VPRIV- velaglucerase alfa injection, powder, lyophilized, for solution
Takeda Pharmaceuticals America, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VPRIV safely and effectively. See full prescribing information for VPRIV.
VPRIV® (velaglucerase alfa) for injection, for intravenous use
Initial U.S. Approval: 2010
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
VPRIV is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions Including Anaphylaxis:
Most common adverse reactions (≥ 10%) are: hypersensitivity reactions, headache, dizziness, abdominal pain, nausea, back pain, joint pain, prolonged activated PTT, fatigue/asthenia, and pyrexia (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
VPRIV is indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease.
VPRIV should be administered under the supervision of a healthcare professional. The recommended starting VPRIV dosage in naïve adults and naïve pediatric patients 4 years of age and older is 60 Units/kg administered every other week as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient's therapeutic goals.
Adults and pediatric patients 4 years of age and older currently being treated on a stable dosage of imiglucerase for type 1 Gaucher disease may be switched to VPRIV by starting treatment with VPRIV at the previous imiglucerase dosage two weeks after the last imiglucerase dose. VPRIV should be administered under the supervision of a healthcare professional as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient's therapeutic goals.
VPRIV is a lyophilized powder, which requires reconstitution and dilution, using sterile technique, prior to intravenous infusion. VPRIV should be prepared as follows:
Consider pre-treatment with antihistamines and/or corticosteroids in patients who exhibited symptoms of hypersensitivity associated with prior velaglucerase alfa product infusions. Appropriate medical support should be readily available when VPRIV is administered [see Warnings and Precautions (5.1)].
For injection: 400 units of a sterile, white to off-white, lyophilized powder in single-dose vials for reconstitution and dilution.
Hypersensitivity reactions, including anaphylaxis, occurred in clinical studies and postmarketing experience [see Adverse Reactions (6.1)]. Hypersensitivity reactions were the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies. Patients were not routinely pre-medicated prior to infusion of VPRIV during clinical studies. The most commonly observed symptoms of hypersensitivity reactions were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia/body temperature increased. Generally the reactions were mild and, in treatment-naïve patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Additional hypersensitivity reactions of chest discomfort, dyspnea, pruritus and vomiting have been reported in post-marketing experience.
As with any intravenous protein product, hypersensitivity reactions are possible, therefore appropriate medical support including personnel adequately trained in cardiopulmonary resuscitative measures and access to emergency measures should be readily available when VPRIV is administered. If anaphylactic or other acute reactions occur, immediately discontinue the infusion of VPRIV and initiate appropriate medical treatment.
The management of hypersensitivity 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. In cases where patients have exhibited symptoms of hypersensitivity to velaglucerase alfa or excipients in the drug product or to other enzyme replacement therapy, pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions.
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 data described below reflect exposure of 94 patients with type 1 Gaucher disease who received VPRIV at doses ranging from 15 Units/kg to 60 Units/kg every other week in 5 clinical studies. Fifty-four (54) patients were naïve to enzyme replacement therapy (ERT) and received VPRIV for 9 months and 40 patients switched from imiglucerase to VPRIV treatment and received VPRIV for 12 months [see Clinical Studies (14)]. Patients were between 4 and 71 years old at time of first treatment with VPRIV, and included 46 male and 48 female patients.
The most serious adverse reactions in patients treated with VPRIV were hypersensitivity reactions [see Warnings and Precautions (5.1)].
The most commonly reported adverse reactions (occurring in ≥10% of patients) that were considered related to VPRIV are shown in Table 1. The most common adverse reactions were hypersensitivity reactions.
|Adverse Reaction||Naïve to ERT|
N = 54
Number of patients (%)
|Switched from imiglucerase to VPRIV
N = 40
Number of patients (%)
|Hypersensitivity reaction*||28 (52)||9 (23)|
|Headache||19 (35)||12 (30)|
|Dizziness||12 (22)||3 (8)|
|Pyrexia||12 (22)||5 (13)|
|Abdominal pain||10 (19)||6 (15)|
|Back pain||9 (17)||7 (18)|
|Joint pain (knee)||8 (15)||3 (8)|
|Asthenia/Fatigue||8 (15)||5 (13)|
|Activated partial thromboplastin time prolonged||6 (11)||2 (5)|
|Nausea||3 (6)||4 (10)|
Less common adverse reactions affecting more than one patient (>2% in the treatment-naïve group and > 3% in patients switched from imiglucerase to VPRIV treatment) were bone pain, tachycardia, rash, urticaria, flushing, hypertension, and hypotension.
