Dosing & Uses
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 10mg/vial (single-dose)
Alpha-Mannosidosis
Indicated for treatment of noncentral nervous system manifestations of alpha-mannosidosis in adult and pediatric patients
1 mg/kg (actual body weight) IV infusion qWeek
Dosage Modifications
Hypersensitivity reactions or infusion-associated reactions (IARs)
-
Mild to moderate
- Consider temporarily holding infusion for 15-30 minutes, slowing infusion rate to 25-50% of the recommended rate, and initiating appropriate medical treatment
- If symptoms persist despite temporarily holding or slowing infusion, stop the infusion and monitor
- If symptoms continue to persist, discontinue infusion, and consider reinitiating infusion within 7-14 days at 25-50% of the recommended rate with appropriate pretreatment
- If symptoms subside following holding or slowing the infusion, resume infusion at 25-50% of the recommended rate
- If tolerated, increase the infusion rate by increments of 25% of recommended rate until the recommended infusion rate is reached; closely monitor
-
Severe
- Immediately discontinue administration and initiate appropriate medical treatment
Dosing Considerations
Verify pregnancy status in females of reproductive potential
Consider premedicating with antihistamines, antipyretics, and/or corticosteroids before administration
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 10mg/vial (single-dose)
Alpha-Mannosidosis
Indicated for treatment of noncentral nervous system manifestations of alpha-mannosidosis in adult and pediatric patients
Use is supported by evidence from an adequate and well-controlled clinical trial in adult and pediatric patients, and from an open label trial in 5 pediatric patients (aged <6 years)
1 mg/kg (actual body weight) IV infusion qWeek
Dosage Modifications
Hypersensitivity reactions or infusion-associated reactions (IARs)
-
Mild to moderate
- Consider temporarily holding infusion for 15-30 minutes, slowing infusion rate to 25-50% of the recommended rate, and initiating appropriate medical treatment
- If symptoms persist despite temporarily holding or slowing infusion, stop the infusion and monitor
- If symptoms continue to persist, discontinue infusion, and consider reinitiating infusion within 7-14 days at 25-50% of the recommended rate with appropriate pretreatment
- If symptoms subside following holding or slowing the infusion, resume infusion at 25-50% of the recommended rate
- If tolerated, increase the infusion rate by increments of 25% of recommended rate until the recommended infusion rate is reached; closely monitor
-
Severe
- Immediately discontinue administration and initiate appropriate medical treatment
Dosing Considerations
Verify pregnancy status in females of reproductive potential
Consider premedicating with antihistamines, antipyretics, and/or corticosteroids before administration
Higher incidence of hypersensitivity reactions reported in children compared to adults
Adverse Effects
>10%
Nasopharyngitis (66%)
Pyrexia (40%)
Headache (33%)
Arthralgia (20%)
Acute tonsillitis (13%)
Urinary tract infection (13%)
Eye pruritus (13%)
Gastroenteritis (13%)
Hypersensitivity (13%)
Influenza (13%)
Syncope (13%)
Toothache (13%)
Back pain (13%)
Ear infection (13%)
Postmarketing Reports
Cardiac disorders: Aortic valve incompetence, palpitations, tachycardia
Ear and labyrinth disorders: Deafness
Eye disorders: Lacrimation increased
Gastrointestinal disorders: Odynophagia
General disorders and administration site conditions: Asthenia, fatigue
Infections and infestations: Endocarditis, staphylococcal infection, bacterial disease carrier, furuncle
Metabolism and nutrition disorders: Decreased appetite
Musculoskeletal and connective tissue disorders: Joint swelling, joint warmth
Nervous system disorders: Ataxia, nervous system disorder, somnolence
Psychiatric disorders: Psychotic disorder, agitation, encopresis, nervousness
Respiratory, thoracic, and mediastinal disorders: Pharyngeal edema, wheezing
Skin, subcutaneous tissue disorders: Angioedema
Vascular disorders: Vascular fragility, hypotension
Warnings
Black Box Warnings
Severe hypersensitivity reactions
- Treated patients have experienced hypersensitivity reactions, including anaphylaxis
- Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during administration
- If severe hypersensitivity reaction (eg, anaphylaxis) occurs, discontinue immediately and initiate appropriate treatment
- Consider a desensitization procedure in patients with severe hypersensitivity reaction
Contraindications
None
Cautions
Based on findings from animal reproduction studies, embryofetal harm when administered to pregnant females
Infusion-related reactions
- Infusion-associated reactions (IARs) reported
- Symptoms include pyrexia, chills, erythema, vomiting, cough, urticaria, rash, and conjunctivitis
- Similar symptoms were observed in adult and pediatric populations
- Before administering, consider pretreating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs
- If a severe IAR occurs, discontinue immediately and initiate appropriate medical treatment; consider the risks and benefits of readministering following a severe IAR
- May rechallenge using slower infusion rates
- Once the patient tolerates the infusion, may increase infusion rate to reach the recommended infusion rate
- If a mild or moderate IAR occurs, consider slowing the infusion rate or temporarily withholding the dose
Hypersensitivity reactions
- Hypersensitivity reactions including anaphylaxis reported
- Anaphylaxis and severe hypersensitivity signs and symptoms include cyanosis, hypotension, emesis, urticaria, erythema, facial swelling, pyrexia, and tremor
