Velmanase alfa is an enzyme replacement therapy approved for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. Alpha-mannosidosis is a rare genetic condition characterized by the lack of the enzyme alpha-D-mannosidase, resulting in accumulation of mannose-rich oligosaccharides in lysosomes. Symptoms of alpha-mannosidosis may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and immune system dysfunction. Treatment with velmanase alfa in a randomized study of 25 patients resulted in a reduction of serum oligosaccharide concentration, and improved a 3-minute stair climbing test, 6-minute walking test, and forced vital capacity. Serious hypersensitivity reactions including anaphylaxis and infusion-related reactions can occur. Administration requires a specialized care setting where cardiopulmonary resuscitation equipment is readily available. Pretreatment with antihistamines, antipyretics, and/or corticosteroids may be required.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Prior to administration of velmanase alfa, consider pretreating with antihistamines, antipyretics, and/or corticosteroids.
-Visually inspect parenteral products prior to reconstitution and administration for particulate matter and discoloration whenever solution and container permit. Velmanase alfa is a white to off-white lyophilized powder with a cake-like appearance. After reconstitution, the solution should be clear to slightly opalescent.
-If 1 or more doses are missed, and it is at least 3 days from the next scheduled dose, restart the treatment as soon as possible. If it is within 3 days from the next scheduled dose, give only the next dose per schedule.
Intravenous Administration
Reconstitution
-Determine the number of velmanase alfa vials to be reconstituted based on the patient's weight in kilograms and the recommended dose; round the number of vials up to the nearest whole number of vials.
-Remove vials from the refrigerator 30 minutes prior to reconstitution to allow vials to reach room temperature.
-Reconstitute each vial using aseptic technique by slowly injecting 5 mL of Sterile Water for Injection down the inside wall of each vial. Avoid forcefully or directly injecting Sterile Water for Injection onto the lyophilized powder to minimize foaming.
-Allow the reconstituted vials to stand for 5 to 15 minutes. Then gently tilt and roll each vial for 15 to 20 seconds. Do not invert, swirl, or shake the vials.
-Each vial will yield a concentration of 2 mg/mL.
-Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution should be clear to slightly opalescent. The solution may contain some proteinaceous thin white strands or translucent fibers which will be removed by the in line filter during infusion. Discard if opaque particles are present or the solution is discolored.
-Withdraw the required volume of reconstituted solution from the vials into 1 or more syringes for infusion. Use caution to avoid foaming.
-Discard the unused portion remaining in the vials.
-Storage: If the reconstituted solution is not used immediately, store the vial in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F) for up to 24 hours, inclusive of infusion time. Do not freeze. Protect reconstituted solution from light during refrigeration. Reconstituted solution must be infused within 10 hours after removal from the refrigerator, inclusive of the infusion time. Discard if not used within 10 hours after removal from the refrigerator.
Intermittent IV Infusion
-Do not shake the syringe.
-Use an infusion set equipped with a pump and a low protein binding, 0.2-micron, in-line filter.
-For patients weighing 49 kg or less: Infuse over a minimum of 60 minutes
-For patients weighing 50 kg or more: Infuse at a maximum rate of 25 mL/hour.
-When the last syringe is empty, replace the dosage syringe with 20 mL syringe filled with 0.9% Sodium Chloride Injection. Flush the infusion system with 10 mL 0.9% Sodium Chloride Injection to infuse the remaining velmanase alfa in the line.
Modifications due to hypersensitivity reactions and/or infusion-associated reactions
-For severe hypersensitivity reactions, including anaphylaxis, or severe infusion-associated reactions:
--Discontinue velmanase alfa.
-Initiate appropriate medical treatment.
-For mild to moderate hypersensitivity reactions or mild to moderate infusion-associated reactions:
--Consider temporarily holding the infusion for 15 to 30 minutes.
-Restart at a slower infusion rate of 25% to 50% of the recommended rate.
-Initiate appropriate medical treatment.
-If symptoms of hypersensitivity or infusion-related reaction persist despite holding or slowing the infusion:
--Stop the infusion and monitor the patient.
-Consider reinitiating the infusion within 7 to 14 days at 25% to 50% of the recommended rate with appropriate pretreatment.
-If symptoms of hypersensitivity or infusion-related reaction subside after holding or slowing the infusion:
--Resume the infusion at 25% to 50% of the recommended rate.
-If tolerated, increase the infusion rate by increments of 25% of the recommended rate until the recommended infusion rate is reached.
-Closely monitor the patient.
