 4 mg/kg intravenously every other week for
up to 124 weeks.
In Study 301, motor function, forced vital capacity, and visual acuity were assessed after 24 weeks of
MEPSEVII treatment and measured against pre-specified minimal important differences. The
extremely small population of patients with MPS VII globally necessitated the enrollment of all
patients able to participate resulting in a highly heterogeneous group. Clinical endpoints were not
assessable in some patients due to their extent of disease, age or level of cognition. Repeated
assessments of the six minute walk test (6MWT) were feasible in ten of 12 patients and are described
further below. Of the three patients who improved on their 6MWT (Figure 1, left panel), two also were
noted to have improvement in balance and gross motor proficiency as assessed by the Bruininks-
Oseretsky Test of Motor Proficiency (BOT-2).
In this trial, the mean difference in 6MWT distance between MEPSEVII and placebo treatment
periods in patients able to perform the test at baseline and subsequent visits through Week 24 is
shown in Table 3. The mean difference in 6MWT distance increases with increased treatment
duration, however, due to the small size of the trial, standard errors are large.
Table 3. Mean Difference in 6MWT Distance (meters) Between MEPSEVII and Placebo
Treatment (Study 301) in Patients with MPS VII
Duration of MEPSEVII
LS mean 6MWT (meters)
(± Standard Error)*
Number and Treatment Assignment of
Patients Included in Analyis**
-11 (± 24)
5 placebo period; 8 MEPSEVII period
13 (± 32)
5 placebo period; 8 MEPSEVII period
18 (± 33)
5 placebo period; 8 MEPSEVII period
*ANCOVA analysis of change from baseline in least squares (LS) mean between placebo and MEPSEVII for different
periods, after adjusting for study cohort, age, and baseline 6MWT distance. Patients who used assistive devices were
imputed as zeros in the analysis.
**Number and treatment assignment of patients included in the analysis was based upon a randomized start trial design
and patient ability to complete testing. Due to no placebo period for the three patients who received 48 weeks of
MEPSEVII in the first cohort of the randomized start design, more data were available for analyses during the treatment
period (n=8) than during the placebo period (n=5). While data from 8 participants were available at each time point, due to
missing observations, the 8 participants were not the same across all time points.
The observed individual 6MWT distances for the 10 patients who could perform the test in Study 301
and Study 202 through Week 120 are presented in Figure 1. The course of three patients with
improvement in distance walked of at least 60 meters compared to the start of MEPSEVII treatment
(Week 0) is shown in the left panel; the relatively stable course in the remaining seven patients,
including those who used assistive devices, is shown in the right panel.
Figure 1. 6MWT Distance for MPS VII Patients in Studies 301 and 202
Patient 10 did not use an assistive device at baseline but started using an assistive device post-baseline from Treatment
Week 8. Patients 6 and 9 consistently used an assistive device at all visits. A solid line indicates the unassisted
assessments and a dotted line indicates the assisted assessments.
Liver And Spleen Volume
In Study 301, imaging by MRI or ultrasound to assess liver and spleen volume was performed in
seven of the 12 patients. Most liver volumes were normal or below normal size at baseline (mean
1,591 mL, range 742 to 2,207 mL), and on average were unchanged after treatment (mean 1,459 mL,
range 876 to 1,851 mL).
Spleen volumes generally were normal or below normal size at baseline (mean 325 mL, range 131 to
491 mL) and on average were unchanged after treatment (mean 360 mL, range 200 to 582 mL).
Study UX003-CL201 (referred to as Study 201, NCT01856218) was a single arm, open-label, dose
exploration trial completed outside the United States that enrolled three MPS VII patients, ranging in
age from 5 years to 25 years. Two patients were male; two patients were white and one was Asian.
After 120 weeks of exposure to MEPSEVII, one patient demonstrated a 21% improvement over
baseline in forced vital capacity (FVC% predicted) on pulmonary function testing in addition to a 105
meter improvement in the 6MWT. Two other patients with baseline hepatosplenomegaly had
reduction in liver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of
Expanded access to MEPSEVII treatment was provided to a pediatric patient with MPS VII who
required continuous ventilatory support at the start of treatment and was subsequently able to tolerate
9 hours daily off ventilator support after 164 weeks of MEPSEVII treatment.
Advise patients and caregivers that anaphylaxis has occurred with MEPSEVII administration. Inform
patients of the signs and symptoms of anaphylaxis, and have them seek immediate medical care
should signs and symptoms occur [see WARNINGS AND PRECAUTIONS].