Introduction

Biosynthetic (recombinant DNA origin) form of human acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes hydrolysis of sphingomyelin.

Uses for Olipudase Alfa-rpcp (Systemic)

Acid Sphingomyelinase Deficiency

Treatment of non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) in adults and pediatric patients; designated an orphan drug by FDA for this condition.

Provides an exogenous source of ASM and has been shown to improve visceral manifestations of the disease in patients with ASMD.

Not expected to cross the blood-brain barrier or modulate CNS manifestations of ASMD.

Olipudase Alfa-rpcp (Systemic) Dosage and Administration

General

Pretreatment Screening

• Obtain baseline ALT and AST levels within 1 month prior to initiating treatment.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Assess ALT and AST within 72 hours prior to any infusion during dose escalation (including the first dose of 3 mg/kg), and prior to the next scheduled infusion upon resuming treatment following a missed dose.

• During maintenance treatment, continue monitoring ALT and AST as part of routine clinical management.

Premedication and Prophylaxis

• Consider premedication with antihistamines, antipyretics, and/or corticosteroids prior to administration.

Administration

IV Administration

Administer by IV infusion every 2 weeks.

Administer using an inline, low-protein-binding 0.2-µm filter.

May use polyolefin or polyvinylchloride (PVC) with diethylhexylphthalate (DEHP) for infusion bags; polypropylene for syringes; polyurethane or non-DEHP PVC for infusion sets; and polyethersulfone or polytetrafluoroethylene for inline filters.

Do not infuse in the same IV line with other drugs.

At end of infusion, flush infusion line with 0.9% sodium chloride injection using same infusion rate as for last part of infusion.

Vials contain no preservatives and are intended for single use only.

Prior to administration, inspect syringe or infusion bag for foaming; let any foam dissipate before administering drug.

Home administration under supervision of a clinician may be considered for patients receiving a maintenance dose who are tolerating infusions well. Dosage and infusion rate should remain constant for home administration; do not change without supervision of a physician. Contact physician in case of a missed dose or delayed infusion.

Reconstitution

Must reconstitute and dilute commercially available lyophilized powder for injection prior to administration.

Use aseptic technique during reconstitution.

Determine number of vials needed based on calculated dose. Remove vials from refrigerator and set aside for approximately 20–30 minutes to allow them to reach room temperature.

Reconstitute each 4-mg vial with 1.1 mL and each 20-mg vial with 5.1 mL of sterile water for injection to yield a clear, colorless solution containing olipudase alfa-rpcp 4 mg/mL; direct diluent flow to inside wall of vial to avoid foaming. Gently roll and tilt vial(s) to reconstitute drug, avoiding foaming.

Visually inspect reconstituted solution for particulate matter and discoloration; discard any vials containing solution that is discolored or contains visible particulate matter.

Vials are for single use only; discard any unused reconstituted solution.

Dilution

Must dilute commercially available lyophilized powder for injection after reconstitution and prior to administration.

Use aseptic technique during dilution.

Withdraw required volume of reconstituted olipudase alfa-rpcp 4-mg/mL solution from vial(s) and dilute with 0.9% sodium chloride injection in a syringe or infusion bag depending on the final volume of infusion (see Tables 1 and 2).

For patients who weigh <10 kg receiving doses of 0.03 mg/kg or 0.1 mg/kg and patients who weigh 10–20 kg receiving a dose of 0.03 mg/kg, volume of infusion will vary to achieve a final concentration of 0.1 mg/mL (see Tables 1 and 2); prepare required dose diluted to a final concentration of 0.1 mg/mL in a syringe for infusion.

For all other patient weights and doses, final concentration will vary to achieve a fixed total volume (see Tables 1 and 2).

If total infusion volume is ≤20 mL, prepare a syringe for infusion by injecting required volume of reconstituted 4-mg/mL olipudase alfa-rpcp solution slowly down inside wall of syringe, then slowly add a sufficient volume of 0.9% sodium chloride injection to obtain required total infusion volume (see Tables 1 and 2); avoid foaming within syringe.