As with all therapeutic proteins, there is a 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 VPRIV in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In clinical studies, 1 of 54 (2%) enzyme treatment-naïve patients treated with VPRIV developed IgG antibodies to VPRIV. One additional patient developed IgG antibodies to VPRIV during an extension study. In both patients, the IgG antibodies to VPRIV were determined to be neutralizing in an in vitro assay. The presence of IgG antibodies to VPRIV was not associated with hypersensitivity reactions. It is unknown if the presence of IgG antibodies to VPRIV is associated with a higher risk of infusion reactions. Patients with an immune response to other enzyme replacement therapies who are switching to VPRIV should continue to be monitored for antibodies to VPRIV.
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.
Gastrointestinal disorders: vomiting (in some cases vomiting can be serious, requiring hospitalization and/or drug discontinuation)
Available data on use of velaglucerase alfa in pregnant women includes more than 300 pregnancies reported from the pharmacovigilance database and published observational cohort studies, including the international Gaucher Disease registry. While available data cannot definitively establish or exclude the absence of a velaglucerase alfa associated risk during pregnancy, these data have not identified an association with use of velaglucerase alfa during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies no fetal harm was observed in rats or rabbits when velaglucerase alfa was administered intravenously during organogenesis at doses with exposures up to 1.8 times and 4.3 times, respectively, the recommended human daily 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 major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-Associated Maternal and Embryo/Fetal Risk
Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes including hepatosplenomegaly which can interfere with the normal growth of a pregnancy, and thrombocytopenia which can lead to excessive bleeding .
Embryo-fetal development studies with velaglucerase alfa have been performed during the period of organogenesis in pregnant rats (gestation days 7 through 17) and rabbits (gestation days 6 through 18). In pregnant rats intravenous doses up to 17 mg/kg (102 mg/m2, about 1.8 times the recommended human dose of 60 Units/kg or 1.5 mg/kg or 55.5 mg/m2 based on the body surface area) were administered two to three times weekly. In pregnant rabbits intravenous doses up to 20 mg/kg (240 mg/m2, about 4.3 times the recommended human dose of 60 Units/kg based on the body surface area) were administered two to three times weekly. These studies did not reveal any evidence of impaired fertility or harm to the fetus due to velaglucerase alfa.
In a pre- and postnatal development study, velaglucerase alfa was administered intravenously to pregnant rats twice weekly from gestation day 6 to lactation day 19. There was no evidence of any adverse effect on pre-and postnatal development at doses up to 17 mg/kg/day (102 mg/m2, about 1.8 times the recommended human dose of 60 Units/kg based on the body surface area).
There are no data available on the presence of velaglucerase alfa in human milk. The reported cases from the pharmacovigilance database are insufficient to determine any effects on the breastfed infant or on milk production. Endogenous beta-glucocerebrosidase is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VPRIV and any potential adverse effects on the breastfed child from VPRIV or from the underlying maternal condition.
The safety and effectiveness of VPRIV have been established for enzyme replacement therapy (ERT) in patients between 4 and 17 years of age with type 1 Gaucher disease. Use of VPRIV in this age group is supported by evidence from adequate and well-controlled studies of VPRIV in 74 adult patients and 20 pediatric patients. The safety and efficacy profiles were similar between pediatric and adult patients [see Adverse Reactions (6.1), Clinical Studies (14)]. The efficacy and safety of VPRIV has not been established in pediatric patients younger than 4 years of age.
In clinical studies of VPRIV in Gaucher's disease, a total of 56 VPRIV-treated patients were 65 years of age or older including 10 patients who were 75 years of age or older. Among 205 patients who switched from imiglucerase to VPRIV, 52 patients were 65 years of age or older of which 10 were 75 years and older. The adverse reaction profile in elderly patients was consistent with that previously observed across pediatric and adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be approached cautiously, considering potential comorbid conditions.
