velmanase alfa (Rx)

>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

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

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.

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

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