If total infusion volume is ≥50 mL, prepare an infusion bag by slowly adding required volume of reconstituted 4-mg/mL olipudase alfa-rpcp solution to appropriately sized 0.9% sodium chloride injection infusion bag to achieve a fixed total volume (see Tables 1 and 2); avoid foaming within infusion bag.

Gently invert syringe or infusion bag to mix solution. Do not shake syringe or infusion bag; slight flocculation (described as thin translucent fibers) occasionally occurs following dilution.

Rate of Administration

Infuse diluted solutions of olipudase alfa-rpcp using infusion rates described in Tables 3 and 4. In the absence of infusion-associated reactions (IARs), increase the infusion rate according to the steps of infusion rate escalation as indicated (±5 minutes) in Tables 3 and 4. Each step of the infusion rate escalation will last for 20 minutes with the exception of the final step, which should last until completion of the infusion volume.

Dosage

Pediatric Patients

Acid Sphingomyelinase Deficiency

IV

Dosage of olipudase alfa-rpcp is based on weight. Use actual body weight in patients with BMI ≤30 kg/m². In patients with BMI >30 kg/m², use an adjusted body weight calculated by the following formula: adjusted body weight (kg) = (actual height in m)² x 30.

Always initiate treatment via a dose escalation regimen followed by a maintenance dose.

Recommended initial dose: 0.03 mg/kg.

Recommended maintenance dosage: 3 mg/kg every 2 weeks.

To reduce risk of hypersensitivity and IARs or elevated transaminase levels, follow recommended dosage titration schedule shown in Table 5.

Adults

Acid Sphingomyelinase Deficiency

IV

Dosage of olipudase alfa-rpcp is based on weight. Use actual body weight in patients with BMI ≤30 kg/m². In patients with BMI >30 kg/m², use an adjusted body weight calculated by the following formula: adjusted body weight (kg) = (actual height in m)² x 30.

Always initiate treatment via a dose escalation regimen followed by a maintenance dose.

Recommended initial dose: 0.1 mg/kg.

Recommended maintenance dosage: 3 mg/kg every 2 weeks.

To reduce risk of hypersensitivity and IARs or elevated transaminase levels, follow recommended dosage titration schedule shown in Table 6.

Instructions for Missed Doses

A dose is considered missed if it is not administered within 3 days of scheduled infusion date. Instructions for a missed dose depend on whether patient is in escalation phase or maintenance phase and on how many consecutive doses have been missed (see Table 7).

Dosage Modification for Toxicity

Hypersensitivity Reactions and Infusion-associated Reactions

Severe hypersensitivity reaction (e.g., anaphylaxis) or severe IAR: Immediately discontinue olipudase alfa-rpcp administration and initiate appropriate medical treatment.

Mild to moderate hypersensitivity reaction or mild to moderate IAR: Consider temporarily holding infusion or slowing infusion rate, and/or reducing dosage of olipudase alfa-rpcp.

If dosage is reduced, reescalate following dose escalation instructions in Tables 5 and 6 for pediatric patients and adults, respectively.

Transaminase Elevations

If transaminase levels are elevated above baseline and >2 times the upper limit of normal (ULN) prior to the next scheduled administration, adjust olipudase alfa-rpcp dose (prior dose repeated or reduced) or temporarily withhold treatment until liver transaminases return to patient’s baseline value.

Special Populations

No special population dosage recommendations at this time.

Contraindications

• None.

Warnings/Precautions

Warnings

Severe Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported. (See Boxed Warning.)

Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during olipudase alfa-rpcp administration. Consider premedication with antihistamines, antipyretics, and/or corticosteroids.

If a mild or moderate hypersensitivity reaction occurs in a patient receiving olipudase alfa-rpcp, the infusion rate may be slowed or the infusion temporarily withheld, and/or the olipudase alfa-rpcp dose may be reduced.

If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue olipudase alfa-rpcp immediately and initiate appropriate medical treatment. Consider risks and benefits of retreatment following a severe hypersensitivity reaction (including anaphylaxis).

In patients who have experienced a severe hypersensitivity reaction, may consider a tailored desensitization procedure. If drug is readministered, ensure that the patient tolerates the infusion. If infusion is tolerated, dosage (dose and/or the rate) may be increased to reach recommended maintenance dosage.

