olipudase alfa (Rx)

>10%

Adults

• Headache (54%)
• Cough (31%)
• Diarrhea (15%)
• Hypotension (15%)
• Ocular hyperemia (15%)
• Elevated transaminase levels (13%)

Children

• Pyrexia (100%)
• Cough (75%)
• Diarrhea (75%)
• Rhinitis (75%)
• Abdominal pain (63%)
• Vomiting (50%)
• Headache (50%)
• Urticaria (50%)
• Nausea (38%)
• Rash (38%)
• Arthralgia (38%)
• Pruritus (25%)
• Fatigue (25%)
• Pharyngitis (25%)
• C-reactive protein increased (13%)
• Hypotension (13%)
• Anaphylactic reaction (13%)
• Hypersensitivity (13%)
• Infusion site swelling (13%)
• Tachycardia (13%)
• Pharyngeal swelling (13%)
• Elevated transaminase levels (13%)

1-10%

Adults

• Erythema (8%)
• Asthenia (8%)
• Pharyngitis (8%)
• Dyspnea (8%)
• Urticaria (8%)
• Papule (8%)
• Myalgia (8%)
• Throat irritation (8%)
• C-reactive protein abnormal (8%)

Contraindications

None

Cautions

May cause fetal harm

Hypersensitivity reactions including anaphylaxis

• Consider pretreating with antihistamines, antipyretics, and/or corticosteroids before infusions
• 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 medical treatment
• Following severe hypersensitivity reactions (including anaphylaxis), consider risks and benefits of readministering
• If a patient has been rechallenged using slower infusion rates at a dosage lower than recommended dosage; a tailored desensitization procedure to therapy may be considered
• If decision is made to readminister, ensure patient tolerates infusion; if tolerated, dosage (dose and/or rate) may be increased to reach recommended dosage
• If mild or moderate reaction occurs, infusion rate may be slowed or temporarily withheld, and or dose reduced

Infusion-associated reactions

• Antihistamines, antipyretics, and/or corticosteroids may be given before administration to reduce risk of infusion-associated reactions (IARs); however, IARs may still occur in patients after receiving pretreatment
• If severe IARs occur, discontinue immediately and initiate appropriate medical treatment
• Consider risks and benefits of re-administering following severe IARs
• If mild or moderate IAR occurs, slow infusion rate or temporarily withhold and/or reduce dose

Elevated transaminases levels

• May be associated with elevated transaminases (ALT, AST, or both) within 24-48 hr after infusion
• Assess ALT and AST within 1 month before initiating, within 72 hr before any infusion during dose escalation, which includes the first 3 mg/kg dose, or prior to next scheduled infusion upon resuming treatment following a missed dose
• If baseline or pre-infusion transaminase level (during the dose escalation phase) is >2x ULN, repeat transaminase levels within 72 hr after infusion
• If pre-infusion transaminase levels are elevated above baseline and >2x ULN before next scheduled administration, may either reduce dose (repeat prior lower dose or reduce the dose) or temporarily withhold until transaminases return to baseline
• Continued transaminase testing recommended as part of routine clinical management upon reaching recommended maintenance dose

Pregnancy

Based on findings from animal reproduction studies, may cause embryo-fetal harm when administered to pregnant females

Dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase risk of fetal malformations

However, the decision to continue or discontinue maintenance dosing in pregnancy should consider the female’s need for the drug and potential drug-related risks to the fetus, and potential adverse outcomes from untreated maternal ASMD disease

Animal data

• In pregnant mice, exencephaly was observed in offspring at an exposure less than the exposure at the maximum recommended human dose

Contraception

• Verify pregnancy status in females of reproductive potential before initiating
• Advise females of reproductive potential to use effective contraception during treatment and for 14 days after last dose if olipudase alfa is discontinued

Lactation

Data are not available on presence in human milk, effects on breastfed infants, or effects on milk production

Present in animal milk; when a drug is present in animal milk, it is likely that the drug will be present in human milk

Animal data

• Administered as a single IV dose (3 mg/kg) to lactating mice on post-partum day 7
• Milk was not evaluated until post-partum day 9, at which time concentrations detected were ~1.3% the estimated maximal maternal plasma concentration

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

Recombinant human acid sphingomyelinase enzyme for replacement therapy

Acid sphingomyelinase deficiency is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 gene

ASM degrades sphingomyelin to ceramide and phosphocholine

ASM deficiency causes intra-lysosomal accumulation of sphingomyelin (and cholesterol and other cell membrane lipids) in various tissues

Not expected to modulate CNS manifestations of ASMD

Absorption

Peak plasma concentration: 30 mcg/mL (adults); 24.3 mcg/mL (children)

AUC: 607 mcg⋅hr/mL (adults); 499 mcg⋅hr/mL (children)

Distribution

Vd: 13 L (adults)

Does not cross blood-brain barrier or modulate CNS manifestations

Metabolism

Not characterized; expected to be metabolized into small peptides and amino acids via catabolic pathways

Elimination

Half-life: 32-38 hr (adults)

Clearance: 0.33 L/hr (adults)

