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Velaglucerase Alfa
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60 units/kg IV administered as a 60-minute infusion every other week for treatment naive patients. Dosage adjustments may be made based on achievement and maintenance of therapeutic goals. Clinical studies evaluated doses ranging from 15 to 60 units/kg IV every other week. Patients currently treated with a stable dose imiglucerase may be switched to the same dose of velaglucerase alfa (i.e. same number of units per dose as imiglucerase dose) 2 weeks after the last imiglucerase dose. In a 12-month, open-label study of 40 patients (aged 9 years and older) who had received at least 30 months of imiglucerase therapy, patients switched to velaglucerase alfa at the same dose and had stable hemoglobin and platelet counts during the 12 months after the switch. No patient required dosage adjustment.[49254]
Safety and efficacy have not been established.
A specific maximum dosage is not available, but at the time of approval, the maximum dosage studied was 60 units/kg IV every other week. Dosage is based on disease severity and patient response.
A specific maximum dosage is not available, but at the time of approval, the maximum dosage studied was 60 units/kg IV every other week. Dosage is based on disease severity and patient response.
A specific maximum dosage is not available, but at the time of approval, the maximum dosage studied was 60 units/kg IV every other week. Dosage is based on disease severity and patient response.
>= 4 years: A specific maximum dosage is not available, but at the time of approval, the maximum dosage studied was 60 units/kg IV every other week. Dosage is based on disease severity and patient response.
< 4 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
† Off-label indicationVelaglucerase alfa is an intravenous enzyme replacement therapy used for the long term management of patients with type 1 Gaucher disease.[49254] Velaglucerase alfa replaces the endogenous enzyme beta-glucocerebrosidase. Velaglucerase alfa is produced by gene activation technology in a human fibroblast cell line and has the same amino acid sequence as the naturally occurring human enzyme. Two related products include imiglucerase (Cerezyme) and alglucerase (Ceredase).
For storage information, see the specific product information within the How Supplied section.
Reconstitution:
Dilution:
IV infusion:
In clinical trials with velaglucerase alfa, headache was reported by 30—35% of patients, and dizziness was reported by 8—22% of patients. Headache and dizziness have both been associated with infusion reactions, and both adverse reactions were more common in enzyme-replacement naive patients compared to those who were switched from imiglucerase therapy.[49254]
In clinical trials with velaglucerase alfa, abdominal pain was reported by 15—19% of patients and nausea was reported by 6—10% of patients. Nausea has been associated with infusion reactions.[49254]
In pre-marketing clinical trials with velaglucerase alfa, back pain was observed in 17 to 18% of patients and joint (knee) pain was reported in 8 to 15% of patients. Bone pain affected > 2% of treatment-naive patients and > 3% of patients switched from imiglucerase.[49254]
In clinical trials with velaglucerase alfa, prolonged activated partial thromboplastin time (aPTT) / prolonged bleeding time was observed in 5—11% of patients. Prolonged aPTT is more commonly seen in pediatric patients as compared to adults (> 10% difference).[49254]
In pre-marketing clinical trials with velaglucerase alfa, fever was observed in 13—22% of patients. Pyrexia has been associated with infusion reactions and is more commonly seen in pediatric patients as compared to adults (> 10% difference).[49254]
In clinical trials with velaglucerase alfa, asthenia and/or fatigue was observed in 13% to 15% of patients. Asthenia/fatigue has been associated with infusion reactions.[49254]
In clinical trials with velaglucerase alfa, less common reactions affecting more than 2% of treatment-naive patients and more than 3% of patients switched from imiglucerase to velaglucerase alfa included urticaria and rash (unspecified). Rash is more commonly seen in pediatric patients as compared to adults (more than a 10% difference in incidence).[49254]
In clinical trials with velaglucerase alfa, less common reactions affecting more than 2% of treatment-naive patients and more than 3% of patients switched from imiglucerase to velaglucerase alfa included sinus tachycardia, flushing, hypertension, and hypotension. Hypertension and hypotension have both been associated with infusion reactions.[49254]