Consider testing for anti-olipudase alfa-rpcp IgE antibodies in patients who experience a severe hypersensitivity reaction, including anaphylaxis. Testing for antibodies against olipudase alfa-rpcp is available through Genzyme Corporation (at 1-800-745-4447). In addition, consider other clinical laboratory testing (e.g., serum tryptase and complement activation) in patients receiving olipudase alfa-rpcp who experience anaphylaxis.

Other Warnings/Precautions

Infusion-associated Reactions

IARs occurred in approximately 50% of adults; most frequent (≥10%) IARs in adults were headache, pruritus, vomiting, and urticaria.

IARs occurred in approximately 75% of pediatric patients and were severe in 12.5% of patients. Most frequent IARs (>20%) in pediatric patients were urticaria, erythema, headache, nausea, pyrexia, and vomiting.

May premedicate with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs; however, IARs may still occur.

If a mild or moderate IAR occurs, infusion rate may be slowed or the infusion temporarily withheld, and/or olipudase alfa-rpcp dosage may be reduced.

If severe IARs occur, discontinue olipudase alfa-rpcp immediately and initiate appropriate medical treatment. Consider risks and benefits of readministering olipudase alfa-rpcp following severe IARs.

Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, reported. Generally occurred at 48 hours post-infusion during dose escalation period. Manage as with other IARs.

Elevated Transaminases Levels

Elevated transaminases (ALT, AST, or both) within 24–48 hours after infusion reported. Levels generally returned to baseline by time of next scheduled infusion.

Assess ALT and AST within 1 month prior to initiation of olipudase alfa-rpcp, within 72 hours prior to any infusion during dose escalation (including first dose of 3 mg/kg), and prior to next scheduled infusion upon resuming treatment following a missed dose. Upon reaching recommended maintenance dose, continue transaminase testing as part of routine clinical management.

If baseline or preinfusion transaminase level (during dose escalation phase) is >2 times ULN, repeat transaminase levels within 72 hours after end of infusion. If preinfusion transaminase levels are elevated above baseline and >2 times the ULN prior to next scheduled administration, may reduce dosage (i.e., repeat prior lower dose or reduce the dose) or temporarily withhold drug until liver transaminase levels return to baseline.

Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy

There is no evidence that olipudase alfa-rpcp crosses the placenta; however, initiation or dosage escalation of drug is not recommended at any time during pregnancy, as it may lead to elevated sphingomyelin metabolite levels, possibly increasing risk of fetal malformations.

Decision to continue or discontinue maintenance dosing of olipudase alfa-rpcp during pregnancy should take into account the female’s need for olipudase alfa-rpcp, potential drug-related risks to fetus, and potential adverse outcomes from untreated maternal ASMD disease.

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

Immunogenicity and Antidrug Antibody-Associated Adverse Reactions

Development of anti-olipudase alfa-rpcp IgG antibodies (IgG ADA), including neutralizing antibodies (NAb), reported. NAb that inhibited the cellular uptake of olipudase alfa-rpcp not observed. In addition, no clinically important effect of ADA on pharmacokinetics of olipudase alfa-rpcp reported.

IARs (including hypersensitivity reactions) occurred in a higher percentage of adult patients receiving olipudase alfa-rpcp who developed IgG ADA compared to those who did not develop IgG ADA.

Anaphylaxis occurred in a pediatric patient 18 months of age during the sixth infusion of olipudase alfa-rpcp in a clinical trial; the patient developed IgE ADA, with the highest IgG ADA titersamong all patients in the trial. Olipudase alfa-rpcp was discontinued and then resumed 4 months later using a diluted drug solution and a desensitization procedure.

Anaphylaxis occurred during both the fifth and sixth infusions in a pediatric patient 16 months of age who had ASMD type A and received a version of olipudase alfa manufactured from a different process; this patient developed IgG ADA and IgE ADA.

Specific Populations

Pregnancy

May cause fetal harm based on animal findings. Insufficient data in pregnant women.

Rare malformation (exencephaly) observed in offspring in mice at an exposure less than the exposure at the maximum recommended human dose.