Serious hypersensitivity reactions or anaphylaxis have occurred in patients treated with velmanase alfa. In clinical trials, 19 (50%) velmanase alfa treated patients experienced hypersensitivity reactions; this included 2 (5%) who experienced anaphylaxis and 3 (8%) who experienced severe hypersensitivity reactions that required medical treatment. In the 5 patients who experienced anaphylaxis or severe hypersensitivity requiring medical treatment, 4 (80%) tested positive for anti-drug antibodies. Hypersensitivity reactions were reported in 36% of adult patients and 58% of pediatric patients. Signs and symptoms of severe hypersensitivity or anaphylaxis included cyanosis, hypotension, vomiting, urticaria, erythema, facial swelling (edema), fever, and tremor. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of readministration after a severe reaction. Some patients may be rechallenged using slower infusion rates. Desensitization measures may be considered. If readministration occurs, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, consider increasing the infusion rate to the recommended rate. If a mild-to-moderate hypersensitivity reaction occurs, consider slowing the infusion rate or temporarily withholding the dose and initiate appropriate medical treatment. Hypotension and angioedema were reported with postmarketing use of velmanase alfa.
Infusion-associated reactions have occurred in patients treated with velmanase alfa. In clinical trials, 19 (50%) velmanase alfa treated patients experienced infusion-associated reactions; 5 (13%) patients required pretreatment in clinical trials and 1 patient was discontinued due to recurrent infusion-associated reactions. In a clinical trial, 2 out of 4 anti-drug antibody (ADA)-positive patients experienced severe infusion-related reactions. In another clinical trial, infusion-associated reactions were reported in 3 (9.1%) patients; 2 of these patients were ADA-positive. The most frequent infusion-associated reactions that occurred in more than 10% of patients in clinical trials included fever, chills, erythema, vomiting, cough, urticaria, rash, and conjunctivitis. If a severe infusion-associated reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of readministration after a severe infusion-related reaction. Some patients may be rechallenged using slower infusion rates. If readministration occurs, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, consider increasing the infusion rate to the recommended rate. If a mild-to-moderate infusion-associated reaction occurs, consider slowing the infusion rate or temporarily withholding the dose.
Acute renal failure was reported in 1 (3%) patient during clinical trials of velmanase alfa. The patient paused velmanase alfa treatment for 4 weeks; acute renal failure resolved within 12 weeks. The patient received ibuprofen concomitantly.
Headache and arthralgia were reported in 5 (33%) and 3 (20%) patients, respectively, during clinical trials of velmanase alfa. Asthenia, fatigue, joint swelling, and joint warmth were reported in postmarketing use of velmanase alfa.
Urinary tract infection (2 patients; 13%), influenza (2 patients; 13%), ear infection (2 patients; 13%), acute tonsillitis (2 patients; 13%), and naso-pharyngitis (10 patients; 66%) were reported during clinical trials of velmanase alfa. Rhinitis, upper respiratory tract infection, and otitis media occurred in 2 or more out of 5 patients during clinical trials of velmanase alfa. Endocarditis, staphylococcal infection, bacterial disease carrier, furunculosis (furuncle), pharyngeal edema, and wheezing were reported with postmarketing use.
Ocular pruritus (eye pruritus) was reported in 2 (13%) patients during clinical trials of velmanase alfa. Increased lacrimation and hearing loss have been reported with postmarketing use.
Upper abdominal pain and weight gain were reported in 10% or more of patients during clinical trials of velmanase alfa. Gastroenteritis was reported in 2 (13%) patients during clinical trials of velmanase alfa. Odynophagia and decreased appetite (anorexia) were reported with postmarketing use.
Back pain was reported in 2 (13%) patients during clinical trials of velmanase alfa. Fall or ligament sprain occurred in 2 or more out of 5 patients and contusion, wound, excoriation, or post-lumbar puncture syndrome were reported in 10% or more of patients during clinical trials of velmanase alfa.
Syncope was reported in 2 (13%) patients during clinical trials of velmanase alfa. Seizures were reported in 1 (3%) patient who had no prior history of seizures during clinical trials of velmanase alfa. Ataxia, nervous system disorder, and somnolence were reported with postmarketing use.
Immunoglobulin A vasculitis reported as Henoch Schonlein Purpura was reported in 1 (3%) patient during clinical trials of velmanase alfa. Vascular fragility was reported with postmarketing use.
Toothache (dental pain) was reported in 2 (13%) patients, oropharyngeal pain occurred in 2 or more out of 5 patients, and tooth extraction was reported in 10% or more of patients during clinical trials of velmanase alfa.
Antibody formation has been reported after treatment with velmanase alfa. In a clinical trial, 4 out of 5 pediatric patients developed anti-drug antibodies (ADA); 3 out of 4 ADA-positive patients developed neutralizing antibodies that inhibit velmanase alfa enzyme activity. In another clinical trial in 33 adult and pediatric patients, 4 patients developed ADA after treatment with velmanase alfa. Antibody formation was associated with lower plasma concentrations of velmanase alfa and 2 pediatric patients who developed ADA had a reduced pharmacodynamic response (reduced serum oligosaccharides) at the time high ADA concentrations were observed. Infusion-related reactions and severe hypersensitivity reactions, including anaphylaxis, occurred at a higher incidence in velmanase alfa treated patients who developed ADA compared to patients who were ADA negative.
Cardiac disorders including aortic valve incompetence, palpitations, and tachycardia (sinus tachycardia) have been reported with postmarketing use of velmanase alfa.
