VPRIV: Indications, Dosage, Precautions, Adverse Effects
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VPRIV - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Gaucher Disease
Class: Lysosomal enzymes
Form: Intravenous (IV), Powder
Ingredients: velaglucerase alfa, citric acid monohydrate, polysorbate 20, sodium citrate dihydrate, and sucrose

velaglucerase alfa

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Intravenous (IV) Powder for solution for injection/ 400 U/vial None
For a complete listing see Dosage Forms, Composition and Packaging section.

After reconstitution with sterile water for injection, each vial contains 100 U/mL. VPRIV is dosed by units (U/kg), where one unit (U) of enzyme activity is defined as the quantity of enzyme required to convert one micromole of p-nitrophenyl-ß-D-glucopyranoside to p-nitrophenol per minute at 37ºC.

Description

Velaglucerase alfa is produced by gene activation technology in a human cell line. Velaglucerase alfa is a glycoprotein with the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. Velaglucerase alfa catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide in the lysosome.

Indications and Clinical Use

VPRIV (velaglucerase alfa) is indicated for

  • long-term enzyme replacement therapy (ERT) for pediatric and adult patients with type 1 Gaucher disease.

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

Warnings and Precautions

General

No studies of VPRIV on the effects on the ability to drive and use machines have been performed.

Hypersensitivity Reactions

Immune

Hypersensitivity reactions including symptoms consistent with anaphylaxis have been reported in patients in clinical studies and in post-marketing experience. As with any intravenous protein product, hypersensitivity reactions are possible, therefore appropriate medical support should be readily available when VPRIV is administered. If a severe reaction occurs, current medical standards for emergency treatment are to be followed.

Treatment with VPRIV should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the active ingredient or excipients in the drug product or to other enzyme replacement therapy.

Infusion-Related Reactions

Infusion-related reactions, the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies, occurred in 28/54 (51.9%) of patients who were naïve to therapy and in 9/40 (22.5%) of patients who switched from imiglucerase to VPRIV. Most of the infusion-related reactions were mild. The most commonly observed symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia/body temperature increased. In treatment-naïve patients, the majority of infusion-related reactions occurred during the first 6 months of treatment with VPRIV. Additional infusion-related reactions of chest discomfort, dyspnea, and pruritis have been reported in post-marketing experience.

The management of infusion-related reactions should be based on the severity of the reaction, e.g. slowing the infusion rate, treatment with medications such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion time.

Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to infusion of VPRIV during clinical studies.

Immunogenicity

In clinical studies, 1 of 94 (1%) patients treated with VPRIV developed IgG-class antibodies to velaglucerase alfa. In this one event the antibodies were determined to be neutralizing in an in vitro assay. No infusion-related reactions were reported for this patient. It is unknown if the presence of IgG antibodies to velaglucerase alfa is associated with a higher risk of infusion reactions. No patients developed IgE antibodies to velaglucerase alfa.

Carcinogenesis and Mutagenesis

See Toxicology.

Hepatic/ Biliary/Pancreatic

No studies have been performed in patients with hepatic impairment.

Renal

No studies have been conducted in patients with renal impairment.

Special Populations

Pregnant Women

There are no data from studies in pregnant women and there are limited data from the use of VPRIV in pregnant women. It is not known whether VPRIV would cause fetal harm when administered to a pregnant woman or would affect reproductive capacity. VPRIV should be administered during pregnancy only when clearly needed.

In Segment I, II, and III animal reproductive and developmental toxicology studies (see Toxicology) in rats and rabbits, the no observed effect level/no observed adverse effect level (NOEL/NOAEL) for velaglucerase alfa was the maximum dose evaluated: 17 mg/kg/dose for rats and 20 mg/kg/dose in rabbits, equal to 11-fold and 13-fold the maximum human dose of 60 U/kg on a milligrams-per-kilogram (mg/kg) basis. Velaglucerase alfa showed no evidence of impaired fertility or maternal or developmental treatment-related effects.

Nursing Women

There are no data from studies in lactating women. It is unknown if VPRIV is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VPRIV is administered to a lactating woman.

Pediatrics (2 - 17 years of age)

Twenty (20) of the 94 patients (21%) who received VPRIV during clinical studies were in the pediatric age range (2 to 17 years). No data are available from children under the age of 4 years. The safety and efficacy profiles were similar between pediatric and adult patients.