Initiation or dosage escalation not recommended at any time during pregnancy as it may lead to elevated sphingomyelin metabolite levels, possibly increasing risk of fetal malformations.

Decision to continue or discontinue maintenance dosing during pregnancy should consider female’s need for olipudase alfa-rpcp, potential drug-related risks to fetus, and potential adverse outcomes from untreated maternal disease. Advise pregnant females of potential risk to fetus.

Lactation

Not known whether olipudase alfa is distributed into human milk, affects the breast-fed infant, or affects milk production. Distributed into milk in mice.

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for olipudase alfa and any potential adverse effects on breast-fed infant from drug or from underlying maternal condition.

Females and Males of Reproductive Potential

May cause embryofetal harm when administered during first trimester of pregnancy.

Verify pregnancy status in females of reproductive potential prior to initiating olipudase alfa-rpcp. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after last dose of drug.

Pediatric Use

Safety and efficacy of olipudase alfa for treatment of non-CNS manifestations of ASMD established in pediatric patients, including neonates.

Compared with adults, a higher percentage of pediatric patients experienced treatment-related serious adverse reactions, anaphylaxis, hypersensitivity reactions, and IARs that occurred within 24 hours of infusion.

Geriatric Use

Clinical trials did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.

Common Adverse Effects

Common adverse effects (≥10%) in adults: Headache, cough, diarrhea, hypotension, ocular hyperemia.

Common adverse effects ( ≥20%) in pediatric patients: Pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, pharyngitis.

General

Pretreatment Screening

• Obtain baseline ALT and AST levels within 1 month prior to initiating treatment.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Assess ALT and AST within 72 hours prior to any infusion during dose escalation (including the first dose of 3 mg/kg), and prior to the next scheduled infusion upon resuming treatment following a missed dose.

• During maintenance treatment, continue monitoring ALT and AST as part of routine clinical management.

Premedication and Prophylaxis

• Consider premedication with antihistamines, antipyretics, and/or corticosteroids prior to administration.

Administration

IV Administration

Administer by IV infusion every 2 weeks.

Administer using an inline, low-protein-binding 0.2-µm filter.

May use polyolefin or polyvinylchloride (PVC) with diethylhexylphthalate (DEHP) for infusion bags; polypropylene for syringes; polyurethane or non-DEHP PVC for infusion sets; and polyethersulfone or polytetrafluoroethylene for inline filters.

Do not infuse in the same IV line with other drugs.

At end of infusion, flush infusion line with 0.9% sodium chloride injection using same infusion rate as for last part of infusion.

Vials contain no preservatives and are intended for single use only.

Prior to administration, inspect syringe or infusion bag for foaming; let any foam dissipate before administering drug.

Home administration under supervision of a clinician may be considered for patients receiving a maintenance dose who are tolerating infusions well. Dosage and infusion rate should remain constant for home administration; do not change without supervision of a physician. Contact physician in case of a missed dose or delayed infusion.

Reconstitution

Must reconstitute and dilute commercially available lyophilized powder for injection prior to administration.

Use aseptic technique during reconstitution.

Determine number of vials needed based on calculated dose. Remove vials from refrigerator and set aside for approximately 20–30 minutes to allow them to reach room temperature.

Reconstitute each 4-mg vial with 1.1 mL and each 20-mg vial with 5.1 mL of sterile water for injection to yield a clear, colorless solution containing olipudase alfa-rpcp 4 mg/mL; direct diluent flow to inside wall of vial to avoid foaming. Gently roll and tilt vial(s) to reconstitute drug, avoiding foaming.

Visually inspect reconstituted solution for particulate matter and discoloration; discard any vials containing solution that is discolored or contains visible particulate matter.

Vials are for single use only; discard any unused reconstituted solution.

Dilution

Must dilute commercially available lyophilized powder for injection after reconstitution and prior to administration.

Use aseptic technique during dilution.

Withdraw required volume of reconstituted olipudase alfa-rpcp 4-mg/mL solution from vial(s) and dilute with 0.9% sodium chloride injection in a syringe or infusion bag depending on the final volume of infusion (see Tables 1 and 2).