Velaglucerase alfa is a hydrolytic lysosomal glucocerebroside-specific enzyme produced by gene activation technology in a human fibroblast cell line. Velaglucerase alfa is a glycoprotein of 497 amino acids and a molecular weight of approximately 63 kDa. Velaglucerase alfa has the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. Velaglucerase alfa contains five potential N-linked glycosylation sites; four of these sites are occupied by glycan chains. Velaglucerase alfa contains predominantly high mannose-type N-linked glycan chains. The high mannose type N-linked glycan chains are specifically recognized and internalized via the mannose receptor present on the surface on macrophages, the cells that accumulate glucocerebroside in Gaucher disease.
VPRIV is dosed by units/kg, where one unit 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.
VPRIV (velaglucerase alfa) for injection is supplied as a sterile, preservative free, white to off-white lyophilized powder in single-dose vials for intravenous infusion after reconstitution and dilution. Each single-dose vial contains 400 units of velaglucerase alfa, and citric acid, monohydrate (5.04 mg), polysorbate 20 (0.44 mg), sodium citrate, dihydrate (51.76 mg), and sucrose (200 mg). After reconstitution with 4.3 mL Sterile Water for Injection, USP, the final concentration is 100 units/mL with a pH of approximately 6.0.
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. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells". Velaglucerase alfa catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside. In clinical trials VPRIV reduced spleen and liver size, and improved anemia and thrombocytopenia.
In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of Gaucher cells in the liver and spleen leads to organomegaly. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia.
In a multicenter study conducted in pediatric (N=7, 4 to 17 years old) and adult (N=15, 19 to 62 years old) patients with type 1 Gaucher disease, pharmacokinetic evaluations were performed at Weeks 1 and 37 following 60-minute intravenous infusions of VPRIV 60 Units/kg every other week. Serum velaglucerase alfa concentrations declined rapidly with a mean half life of 11 to 12 minutes. The mean velaglucerase alfa clearance ranged from 6.72 to 7.56 mL/min/kg. The mean volume of distribution at steady state ranged from 82 to 108 mL/kg (8.2% to 10.8% of body weight).
No accumulation or change in velaglucerase alfa pharmacokinetics over time from Weeks 1 to 37 was observed upon multiple-dosing 60 Units/kg every other week.
Based on the limited data, there were no notable pharmacokinetic differences between male and female patients in this study. The effect of age on pharmacokinetics of velaglucerase alfa was inconclusive.
The effect of anti-drug antibody formation on the pharmacokinetic parameters of velaglucerase alfa is unknown.
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with velaglucerase alfa.
In a fertility study in male and female rats, velaglucerase alfa did not cause any significant adverse effect on male or female fertility parameters up to a maximum intravenous dose of 17 mg/kg (102 mg/m2, about 1.8 times the recommended human dose of 60 Units/kg based on the body surface area).
The efficacy of VPRIV was assessed in three clinical trials in a total of 99 patients with type 1 Gaucher disease: 82 patients age 4 years and older received VPRIV and 17 patients age 3 years and older received imiglucerase. Studies I and II were conducted in patients who were not currently receiving Gaucher disease-specific therapy. Study III was conducted in patients who were receiving imiglucerase treatment immediately before starting VPRIV. The long-term safety of VPRIV was assessed in Study IV, an open-label extension trial in a total of 93 patients with type 1 Gaucher disease ages 3 years and older. Patients who had completed Studies I to III were eligible to participate in Study IV. In Studies I through IV, VPRIV was administered intravenously over 60 minutes at a maximum dose of 60 Units/kg every other week. Doses above 60 Units/kg were not studied in these trials.
Study I was a 12-month, randomized, double-blind, parallel-dose-group, multinational trial in 25 patients age 4 years and older with Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients were not allowed to have had disease-specific therapy for at least the previous 30 months; all but one had no prior therapy. The mean age was 26 years and 60% were male. Patients were randomized to receive VPRIV at a dose of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week. The recommended starting dose in naïve patients is 60 Units/kg. The 45 Units/kg dosage is not recommended as a starting dose in naïve patients [see Dosage and Administration (2.1)].
At baseline, mean hemoglobin concentration was 10.6 g/dL, mean platelet count was 97 × 109/L, mean liver volume was 3.6 % of body weight (% BW), and mean spleen volume was 2.9 % BW.