Table 1 - Age Distribution of Pediatric Patients (2 to 17 years) by Clinical Trial
Study
Age (years) 032 034 039
4 1
6 2
7 1 1
9 1 1 1
10 1
12 1
13 2
14 3 2
15 1
16 1 1

Geriatrics (>65 years of age)

In clinical studies, a total of 57 patients 65 years of age or older were treated with velaglucerase alfa. Among 205 patients who participated in a clinical safety study and switched from imiglucerase to velaglucerase alfa, 52 patients were 65 years of age or older. The safety profile in elderly patients was consistent with that previously observed across pediatric and adult patients.

Monitoring and Laboratory Tests

No special laboratory tests are required for patients receiving VPRIV other than the usual tests that are required for monitoring patients with type 1 Gaucher disease.

Adverse Reactions

Adverse Drug Reaction Overview

Adverse drug reactions (ADR) are listed in Table 2. Information is presented by system organ class and frequency (very common ≥10%; common ≥1% and <10%). Within each frequency grouping, undesirable effects are presented by preferred term in order of decreasing seriousness.

The most common adverse reactions were infusion-related reactions. The only adverse reaction leading to discontinuation of VPRIV was an infusion-related reaction.

Table 2 - Adverse Drug Reactions Reported with VPRIV in Patients with Type 1 Gaucher Disease 1
System Organ Class
Incidence Category
Adverse Drug Reaction
(Preferred Term)
Nervous system disorders
Very common dizziness, headache
Gastrointestinal disorders
Very common abdominal pain/abdominal pain upper
Common nausea
Musculoskeletal and connective tissue disorders
Very common arthralgia, back pain, bone pain
Investigations
Common activated partial thromboplastin time prolonged, neutralizing antibody positive
General disorders and administration site conditions
Very common asthenia/fatigue,infusion-related reaction, pyrexia/body temperature increased
Vascular disorders
Common flushing, hypertension, hypotension
Cardiac disorders
Common tachycardia
Skin and subcutaneous tissue disorders
Common rash, urticaria
Immune system disorders
Common hypersensitivity reactions§

1 Changes reflect actual calculation

See Warnings and Precautions, Immune

Reactions occurring up to 24 hours after the start of the infusion

§ Includes dermatitis and anaphylactoid reaction

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The data described below reflect exposure of 94 patients with type 1 Gaucher disease who received VPRIV at doses ranging from 15 to 60 U/kg every other week in 5 clinical studies. Fifty-four (54) patients were naïve to ERT and 40 patients switched from imiglucerase to VPRIV. Patients were between 4 and 71 years old at the time of first treatment with VPRIV, and included 46 male and 48 female patients.

The most serious adverse reactions in patients in clinical trials were hypersensitivity reactions. See Warnings and Precautions, Immune and Adverse Reaction Overview, Table 2.

Adverse drug reactions considered related to VPRIV are shown in Table 3.

Table 3 - Adverse Drug Reactions Reported in Patients with Type 1 Gaucher Disease Treated With VPRIV During Clinical Trials
System Organ Class
Preferred Term
Naïve to ERT N = 54 Switched from imiglucerase to VPRIV N = 40
Number of Patients (% )
Nervous system disorders
Headache 19 (35.2) 12 (30.0)
Dizziness 12 (22.2) 3 (7.5)
Gastrointestinal disorders
Abdominal pain/abdominal pain upper 10 (18.5) 6 (15)
Nausea 3 (5.6) 4 (10.0)
Musculoskeletal and connective tissue disorders
Bone pain 13 (24.1) 1 (2.5)
Arthralgia 12 (22.2) 9 (22.5)
Back pain 9 (16.7) 7 (17.5)
Infections and Infestations
Upper respiratory tract infections 17 (31.5) 12 (30.0)
Investigations
Activated partial thromboplastin time prolonged 6 (11.1) 2 (5.0)
Neutralizing antibody positive 1 (1.9) 0 (0.0)
General disorders and administration site conditions
Infusion-related reaction 28 (51.9) 9 (22.5)
Asthenia/fatigue 8 (14.8) 5 (12.5)
Pyrexia/body temperature increased 14 (25.9) 5 (12.5)
Vascular disorders
Hypertension 4 (7.4) 3 (7.5)
Hypotension 4 (7.4) 0 (0.0)
Flushing 0 (0.0) 1 (2.5)
Cardiac disorders
Tachycardia 2 (3.7) 0 (0.0)
Skin and subcutaneous tissue disorders
Rash 2 (3.7) 1 (2.5)
Urticaria 2 (3.7) 1 (2.5)
Immune system disorders
Hypersensitivity reactions 2 (3.7) 1 (2.5)

In clinical studies, 1 of 94 patients treated with VPRIV developed IgG-class antibodies to velaglucerase alfa. In this one event the antibodies were determined to be neutralizing in an in vitro assay. No infusion-related reactions were reported for this patient. It is unknown if the presence of IgG antibodies to velaglucerase alfa is associated with a higher risk of infusion reactions. No patients developed IgE antibodies to velaglucerase alfa.