In clinical trials, hypersensitivity reactions were the most serious and most common adverse reactions associated with velaglucerase alfa. Infusion-related reactions occurring within 24 hours of treatment occurred in 23% to 52% of patients and were more common in enzyme-replacement naive patients compared to those who were switched from imiglucerase therapy. Reactions were generally mild, typically occurred within the first 6 months of therapy, and occurred less frequently with time. The most commonly observed symptoms of hypersensitivity reactions were headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia; however, serious reactions (e.g., anaphylactic shock) have occurred. Additionally, chest pain (unspecified), dyspnea, pruritis, and vomiting have been reported in postmarketing experience. In some cases, vomiting can be serious, requiring hospitalization and/or drug discontinuation. If an infusion related reaction occurs, symptoms can be abated with temporary interruption or slowing of the infusion and the administration of antihistamines, antipyretics, and, occasionally, corticosteroids. Pretreatment with antihistamines and/or corticosteroids can be considered prior to subsequent infusions in patients who experience a reaction; however, pretreatment was not routinely administered in clinical trials. Appropriate emergency medical support should be readily available in the event of anaphylactoid reactions.[49254]
Antibody formation, in the form of IgG antibodies, occurred in 1 of 54 (2%) treatment naive patients receiving velaglucerase alfa in clinical trials. One additional patient developed IgG antibodies to velaglucerase alfa during an extension study. The IgG antibodies in both patients were determined to be neutralizing in an in vitro assay. The presence of IgG antibodies to velaglucerase alfa was not associated with hypersensitivity reactions. It is unknown whether the development of antibodies is associated with a higher risk of infusion reactions. Monitor patients with an immune response to other enzyme replacements switching to velaglucerase alfa for antibody formation.[49254]
Velaglycerase alfa therapy carries a risk of serious hypersensitivity reactions or anaphylaxis and may also cause infusion-related reactions. Hypersensitivity and infusion-related reactions were the most commonly observed adverse events in velaglucerase alfa clinical trials. Generally, reactions were mild, however, anaphylaxis has been reported. In treatment-naive patients, onset of these reactions occurred mostly during the first 6 months of treatment and dissipated over time. Symptoms of hypersensitivity and infusion-related reactions include headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia/increased body temperature. Chest discomfort, dyspnea, and pruritus have been reported in post-marketing experience. Use caution in patients who have exhibited symptoms of hypersensitivity to velaglucerase alfa or to other enzyme replacement therapy. Appropriate medical support and supplies must be readily available at the time of administration to treat hypersensitivity reactions should they occur. If anaphylactic or other acute reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment. Less severe hypersensitivity and infusion-related reactions can be managed by slowing the infusion rate and treatment with antihistamines, antipyretics, and/or corticosteroids. Stopping and resuming treatment with an increased infusion time may also be implemented. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions.[49254] As with all therapeutic proteins, there is a risk for immunogenicity. It is unknown if the presence of IgG antibodies to velaglucerase alfa is associated with a higher rate of infusion reactions. Patients with an immune response to other enzyme replacement therapies who are switching to velaglucerase alfa should continue to be monitored for antibodies.[49254]
Clinical trials of velaglucerase alfa did not included a sufficient number of geriatric patients aged 65 years and over to determine treatment response differences. Dose selection for elderly patients should be approached cautiously, considering potential comorbid conditions.
The safety and efficacy of velaglucerase alfa has been established in children 4 years old and older and in adolescents. Safety and efficacy profiles were similar between pediatric and adult patients. Safety and efficacy have not been established in neonates, infants, or children less than 4 years of age.