For patients who weigh <10 kg receiving doses of 0.03 mg/kg or 0.1 mg/kg and patients who weigh 10–20 kg receiving a dose of 0.03 mg/kg, volume of infusion will vary to achieve a final concentration of 0.1 mg/mL (see Tables 1 and 2); prepare required dose diluted to a final concentration of 0.1 mg/mL in a syringe for infusion.

For all other patient weights and doses, final concentration will vary to achieve a fixed total volume (see Tables 1 and 2).

If total infusion volume is ≤20 mL, prepare a syringe for infusion by injecting required volume of reconstituted 4-mg/mL olipudase alfa-rpcp solution slowly down inside wall of syringe, then slowly add a sufficient volume of 0.9% sodium chloride injection to obtain required total infusion volume (see Tables 1 and 2); avoid foaming within syringe.

If total infusion volume is ≥50 mL, prepare an infusion bag by slowly adding required volume of reconstituted 4-mg/mL olipudase alfa-rpcp solution to appropriately sized 0.9% sodium chloride injection infusion bag to achieve a fixed total volume (see Tables 1 and 2); avoid foaming within infusion bag.

Gently invert syringe or infusion bag to mix solution. Do not shake syringe or infusion bag; slight flocculation (described as thin translucent fibers) occasionally occurs following dilution.

Rate of Administration

Infuse diluted solutions of olipudase alfa-rpcp using infusion rates described in Tables 3 and 4. In the absence of infusion-associated reactions (IARs), increase the infusion rate according to the steps of infusion rate escalation as indicated (±5 minutes) in Tables 3 and 4. Each step of the infusion rate escalation will last for 20 minutes with the exception of the final step, which should last until completion of the infusion volume.

Dosage

Pediatric Patients

Acid Sphingomyelinase Deficiency

IV

Dosage of olipudase alfa-rpcp is based on weight. Use actual body weight in patients with BMI ≤30 kg/m². In patients with BMI >30 kg/m², use an adjusted body weight calculated by the following formula: adjusted body weight (kg) = (actual height in m)² x 30.

Always initiate treatment via a dose escalation regimen followed by a maintenance dose.

Recommended initial dose: 0.03 mg/kg.

Recommended maintenance dosage: 3 mg/kg every 2 weeks.

To reduce risk of hypersensitivity and IARs or elevated transaminase levels, follow recommended dosage titration schedule shown in Table 5.

Adults

Acid Sphingomyelinase Deficiency

IV

Dosage of olipudase alfa-rpcp is based on weight. Use actual body weight in patients with BMI ≤30 kg/m². In patients with BMI >30 kg/m², use an adjusted body weight calculated by the following formula: adjusted body weight (kg) = (actual height in m)² x 30.

Always initiate treatment via a dose escalation regimen followed by a maintenance dose.

Recommended initial dose: 0.1 mg/kg.

Recommended maintenance dosage: 3 mg/kg every 2 weeks.

To reduce risk of hypersensitivity and IARs or elevated transaminase levels, follow recommended dosage titration schedule shown in Table 6.

Instructions for Missed Doses

A dose is considered missed if it is not administered within 3 days of scheduled infusion date. Instructions for a missed dose depend on whether patient is in escalation phase or maintenance phase and on how many consecutive doses have been missed (see Table 7).

Dosage Modification for Toxicity

Hypersensitivity Reactions and Infusion-associated Reactions

Severe hypersensitivity reaction (e.g., anaphylaxis) or severe IAR: Immediately discontinue olipudase alfa-rpcp administration and initiate appropriate medical treatment.

Mild to moderate hypersensitivity reaction or mild to moderate IAR: Consider temporarily holding infusion or slowing infusion rate, and/or reducing dosage of olipudase alfa-rpcp.

If dosage is reduced, reescalate following dose escalation instructions in Tables 5 and 6 for pediatric patients and adults, respectively.

Transaminase Elevations

If transaminase levels are elevated above baseline and >2 times the upper limit of normal (ULN) prior to the next scheduled administration, adjust olipudase alfa-rpcp dose (prior dose repeated or reduced) or temporarily withhold treatment until liver transaminases return to patient’s baseline value.

Special Populations

No special population dosage recommendations at this time.