For all studies, liver and spleen volumes were measured by MRI. The changes in clinical parameters after 12 months of treatment are shown in Table 2. The observed change from baseline in the primary endpoint, hemoglobin concentration, was considered to be clinically meaningful in the 60 Units/kg dose, in light of the natural history of untreated Gaucher disease.
|Clinical Parameter||VPRIV 45 Units/kg*
N = 13
Mean ± SE
|VPRIV 60 Units/kg
N = 12
Mean ± SE
|SE = standard error of the mean|
|Hemoglobin concentration change|
|2.4 ± 0.4†||2.4 ± 0.3‡|
|Platelet count change|
|41 ± 14†||51 ± 12†|
|Liver volume change|
|-0.30 ± 0.29||-0.84 ± 0.33|
|Spleen volume change|
|-1.9 ± 0.6†||-1.9 ± 0.5†|
Study II was a 9-month, randomized, double-blind, active-controlled (imiglucerase), parallel-group, multinational study in 34 patients age 4 years and older. Patients were required to have Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients were not allowed to have had disease-specific therapy for at least the previous 12 months. The mean age was 30 years and 53% were female; the youngest patient who received VPRIV was age 4 years. Patients were randomized to receive either 60 Units/kg of VPRIV (N=17) or 60 Units/kg of imiglucerase (N=17) every other week.
At baseline, the mean hemoglobin concentration was 11.0 g/dL, mean platelet count was 171 × 109/L, and mean liver volume was 4.3 % BW. For the patients who had not had splenectomy (7 in each group) the mean spleen volume was 3.4 % BW. After 9 months of treatment, the mean absolute increase from baseline in hemoglobin concentration was 1.6 g/dL ± 0.2 (SE) for patients treated with VPRIV. The mean treatment difference in change from baseline to 9 months [VPRIV – imiglucerase] was 0.1 g/dL ± 0.4 (SE).
In both studies, examination of age and gender subgroups did not identify differences in response to VPRIV among these subgroups. The number of non-Caucasian patients in these studies was too small to adequately assess any difference in effects by race.
In Study IV, treatment naïve patients were administered VPRIV. Treatment-naïve patients continued to show improvements in clinical parameters (hemoglobin concentration, platelet count, liver volume, and spleen volume) compared with baseline for up to 60 months of treatment with ERT.
Study III was a 12-month, open-label, single-arm, multinational study in 40 patients age 9 years and older who had been receiving treatment with imiglucerase at doses ranging between 15 Units/kg to 60 Units/kg for a minimum of 30 consecutive months. Patients also were required to have a stable biweekly dose of imiglucerase for at least 6 months prior to enrollment. The mean age was 36 years and 55% were female. Imiglucerase therapy was stopped, and treatment with VPRIV was administered every other week at the same number of units as the patient's previous imiglucerase dose. Adjustment of dosage was allowed by study criteria if needed in order to maintain clinical parameters [see Dosage and Administration (2.2)].
Hemoglobin concentrations and platelet counts remained stable on average through 12 months of VPRIV treatment. After 12 months of treatment with VPRIV the median hemoglobin concentration was 13.5 g/dL (range: 10.8, 16.1) vs. the baseline value of 13.8 g/dL (range: 10.4, 16.5), and the median platelet count after 12 months was 174 × 109/L (range: 24, 408) vs. the baseline value of 162 × 109/L (range: 29, 399). No patient required dosage adjustment during the 12-month treatment period.
In Study IV, patients who had previously been receiving imiglucerase treatment were administered VPRIV. Patients previously treated with imiglucerase maintained stability in clinical parameters (hemoglobin concentration, platelet count, liver volume, and spleen volume) compared with baseline for up to 60 months of treatment with ERT.
VPRIV (velaglucerase alfa) for injection is a sterile, preservative free, white to off-white lyophilized powder requiring reconstitution and further dilution prior to use. It is supplied in individually packaged single-dose 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. VPRIV is available as: 400 units/vial (NDC 54092-701-04).
Takeda Pharmaceuticals U.S.A., Inc.
Lexington, MA 02421
US License Number: 1898
VPRIV® and VPRIV Logo® are registered trademarks of Shire Human Genetic Therapies, Inc., a Takeda company.
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velaglucerase alfa injection, powder, lyophilized, for solution
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