- Before administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids
- Ensure appropriate medical support measures, including cardiopulmonary resuscitation equipment, is readily available during administration
- If a severe hypersensitivity reaction (eg, anaphylaxis) occurs, discontinue immediately and initiate appropriate medical treatment; consider the risks and benefits of readministering following severe hypersensitivity reactions (including anaphylaxis)
- Rechallenge using slower infusion rates
- In patients with severe hypersensitivity reaction, consider desensitization measures
- If infusion is tolerated, increase the rate to reach the recommended dosage
- If a mild or moderate hypersensitivity reaction occurs, consider slowing the infusion rate or temporarily withholding the dose
Pregnancy & Lactation
Pregnancy
Based on findings from animal reproduction studies, embryofetal harm may occur when administered to pregnant females
No data are available on use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
Advise pregnant females of potential risk to the fetus
Consider need for treatment, potential drug-related risks to the fetus, and potential adverse outcomes from untreated maternal disease to continue or discontinue treatment during pregnancy
Verify pregnancy status in females of reproductive potential
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 14 days after last dose
Animal data
- Major visceral malformations were observed in rats and rabbits when velmanase alfa was administered in pregnant rats and rabbits during organogenesis
- These malformations were observed in rats at the highest dose level, at exposures that were ~7-fold the recommended dose in patients of 1 mg/kg
- Malformations occurred at all dose levels in rabbits with the highest dose exposures ~2.5-fold the recommended patient dose of 1 mg/kg
Lactation
There are no data on the presence of velmanase alfa or its metabolite in either human or animal milk, effects on breastfed infants, or effects on milk production
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Alpha-mannosidase catalyzes the degradation of accumulated mannose-containing oligosaccharides
Deficiency of alpha-mannosidase causes an intralysosomal accumulation of mannose-rich oligosaccharides in various tissues
Velmanase alfa provides an exogenous source of alpha-mannosidase; it eventually internalizes via binding to the mannose-6-phosphate receptor on the T-cell surface and is transported into lysosomes, where it is thought to exert enzyme activity
Absorption
Peak plasma concentration
- Adults: 7.9 mcg/mL
- Pediatric patients (3 to <6 years): 7 mcg/mL
- Pediatric patients (6-17 years): 6.6 mcg/mL
AUC
- Adults: 159.8 mcg⋅hr/mL
- Pediatric patients (3 to <6 years): 75.9 mcg⋅hr/mL
- Pediatric patients (6-17): 109.8 mcg⋅hr/mL
Distribution
Vd: 276 mL/kg
Metabolism
Metabolized into small peptides by catabolic pathways
Elimination
Half-life: 33.6 hr
Clearance: 5.7 mL/hr/kg
Administration
IV Compatibilities
0.9% NaCl
IV Preparation
Use aseptic technique during preparation
Determine number of vials to be reconstituted based on recommended dose
Round number of vials up to the next whole number
Remove vials from refrigerator and set aside for ~30 minutes to allow vials to come to room temperature
Reconstitute each vial by slowly injecting 5 mL of sterile water, down the inside wall of each vial; avoid adding the sterile water to the vial forcefully or directly onto the lyophilized powder to minimize foaming
Allow reconstituted vials to stand on table for 5-15 minutes
Gently tilt and roll each vial for 15-20 seconds to enhance the dissolution process; final concentration is 2 mg/mL
Do not invert, swirl, or shake vials
Visually inspect reconstituted solution in vials for particulate matter and discoloration; solution should be clear to slightly opalescent
Solution may occasionally contain some proteinaceous particles in the form of thin white strands or translucent fibers, which will be removed by inline filter during infusion; discard if opaque particles are present or the solution is discolored
Slowly withdraw the required volume from the vials with caution to avoid foaming in the syringe
If the required drug volume exceeds one syringe capacity, prepare required number of syringes in order to replace the syringe quickly during infusion; discard unused portion remaining in vials
IV Administration
Use an infusion set equipped with a pump and a low protein binding, 0.2-micron, inline filter to administer
Do not shake syringe
When last syringe is empty, replace dosage syringe with a 20 mL syringe filled with 0.9% NaCl, and then continue to infuse an additional 10 mL of 0.9% NaCl through infusion system to infuse remaining fraction in line to patient
Infusion time
- Based on patients’ actual body weight
- ≤49 kg: At least 60 min
- ≥50 kg: Not to exceed 25 mL/hr
Missed 1 or more doses
- <3 days from next scheduled dose: Give only next dose per schedule
- ≥3 days from next rescheduled dose: Restart treatment as soon as possible
Storage
Unopened vials
- Refrigerate at 2-8°C (36-46°F) in original container
- Protect from light
- Do not freeze
Reconstituted vials
- Refrigerate at 2-8°C (36-46°F) for up to 24 hours including infusion time
- Protect from light during refrigeration
- Do not freeze
- Once removed from refrigerator, infuse within 10 hr, inclusive of total infusion time; discard if not used within 10 hr
- Infuse reconstituted solution within 24 hr from time of preparation, which includes storage time in refrigerator, time at room temperature, and duration of infusion
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Formulary
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