Vestronidase alfa

Vestronidase alfa
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Black Box Warning

ANAPHYLAXIS See full prescribing information for complete Boxed Warning. Anaphylaxis has occurred with vestronidase alfa administration, as early as the first dose, therefore appropriate medical support should be readily available when vestronidase alfa is administered. Closely observe patients during and for 60 minutes after vestronidase alfa infusion. Immediately discontinue the vestronidase alfa infusion if the patient experiences anaphylaxis.

Overview

Vestronidase alfa is a recombinant human lysosomal beta glucuronidase that is FDA approved for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome) in pediatric and adult patients. There is a Black Box Warning for this drug as shown here. Common adverse reactions include infusion site extravasation, diarrhea, rash, anaphylaxis, infusion site swelling, peripheral swelling and pruritus.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dosage

• Vestronidase alfa 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.
• The recommended dosage of vestronidase alfa 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.

This image is provided by the National Library of Medicine.

Dosage Forms and Strengths

• Injection: 10 mg/5 mL (2 mg/mL) as a colorless to slightly yellow liquid in a single-dose vial.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding vestronidase alfa Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding vestronidase alfa Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Recommended Dosage

• Vestronidase alfa 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.
• The recommended dosage of vestronidase alfa 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.

This image is provided by the National Library of Medicine.

Dosage Forms and Strengths

• Injection: 10 mg/5 mL (2 mg/mL) as a colorless to slightly yellow liquid in a single-dose vial.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding vestronidase alfa Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding vestronidase alfa Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

• None.

Warnings

ANAPHYLAXIS See full prescribing information for complete Boxed Warning. Anaphylaxis has occurred with vestronidase alfa administration, as early as the first dose, therefore appropriate medical support should be readily available when vestronidase alfa is administered. Closely observe patients during and for 60 minutes after vestronidase alfa infusion. Immediately discontinue the vestronidase alfa infusion if the patient experiences anaphylaxis.

Anaphylaxis

• Anaphylaxis to vestronidase alfa was reported in 2 of 20 patients in the clinical program. These reactions occurred during vestronidase alfa infusion and were observed as early as the first dose of vestronidase alfa for one patient. Manifestations included respiratory distress, cyanosis, decreased oxygen saturation, and hypotension. The two patients with anaphylaxis to vestronidase alfa during the clinical trials had one occurrence each and tolerated subsequent infusions of vestronidase alfa, without recurrence.
• Anaphylaxis can be life-threatening. Vestronidase alfa should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Patients should be observed for 60 minutes after vestronidase alfa administration. If severe systemic reactions occur, including anaphylaxis, immediately discontinue the vestronidase alfa 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 vestronidase alfa following anaphylaxis.

Adverse Reactions

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 vestronidase alfa clinical program included 23 patients aged 5 months to 25 years who received treatment with vestronidase alfa 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.
• Adverse reactions in Table 2 occurred in one or more patients treated with vestronidase alfa 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.

This image is provided by the National Library of Medicine.

Febrile Convulsion

• One patient receiving a dose of 4 mg/kg experienced a febrile convulsion during vestronidase alfa 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.

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 to vestronidase alfa-vjbk with the incidence of antibodies to other products may be misleading.
• 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 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 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.

Postmarketing Experience

There is limited information regarding Vestronidase alfa Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Vestronidase alfa Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• There are no available data on vestronidase alfa 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.
• 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)

• 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vestronidase alfa in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Vestronidase alfa during labor and delivery.

Nursing Mothers

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 vestronidase alfa and any potential adverse effects on the breastfed infant from vestronidase alfa-vjbk or from the underlying maternal condition.

Pediatric Use

• The safety and effectiveness of vestronidase alfa have been established in pediatric patients less than 18 years of age.

Geriatic Use

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

Gender

There is no FDA guidance on the use of Vestronidase alfa with respect to specific gender populations.

Race

There is no FDA guidance on the use of Vestronidase alfa with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Vestronidase alfa in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Vestronidase alfa in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Vestronidase alfa in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Vestronidase alfa in patients who are immunocompromised.

Administration and Monitoring

Administration

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 vestronidase alfa infusion.
• Observe patients closely during the infusion and following the infusion for a minimum of 60 minutes for the development of anaphylaxis.
• Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis.

Preparation Instructions

• Prepare vestronidase alfa 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 concentration

• The final solution will be a 1:1 dilution of vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa to the infusion bag.
• Gently rock the infusion bag to ensure proper distribution of vestronidase alfa. Do not shake the solution.

Administration Instructions

• Administer vestronidase alfa 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 vestronidase alfa solution.
• Do not flush the line containing vestronidase alfa 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 vestronidase alfa 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).

This image is provided by the National Library of Medicine.

Monitoring

• Improvement in a 6-minute walking test and pulmonary function may indicate efficacy.
• Anaphylaxis: Closely during infusion and for at least 60 minutes afterward.

IV Compatibility

There is limited information regarding the compatibility of Vestronidase alfa and IV administrations.

Overdosage

There is limited information regarding Vestronidase alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Vestronidase alfa Pharmacology in the drug label.

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.

Structure

(Description with picture)

Pharmacodynamics

• In all patients evaluated, vestronidase alfa treatment resulted in reduction of urinary excretion of GAGs including chondroitin sulfate and dermatan sulfate, which was sustained with continued treatment.

Pharmacokinetics

• 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 (C_max) 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 (AUC_0-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.

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 (V_ss) was 260 ± 130 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 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 (t_1/2) 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 13%, respectively.

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.

Nonclinical Toxicology

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 AUC_0-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.

Clinical Studies

• The clinical program for vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa immediately for a duration of 48 weeks, 3 patients received placebo for 8 weeks then vestronidase alfa for 40 weeks, 3 patients received placebo for 16 weeks then vestronidase alfa for 32 weeks, and 3 patients received placebo for 24 weeks then vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa 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 vestronidase alfa 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.

This image is provided by the National Library of Medicine.

• 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 vestronidase alfa 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.

This image is provided by the National Library of Medicine.

• 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).

Other Investigations

• 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 vestronidase alfa, 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 vestronidase alfa treatment.
• Expanded access to vestronidase alfa 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 vestronidase alfa treatment.

How Supplied

• Vestronidase alfa 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).

Storage

• Store under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light.

Images

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Patient Counseling Information

Anaphylaxis

• Advise patients and caregivers that anaphylaxis has occurred with vestronidase alfa administration. Inform patients of the signs and symptoms of anaphylaxis, and have them seek immediate medical care should signs and symptoms occur.

Precautions with Alcohol

Alcohol-Vestronidase alfa interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Mepsevii

Look-Alike Drug Names

There is limited information regarding Vestronidase alfa Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.