Post-market Adverse Drug Reactions

The following adverse reactions have been identified during post approval use of VPRIV. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders and Administration Site Conditions: Chest discomfort

Immune System Disorders: Anaphylactic reaction

Respiratory, Thoracic and Mediastinal Disorder: Dyspnea

Skin and Subcutaneous Tissue Disorders: Pruritis

Drug Interactions

No serious drug interactions have been reported.

Overview

Velaglucerase alfa is a purified form of the naturally occurring enzyme glucocerebrosidase; it is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

Drug-Drug Interactions

Interactions with other drugs have not been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

VPRIV should be administered under the supervision of a healthcare professional. Home administration may be considered for patients who are tolerating their infusions well.

  • Patients currently being treated with other enzyme replacement therapy for type 1 Gaucher disease may be switched to VPRIV using the same dose and frequency.

Recommended Dose and Dosage Adjustment

The recommended dose is 60 U/kg administered every other week as a 60-minute intravenous (IV) infusion.

Dosage adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 U/kg every other week.

Missed Dose

If a scheduled infusion is missed, administer the dose as soon as possible if it can be given at least 7 days before the next scheduled dose.

Administration

VPRIV should be administered by IV infusion over a period of 60 minutes.

Reconstitution

VPRIV should be prepared by and administered under the supervision of a healthcare professional.

Use aseptic technique.

VPRIV is a lyophilized powder, which requires reconstitution and dilution, and is intended for intravenous infusion only. VPRIV contains no preservatives and vials are single-use only. Discard any unused solution.VPRIV should be prepared as follows:

  1. Determine the number of vials to be reconstituted based on the individual patient’s weight and the prescribed dose. Follow the instructions in Table 4 for reconstitution.
    Table 4 - Reconstitution Instructions
    Vial Size Volume of Diluent to be Added to Vial Approximate Available Volume Nominal Concentration per mL
    400 U/vial 4.3 mL 4.0 mL 100 U/mL
  2. Upon reconstitution, mix vials gently. DO NOT SHAKE.
  3. Prior to further dilution, visually inspect the solution in the vials; the solution should be clear to slightly opalescent and colorless; do not use if the solution is discolored or if foreign particles are present.
  4. Withdraw the calculated volume of drug from the appropriate number of vials and dilute the total volume required in 100 mL of 0.9% sodium chloride solution suitable for IV administration. Mix gently. DO NOT SHAKE. Slight flocculation (described as white irregularly shaped particles) may occasionally occur.

VPRIV should be administered through a 0.2 μm in-line filter over a period of 60 minutes. The infusion should be completed within 24 hours of reconstitution of vials. VPRIV should not be infused with other products in the same infusion tubing as the compatibility in solution with other products has not been evaluated.

Overdosage

There is no experience with overdosage of VPRIV in humans.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency causes an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or "Gaucher cells". In this lysosomal storage disorder (LSD), clinical features are reflective of the distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation of glucocerebrosidase in the liver and spleen leads to organomegaly. Bone involvement results in skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and splenic sequestration lead to clinically significant anemia and thrombocytopenia.

Velaglucerase alfa, the active ingredient in VPRIV, supplements or replaces beta-glucocerebrosidase, the enzyme that catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease.

Pharmacodynamics

The active ingredient of VPRIV is velaglucerase alfa which is produced by gene activation technology in a human cell line. Velaglucerase alfa is a glycoprotein; the monomer is approximately 63 kDa, has 497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme glucocerebrosidase.

Velaglucerase alfa is manufactured to contain predominantly high mannose-type N-linked glycans. There are 5 potential N-linked glycosylation sites; four of these sites are occupied. This modification facilitates internalization of the enzyme by the phagocytic target cells via the mannose receptor. Velaglucerase alfa catalyzes the hydrolysis of the glycolipid glucocerebrosidase to glucose and ceramide in the lysosome.

