VPRIV

Velaglucerase alfa is a gene-activated human recombinant glucocerebrosidase used for the treatment of Type 1 Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase.

Additionally, Velaglucerase alfa has also been investigated for use in Type 3 Gaucher disease.

Velaglucerase alfa is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy for pediatric and adult patients with type 1 Gaucher disease.

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. 12.3 Pharmacokinetics 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 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 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 to 108 mL/kg (8.2% to 10.8% of body weight).

No accumulation or change in velaglucerase alfa pharmacokinetics over time from Weeks 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.

The mean volume of distribution at steady state ranges from 82-108 mL/kg (8.2% to 10.8% of body weight).

Mean clearance ranges from 6.72-7.56 mL/min/kg.

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Administration of

VPRIV should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis Recommended Starting Dose in Adults and Pediatric Patients 4 Years of Age or Older: Patients Naïve to Enzyme Replacement Therapy: 60 Units/kg Patients being treated with stable imiglucerase dosages for Gaucher disease: Can switch to VPRIV at previous imiglucerase dose two weeks after last imiglucerase dose Determine number of vials to be reconstituted based on patient's actual weight and prescribed dose Supplied VPRIV lyophilized powder must be reconstituted with Sterile Water for Injection Reconstituted VPRIV solution must be diluted in 100 mL of 0.9% Sodium Chloride Injection prior to intravenous infusion Administer the diluted VPRIV solution through an in-line low protein-binding 0.2 or 0.22 µm filter 2.1 Recommendations Prior to VPRIV treatment Administration of VPRIV should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

VPRIV in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. 2.2 Recommended Starting Dosage in Patients Naïve to Enzyme Replacement Therapy 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. 2.3 Switching from Imiglucerase to VPRIV 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. 2.4 Reconstitution of the VPRIV Lyophilized Powder VPRIV is a lyophilized powder, which requires reconstitution and dilution, using sterile technique, prior to intravenous infusion.

VPRIV should be prepared as follows: (a) Determine the number of vials to be reconstituted based on the individual patient's weight and the prescribed dose. (b) Inject 4.3 mL of Sterile Water for Injection, USP into a vial containing VPRIV lyophilized powder. (c) Mix gently.

The reconstituted

VPRIV solution will have a 100 Units/mL concentration (400 Units VPRIV in 4 mL of solution). (d) If additional vials are needed, repeat steps (b) and (c). (e) Visually inspect the reconstituted VPRIV 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 particulate matter is present. (f) With a single syringe, withdraw the calculated dose of drug from the appropriate number of vials.

Using a separate syringe, withdraw air from a bag of 100 mL of 0.9% Sodium Chloride Injection suitable for intravenous administration.

Then dilute the calculated dose of

VPRIV directly into the 0.9% Sodium Chloride Injection.

Mix gently.

Slight flocculation (described as white irregular shaped particles) may occasionally occur.

Diluted solution with slight flocculation is acceptable for administration. (g) Because VPRIV contains no preservatives, use the reconstituted VPRIV solution and the diluted VPRIV solution immediately.

If immediate use is not possible, the reconstituted VPRIV solution or the diluted VPRIV solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF).

Do not freeze and protect from light.

Complete the infusion within 24 hours of reconstitution of vials. (h) Vials are for one-time use and only for one patient.

Discard any unused solution. 2.5 Important Administration Instructions Administer the diluted VPRIV solution through an in-line low protein-binding 0.2 or 0.22 µm filter over 60 minutes.

Do not infuse

VPRIV with other products in the same infusion tubing because the compatibility of a VPRIV solution with other products has not been evaluated. 2.6 Premedication to Reduce Risk of Subsequent Hypersensitivity Reactions 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.

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).

VPRIV refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light.

Do not freeze.

Do not use

VPRIV after the expiration date on the vial.

VPRIV refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light.

Do not freeze.

Do not use

VPRIV after the expiration date on the vial.

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.

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 to 4% and to 20%, respectively.

Clinical Considerations 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/m 2, about 1.8 times the recommended human dose of 60 Units/kg or 1.5 mg/kg or 55.5 mg/m 2 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/m 2, 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 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/m 2, about 1.8 times the recommended human dose of 60 Units/kg based on the body surface area).

The safety and effectiveness of

VPRIV have been established for enzyme replacement therapy (ERT) in patients between and 17 years of age with type 1 Gaucher disease.

Use of

VPRIV in this 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.

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 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.