Vestronidase alfa is a purified human enzyme for the treatment of adult and pediatric patients with Mucopolysaccharidosis VII (MPS VII; Sly syndrome). It is produced by recombinant technology in a Chinese hamster ovarian cell line and is administered via intravenous infusion every other week. MPS VII is a lysosomal storage disorder that is caused by deficiency of the enzyme beta-glucuronidase (GUS), which leads to the accumulation of glycosaminoglycan (GAG) in cells throughout the body. Vestronidase alfa is intended to provide exogenous GUS enzyme. MPS VII impacts less than 150 patients worldwide and manifestations vary widely between patients, but most patients have skeletal abnormalities that become more pronounced with age, including short stature. Patients can also develop heart valve abnormalities, enlarged liver and spleen, and narrowed airways which can lead to lung infections and difficulty breathing. Some patients do not survive infancy, while others may live into adolescence or adulthood. Affected patients may have developmental delay and progressive intellectual disability. The risk of anaphylaxis is a significant concern with vestronidase alfa. Premedication with antihistamines with or without antipyretics is recommended, and a careful infusion rate titration schedule must be observed. Close monitoring of patients during and after the administration of the infusion is recommended.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-The solution should be colorless to slightly yellow. Slight flocculation (e.g., thin translucent fibers) may occur.
Intravenous Administration
Administer this product under the supervision of a healthcare professional with the ability to manage medical emergencies.
Dilution
-The final solution will be a 1:1 dilution; more than 1:1 dilution may be used if the patient can tolerate additional infusion volume.
-Dilute the calculated dose with 0.9% NaCl Injection; prepare at room temperature.
-Select an empty infusion bag, sized based on total volume of the final solution.
-Slowly withdraw the volume of the calculated vestronidase alfa dose from the appropriate number of vials; use caution to avoid excessive agitation and any air or frothing. Use an 18 gauge needle 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% NaCl Injection 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.
-Storage: If immediate use is not possible, store the diluted solution up to 36 hours under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) followed by up to 6 hours at room temperature up to a maximum of 25 degrees C (77 degrees F).
Intermittent IV Infusion
-Administer the diluted solution using an infusion set equipped with a low-protein binding, 0.2 micrometer in-line filter.
-Administer the infusion over approximately 4 hours. Infuse the first 2.5% of the total volume over the first hour. 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. After the first hour, increase the infusion rate as tolerated in order to complete infusion over the following 3 hours. Recommended rate guidelines are provided in the package insert.
-To avoid a rapid bolus of infused enzyme, do not flush the line containing vestronidase alfa. 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.
-Observe patients closely during the infusion and after 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.
Clinical trials were conducted in 23 patients (ages 5 months to 25 years) receiving vestronidase alfa at doses up to 4 mg/kg/dose once every 2 weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.
During clinical trials, 1 patient receiving vestronidase alfa experienced a febrile convulsion at week 66. Once the infusion was stopped and anticonvulsants, antipyretics, and antibiotics were administered, the adverse reaction resolved. The patient was rechallenged without recurrence and continued on treatment.
Serious hypersensitivity reactions or anaphylaxis has occurred during vestronidase alfa administration. During clinical trials, 2 of 20 patients experienced anaphylactic reactions during vestronidase alfa administration. Manifestations included respiratory distress, cyanosis, decreased oxygen saturations, and hypotension. One patient experienced anaphylaxis during the first dose of vestronidase alfa. Both patients had 1 occurrence each and tolerated subsequent infusions of vestronidase alfa without recurrence.
During clinical trials, infusion-related reactions were reported. Infusion site extravasation occurred in 4 out of 12 patients (33%) receiving vestronidase alfa vs. 1 out of 9 patients (11%) receiving placebo. Rash was reported in 3 out of 12 patients (25%) receiving vestronidase alfa vs. 2 out of 9 patients (22%) receiving placebo. Pruritus was reported in 1 out of 12 patients (8%) receiving vestronidase alfa vs. 0 patients receiving placebo. Infusion site swelling was reported in 1 out of 12 (8%) receiving vestronidase alfa vs. 0 patients receiving placebo. Additionally, peripheral swelling was reported in 1 out of 12 (8%) of patients receiving vestronidase alfa vs. 0 patients receiving placebo.
During clinical trials, diarrhea occurred in 3 out of 12 patients (25%) receiving vestronidase alfa vs. 0 out of 9 patients (0%) receiving placebo.