Psychosis, agitation, encopresis, and nervousness were reported with postmarketing use of velmanase alfa.
Serious hypersensitivity reactions or anaphylaxis have occurred in patients treated with velmanase alfa. Consider pretreatment with antihistamines, antipyretics, and/or corticosteroids. Administration requires a specialized care setting where cardiopulmonary resuscitation equipment is readily available. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of readministration after a severe reaction. Some patients may be rechallenged using slower infusion rates. Desensitization measures may be considered. If readministration occurs, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, consider increasing the infusion rate to the recommended rate. If a mild-to-moderate hypersensitivity reaction occurs, consider slowing the infusion rate or temporarily withholding the dose. In clinical trials, 1 out of 5 anti-drug antibody (ADA)-positive patients developed severe hypersensitivity; this patient had the highest ADA concentration among all the ADA-positive patients in the trial.
Serious infusion-related reactions have occurred in patients treated with velmanase alfa. Consider pretreatment with antihistamines, antipyretics, and/or corticosteroids. If a severe infusion-related reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of readministration after a severe reaction. Some patients have been rechallenged using slower infusion rates. If readministration occurs, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, consider increasing the infusion rate to the recommended rate. If a mild-to-moderate infusion-related reaction occurs, consider slowing the infusion rate or temporarily withholding the dose. In a clinical trial, 2 out of 4 anti-drug antibody (ADA)-positive patients experienced severe infusion-related reactions. In another clinical trial, infusion-associated reactions were reported in 3 (9.1%) patients; 2 of these patients were ADA-positive.
Velmanase alfa may cause fetal harm if administered during pregnancy based on data from animal studies. Advise patients of reproductive potential of the potential hazard to the fetus and to avoid pregnancy during velmanase alfa therapy. Consider the patient's need for treatment, potential risks to the fetus, and potential adverse outcomes of untreated disease when deciding whether to discontinue velmanase alfa during pregnancy. Skeletal and visceral malformations were observed in pregnant rats and rabbits after velmanase alfa doses that were approximately 7- and 2.5-fold, respectively, the human exposure (at the recommended dose).
Counsel patients about the reproductive risk and contraception requirements during velmanase alfa treatment. Perform pregnancy testing prior to starting treatment in patients of reproductive potential. Advise these patients to use effective contraception during and for 14 days after the last dose. Inform patients who become pregnant while receiving velmanase alfa of the potential hazard to the fetus.
It is not known whether velmanase alfa is excreted in human milk or if it has effects on the breast-fed child or on milk production. Consider the developmental and health benefits of breast-feeding along with the patient's clinical need for velmanase alfa, and any potential adverse effects on the breastfed child.
For the treatment of non-central nervous system manifestations of alpha-mannosidosis:
NOTE: The FDA has designated velmanase alfa as an orphan drug for this indication.
Intravenous dosage:
Adults: 1 mg/kg/dose IV once weekly.
Children and Adolescents: 1 mg/kg/dose IV once weekly.
Maximum Dosage Limits:
-Adults
1 mg/kg/dose IV once weekly.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
1 mg/kg/dose IV once weekly.
-Children
1 mg/kg/dose IV once weekly.
-Infants
Safety and efficacy have not been established.
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 Velmanase Alfa products.
Velmanase alfa is a recombinant human lysosomal alpha-mannosidase enzyme, an enzyme that catalyzes the degradation of accumulated mannose-containing oligosaccharides. Alpha-mannosidosis is a lysosomal storage disease caused by reduced activity of alpha-mannosidase, resulting in accumulation of mannose-rich oligosaccharides in lysosomes. Velmanase alfa binds the mannose-6-phosphate receptor and is transported into lysosomes where it exerts enzymatic breakdown of mannose-containing oligosaccharides.
Velmanase alfa is administered intravenously. The mean volume of distribution in patients with alpha-mannosidosis was 276 mL/kg. Velmanase alfa is expected to be metabolized into small peptides by catabolic pathways. The mean total body clearance was 5.7 mL/hour/kg, and the mean terminal half-life was 33.6 hours.
Serum oligosaccharide concentrations are elevated in patients with alpha-mannosidosis; velmanase alfa treatment reduces serum oligosaccharaide concentrations.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous administration of 1 mg/kg/dose in adult patients with alpha-mannosidosis, the mean Cmax was 7.9 mcg/mL and the AUC was 159.8 mcg x hour/mL.
-Special Populations
Pediatrics
Children and Adolescents 6 to 17 years
In patients with alpha-mannosidosis administered 1 mg/kg/dose velmanase alfa intravenously once a week, the mean Cmax and AUC at steady state were 6.6 mcg/mL and 109.8 mcg x hour/mL, respectively.
Children 3 to 5 years
In patients with alpha-mannosidosis administered 1 mg/kg/dose velmanase alfa intravenously once a week, the mean Cmax and AUC at steady state were 7 mcg/mL and 75.9 mcg x hour/mL, respectively.