There are no adequate and well controlled studies with the use of velaglucerase alfa in human pregnancy; there is limited clinical experience in pregnant women. More than 300 pregnancies have been reported from the pharmacovigilance database and published observational cohort studies, including the international Gaucher Disease registry. Available data has not identified an association between velaglucerase use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal 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 greater than, respectively, the recommended human daily dose. Because animal reproduction studies are not always predictive of human response, use the drug during pregnancy only if clearly needed. Pregnant 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 increased bleeding and possible hemorrhage.[49254] Imiglucerase has been suggested as an enzyme-replacement treatment option during pregnancy, based on limited data from case studies.[56701] [56702]
There are no data on the presence of velaglucerase alfa in human breast milk. Reported cases from the pharmacovigilance database are insufficient to determine any effects on the breast-feeding infant or on milk production.[49254] Enzymes such as velaglucerase are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with alglucerase or imiglucerase postpartum. No adverse effects on the nursing infants were reported secondary to enzyme replacement therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] Imiglucerase has been suggested as an enzyme-replacement treatment option, based on limited data from case studies and breast milk concentration data.[56701] [56702] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Velaglucerase alfa substitutes for the deficient enzyme glucocerebrosidase in patients with Gaucher's disease. Gaucher's disease is an autosomal recessive congenital disorder of lipid metabolism and is categorized as a lysosomal storage disorder. The disease is characterized by a deficiency of the lysosomal enzyme glucocerebrosidase, a necessary catalyst for the hydrolysis of glucocerebroside, an endogenous, very insoluble glycolipid. Patients with this condition have a build-up of glucocerebroside in lysosomes of phagocytic cells, which are found in storage cells of the liver, spleen, bone marrow, and other organs. Clinically, this build-up is associated with splenomegaly, hepatomegaly, increased skin pigmentation, painful bone lesions, and blood dyscrasias..[49254]
Velaglucerase alfa is designed to be preferentially taken up by macrophages, the drug's site of action. Treatment with velaglucerase alfa results in hydrolysis of the accumulated glucocerebroside within macrophages and improvement in hemoglobin, hematocrit, and platelet counts, and a decrease in hepatomegaly and splenomegaly. Reductions in size of an enlarged liver and spleen correspond to hematological improvement and patients' subjective improvement. Treatment with velaglucerase alfa does not cure the underlying condition, but it does reverse the disease process and provide symptomatic improvement. Continued use is required to maintain suppression of symptoms.
Revision Date: 09/29/2023, 01:50:00 AMVelaglucerase alfa is administered by intravenous infusion. A multicenter pharmacokinetic study was conducted in pediatric patients (n = 7, 4—17 years old) and adults (n = 15, 19—62 years old) with type 1 Gaucher's disease. After administration (60 units/kg via infusion), serum concentrations of velaglucerase alfa declined rapidly with a mean half-life of 11—12 minutes. The mean clearance ranged from 6.72—7.56 ml/min/kg. The mean volume of distribution at steady state ranged from 82—108 ml/kg (8.2—10.8% of body weight). No accumulation or change in velaglucerase alfa pharmacokinetics over time from weeks 1 to 37 was observed. Due to an inadequately validated analytical assay used in the evaluations, the accurate and definitive pharmacokinetic parameters are not available. The effect of anti-drug antibody formation on the pharmacokinetic parameters of velaglucerase alfa is unknown.
The pharmacokinetic study of velaglucerase alfa included pediatric patients (n = 7, 4—17 years old); however, specific pediatric pharmacokinetic data was not reported separately from the overall data. The effect of age on the pharmacokinetics of velaglucerase alfa was inconclusive.
Based on limited data, no notable pharmacokinetic differences for velaglucerase alfa were noted between male and female patients.
There are no adequate and well controlled studies with the use of velaglucerase alfa in human pregnancy; there is limited clinical experience in pregnant women. More than 300 pregnancies have been reported from the pharmacovigilance database and published observational cohort studies, including the international Gaucher Disease registry. Available data has not identified an association between velaglucerase use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal 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 greater than, respectively, the recommended human daily dose. Because animal reproduction studies are not always predictive of human response, use the drug during pregnancy only if clearly needed. Pregnant 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 increased bleeding and possible hemorrhage.[49254] Imiglucerase has been suggested as an enzyme-replacement treatment option during pregnancy, based on limited data from case studies.[56701] [56702]
There are no data on the presence of velaglucerase alfa in human breast milk. Reported cases from the pharmacovigilance database are insufficient to determine any effects on the breast-feeding infant or on milk production.[49254] Enzymes such as velaglucerase are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with alglucerase or imiglucerase postpartum. No adverse effects on the nursing infants were reported secondary to enzyme replacement therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] Imiglucerase has been suggested as an enzyme-replacement treatment option, based on limited data from case studies and breast milk concentration data.[56701] [56702] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
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