IV Incompatibilities

Do not infuse in same IV line with other products

IV Compatibilities

0.9% NaCl

IV Preparation

Reconstitution

• Determine number of vials to be reconstituted based on calculated dose
• Remove vials from refrigeration and set aside for ~20-30 minutes to reach room temperature
• Reconstitute each vial with 5.1 mL sterile water for injection by directing diluent flow to inside vial wall to avoid foaming
• Gently roll and tilt vial(s) to reconstitute and avoid foaming
• Each reconstituted vial yields 4 mg/mL as a clear, colorless solution
• Visually inspect solution for particulate matter and discoloration; discard if discolored or particulates are visible

Dilution

• Withdraw dose from reconstituted vial(s) and dilute with 0.9% NaCL in syringe or infusion bag depending on volume of infusion
• Weight <10 kg, receiving 0.03-0.1 mg/kg dose: Infusion volume will vary to achieve fixed final concentration of 0.1 mg/mL (prepare in syringe for infusion)
• Weight 10-20 kg, receiving 0.03 mg/kg dose: Infusion volume will vary to achieve fixed final concentration of 0.1 mg/mL (prepare in syringe for infusion)
• All other patient weights and doses: Final concentration will vary to achieve a fixed total volume
• Total volume ≤20 mL (prepare syringe): Inject required volume of reconstituted 4 mg/mL solution slowly down inside wall of syringe; slowly add enough 0.9% NaCl to obtain required total infusion volume (avoid foaming within syringe)
• Total volume ≥50 mL (prepare infusion bag): Slowly add required volume of reconstituted 4 mg/mL solution into appropriate size 0.9% NaCl infusion bag (avoid foaming within bag) to achieve total volume
• Gently invert syringe or infusion bag to mix; do NOT shake
• Since this is a protein solution, slight flocculation (thin translucent fibers) occurs occasionally after dilution
• Vials are for single dose only; discard unused solution

IV Administration

Consider pretreating with antihistamines, antipyretics, and/or corticosteroids

Prior to administration, inspect syringe or infusion bag for foaming; if present, let foam dissipate before administering

Use in-line low protein-binding 0.2-micron filter during administration

The following materials can be used: polyolefin or polyvinylchloride (PVC) with DEHP for infusion bags, polypropylene for syringes, polyurethane or PVC DEHP-free for infusion sets, and polyethersulfone or polytetrafluoroethylene for in-line filters

Infuse using at appropriate infusion rate (below)

In absence of infusion-associated reactions, increase infusion rate per steps of infusion as indicated (+/- 5 minutes)

Each infusion step will last for 20 minutes, except for the final step, which should last until completion of the infusion volume

Flush infusion line with 0.9% NaCl at end of infusion using same infusion rate as the last part of the infusion

Home administration

• Home administration under supervision of healthcare provider may be considered for patients on maintenance dose who are tolerating their infusion well
• Dose and infusion rates should remain constant for home administration and cannot be changed without supervision of a physician; in case of missed doses or delayed infusion, contact physician

Adult infusion rate

• 0.1 mg/kg dose

  • Step 1: 20 mL/hr
  • Step 2: 60 mL/hr

• 0.3-3 mg/kg dose

  • Step 1: 3.33 mL/hr
  • Step 2: 10 mL/hr
  • Step 3: 20 mL/hr
  • Step 4: 33.33 mL/hr

Pediatric infusion rate

• 0.03 mg/kg dose

  • Step 1: 0.1 mg/kg/hr for entire infusion

• 0.1 mg/kg dose

  • Step 1: 0.1 mg/kg/hr
  • Step 2: 0.3 mg/kg hr

• 0.3mg/kg dose

  • Step 1: 0.1 mg/kg/hr
  • Step 2: 0.3 mg/kg/hr
  • Step 3: 0.6 mg/kg/hr

• 0.6-3 mg/kg dose

  • Step 1: 0.1 mg/kg/hr
  • Step 2: 0.3 mg/kg/hr
  • Step 3: 0.6 mg/kg/hr
  • Step 4: 1 mg/kg/hr

Missed doses

• A dose is considered missed when it is not administered within 3 days of the scheduled date

• 1 missed dose

  • Escalation phase: Administer last tolerated dose, then resume dose escalation at next infusion
  • Maintenance phase: Resume maintenance dose

• 2 consecutive missed doses

  • Escalation phase: Administer 1 dose below last tolerated dose, then resume dose escalation at next infusion
  • Maintenance phase: Administer 1 dose below the maintenance dose, then resume the maintenance dose at next infusion

• ≥3 consecutive missed doses

  • Escalation phase: Resume dose escalation starting with 0.3 mg/kg
  • Maintenance phase: Restart dosing at 0.3 mg/kg and follow escalation dosing schedule

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF)
• Do not freeze

Reconstituted vials

• If not used immediately, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr, OR
• Room temperature at 20-25ºC (68-77ºF) for up to 12 hr
• Do not freeze

Diluted solution

• If not administered immediately, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr, OR
• Room temperature at 20-25ºC (68-77ºF) for up to 12 hr (including infusion time)
• Do not freeze