Pharmacokinetics

The pharmacokinetic (PK) characteristics of VPRIV at doses of 15, 30, 45, and 60 U/kg were evaluated in a total of 37 patients with type 1 Gaucher disease receiving 60-minute intravenous infusions every other week (EOW) in 3 clinical studies for up to 2 years (see Table 5).

At all doses, velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusion before leveling off, and Cmax was typically attained between 40 and 60 minutes after the start of the infusion. Tmax values for individual subjects ranged from 20 to 65 minutes after the start of infusion with one exception; one subject had an anomalous pharmacokinetic profile with a Tmax of 5 minutes. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in a monophasic or biphasic fashion with a mean t1/2 ranging from 5 to 12 minutes for the 15, 30, 45, and 60 U/kg doses.

Velaglucerase alfa exhibited an approximately linear (i.e., first-order) pharmacokinetic profile, and Cmax and AUC increased approximately proportional to the dose. The high clearance of velaglucerase alfa from serum (mean 6.7 to 7.6 mL/min/kg in Study 032) is consistent with the rapid uptake of velaglucerase alfa into macrophages via mannose receptors.

For the 2 dose groups in Study 032, the range of velaglucerase alfa clearance in pediatric patients (n=7, age range 4 to 17 years) was contained within the range of clearance values in adult patients (n=15, age range 19 to 62 years). Additionally, there were no apparent pharmacokinetic differences between male and female patients with type 1 Gaucher disease in this study.

None of the subjects were positive for anti-velaglucerase alfa antibodies on the days of pharmacokinetic evaluation. Therefore, it was not possible to evaluate the effect of antibody response on the pharmacokinetic profile of velaglucerase alfa.

Table 5 - Pharmacokinetic Profile of Velaglucerase alfa in Treatment-Naïve Patients with Type 1 Gaucher Disease
Study Dose
(EOW)
Total Weeks on Treatment N t½
(min)
CL
(mL/min/kg)
Vss
(% B.W.)
025 15 U/kg 1 3 5.3 ± 1.3 10.1 ± 2.3 7.5 ± 0.9
30 U/kg 3 2 10.3 ± 1.0 13.1 ± 4.9 19.7 ± 8.9
60 U/kg 1 or 5 11 9.8 ± 2.8 12.6 ± 3.7 17.5 ± 5.1
60 U/kg 37 or 39 8 6.8 ± 1.5 5.6 ± 4.0 5.4 ± 3.7
025EXT 30 U/kg 105 9 8.9 ± 2.2 6.5 ± 2.0 8.3 ± 2.0
32 45 U/kg 1 10 12.4 ± 3.1 7.0 ± 2.6 10.4 ± 6.6
45 U/kg 37 10 11.9 ± 5.5 7.6 ± 3.6 10.8 ± 5.9
60 U/kg 1 12 11.5 ± 3.5 7.2 ± 3.5 10.6 ± 6.0
60 U/kg 37 12 11.4 ± 3.2 6.7 ± 2.9 8.2 ± 3.9

Values are mean ± SD

n=9

Storage and Stability

VPRIV should be stored in a refrigerator at 2 to 8ºC (36 to 46ºF).

Do not use VPRIV after the expiration date on the vial. Do not freeze. Protect from light.

Special Handling Instructions

VPRIV should be administered through a 0.2μm in-line filter over a period of 60 minutes. The infusion should be completed within 24 hours of reconstitution of vials. VPRIV should not be infused with other products in the same infusion tubing as the compatibility in solution with other products has not been evaluated.

As VPRIV contains no preservatives, once reconstituted the product should be used immediately. If immediate use is not possible, the reconstituted or diluted product may be stored for up to 24 hours at 2 to 8ºC (36 to 46ºF). The infusion should be completed within 24 hours of reconstitution of vials.

Dosage Forms, Composition and Packaging

VPRIV is a sterile, preservative free, lyophilized powder requiring reconstitution and further dilution prior to use (see Special Handling Instructions). It is supplied in individually packaged glass vials, which are closed with a butyl rubber stopper with a fluoro-resin coating and are sealed with an aluminum overseal with a flip-off plastic cap. The vials are intended for single use only.

VPRIV is available in vials containing 400 U each.

VPRIV is available in a pack size of 1 vial per carton.

The following is a list of excipients used in the VPRIV formulation:

Citric acid monohydrate.

Polysorbate 20.

Sodium citrate dihydrate.

Sucrose.