As with all therapeutic proteins, there is a potential for immunogenicity. In clinical trials, 18 out of 23 patients (78%) tested positive for anti-drug antibody formation at some point after receiving vestronidase alfa treatment. Among those 18 patients, 10 (55.6%) also showed the presence of neutralizing antibodies. No correlation was observed between the anti-drug antibody (ADA) titer and neutralizing antibody values. Six treatment-naive patients had pre-existing ADA titers at baseline. ADAs were detected in 5 of these 6 patients post-treatment. The post-treatment ADA titers were the same as or below the baseline ADA titer values in 2 patients, but 1 of the 2 patients was positive for neutralizing antibodies. ADA titer values after treatment increased 64-fold, 128-fold, and 364-fold, respectively, in the other 3 patients. The presence of ADA titer does not appear to affect reduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs), as assessed in clinical trials.
Vestronidase alfa is associated with a risk of serious hypersensitivity reactions or anaphylaxis. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended. Personnel, medications, and equipment necessary to manage an acute vestronidase alfa hypersensitivity reaction should be readily available. Follow the recommended infusion rate schedule, and closely monitor patients during and for a minimum of 60 minutes after the infusion. If a severe hypersensitivity reaction occurs, immediately discontinue vestronidase alfa treatment and initiate appropriate medical treatment. Counsel patients and caregivers about hypersensitivity reactions, and instruct them to seek immediate medical attention should any signs or symptoms occur. Consider the risks and benefits of readministering the drug to individual patients after a severe reaction. If the decision is made to readminister the product, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction. During clinical trials, 2 of 20 patients experienced anaphylactic reactions during vestronidase alfa administration. Manifestations included respiratory distress, cyanosis, decreased oxygen saturations, and hypotension. One patient experienced anaphylaxis during the first dose of vestronidase alfa. Both patients had one occurrence each and tolerated subsequent infusions of vestronidase alfa without recurrence.
There are no available data regarding vestronidase alfa use during pregnancy to inform a drug-associated risk. Animal data did not reveal evidence of impaired fertility or harm to the fetus when administered at doses causing maternal serum exposures (AUC) up to 1.6 and 10 times, respectively, the exposure at the recommended human dose.
There are no data on the presence of vestronidase alfa in human milk, the effects on a breast-fed infant, or the effects on milk production. 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.
For the treatment of mucopolysaccharidosis VII (Sly syndrome):
Vestronidase alfa has been designated as an orphan drug for this indication by the FDA.
Intravenous dosage:
Adults: 4 mg/kg/dose IV administered every 2 weeks. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended.
Infants, Children, and Adolescents: 4 mg/kg/dose IV administered every 2 weeks. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended.
Neonates: 4 mg/kg/dose IV administered every 2 weeks. Premedication with antihistamines with or without antipyretics 30 to 60 minutes prior to the infusion is recommended.
Maximum Dosage Limits:
-Adults
4 mg/kg/dose IV every 2 weeks.
-Geriatric
4 mg/kg/dose IV every 2 weeks
-Adolescents
4 mg/kg/dose IV every 2 weeks.
-Children
4 mg/kg/dose IV every 2 weeks.
-Infants
4 mg/kg/dose IV every 2 weeks.
-Neonates
4 mg/kg/dose IV every 2 weeks.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Vestronidase alfa products.
Mucopolysaccharidosis VII (MPS VII; Sly syndrome) is a lysosomal storage disorder that is caused by deficiency of the enzyme beta-glucuronidase (GUS), which leads to the accumulation of glycosaminoglycan (GAG) in cells throughout the body. Patients experience widespread tissue and organ damage, but the course of progression and life expectancy depends on the severity of symptoms. Vestronidase alfa is intended to provide exogenous GUS enzyme. Vestronidase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of vestronidase alfa to mannose-6-phosphate receptors. Once inside the lysosomes, the catabolism of accumulated GAGs is thought to be increased.
Vestronidase alfa is administered via intravenous infusion. Vestronidase alfa is eliminated by proteolytic degradation into small peptides and amino acids; it is not metabolized or expected to be eliminated through renal or fecal excretion.
Affected cytochrome P450 enzymes: none
-Route-Specific Pharmacokinetics
Intravenous Route
Vestronidase alfa pharmacokinetics were evaluated in 23 patients (19 pediatric patients; 4 adults) with Mucopolysaccharidosis VII (MPS VII; Sly syndrome) who received 4 mg/kg/dose IV every other week. The mean Cmax was 17.3 +/- 9.6 mcg/mL (range 4.7 to 35.7 mcg/mL), AUC was 50.9 +/- 32.2 mcg x hour/mL (range: 17.4 to 153 mcg x hour/mL), Vss was 251 +/- 140 mL/kg (range 97 to 598 mL/kg), CL was 83.6 +/- 43.2 mL/hour/kg (range: 38.3 to 184 mL/hour/kg), and half-life was 2.33 +/- 0.75 hours (range: 0.86 to 3.03 hours). The inter-subject variability (coefficient of variation) in total clearance (CL) was 52%. Vestronidase alfa concentrations in pediatric patients younger than 5 years of age were similar to the concentrations in older pediatric patients and adults.