Olipudase alfa is an enzyme replacement therapy approved for adult and pediatric patients with acid sphingomyelinase deficiency (ASMD). Olipudase alfa is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. ASMD is a rare genetic disease caused by the lack of an enzyme needed to break down a complex lipid, called sphingomyelin, that accumulates in the liver, spleen, lung, and brain. Olipudase alfa helps reduce sphingomyelin accumulation in the liver, spleen, and lung. The efficacy of olipudase alfa for the treatment of ASMD was demonstrated in a randomized, double-blind, placebo-controlled study of 31 adult patients and in a multicenter, open-label pediatric study (n = 8). Overall, treatment with olipudase alfa improved lung function and reduced liver and spleen size. Severe hypersensitivity and infusion-related reactions, including anaphylaxis and life-threatening reactions, have been reported during olipudase alfa administration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Olipudase alfa should be used in consultation with a physician knowledgeable in the management of ASMD.
-Consider pretreating with antihistamines, antipyretics, and/or corticosteroids prior to olipudase alfa administration to decrease the risk of hypersensitivity and infusion-related reactions.
-Use actual body weight to calculate the dose for patients with a BMI of 30 or less. For patients with a BMI more than 30, use adjusted body weight calculated with the following formula: Adjusted body weight (kg) = 30 x (actual height in meters)2.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution
-Remove the required number of vials from refrigeration and set aside for approximately 20 to 30 minutes to allow them to reach room temperature.
-Reconstitute each vial by directing the diluent flow to the inside wall of the vial:
--1.1 mL of Sterile Water for injection into the 4 mg vial
-5.1 mL of Sterile Water for injection into the 20 mg vial
-Tilt and roll each vial gently. Each vial will yield a 4 mg/mL clear, colorless solution.
-Discard the solution if discolored or visible particulate matter is present.
-Storage: If the reconstituted vials are not used immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours or at controlled room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to 6 hours. Do not freeze.
Dilution
-Withdraw the volume of reconstituted solution, corresponding to the prescribed dose, from the appropriate number of vials. Dilute reconstituted drug with 0.9% Sodium Chloride Injection in a syringe or infusion bag depending on the recommended volume of infusion.
-Vials are single dose only. Discard any unused solution.
-Recommended infusion volume for Adults:
--0.1 mg/kg/dose: 20 mL
-0.3 to 3 mg/kg/doses: 100 mL
-Recommended infusion volume for Pediatrics
--0.03 mg/kg/dose: 0.6 to 3 mL (2 to 9 kg); 3 to 6 mL (10 to 19 kg); 5 mL (20 kg or more)
-0.1 mg/kg/dose: 2 to 10 mL (2 to 9 kg); 5 mL (10 to 19 kg); 10 mL (20 kg or more)
-0.3 mg/kg/dose: 5 mL (2 to 9 kg); 10 mL (10 to 19 kg); 20 mL (20 kg or more)
-0.6 mg/kg/dose: 10 mL (2 to 9 kg); 20 mL (10 to 19 kg); 50 mL (20 kg or more)
-1 mg/kg/dose: 20 mL (2 to 9 kg); 50 mL (10 to 19 kg); 100 mL (20 kg or more)
-2 mg/kg/dose: 50 mL (2 to 9 kg); 75 mL (10 to 19 kg); 200 mL (20 kg or more)
-3 mg/kg/dose: 50 mL (2 to 9 kg); 100 mL (10 to 19 kg); 250 mL (20 kg or more)
-For a total volume greater than or equal to 50 mL, prepare an infusion bag:
--Add the required volume of the reconstituted olipudase alfa (4 mg/mL) solution slowly into the appropriate size 0.9% Sodium Chloride Injection infusion bag (avoid foaming within the bag).
-Gently invert the infusion bag to mix. Do not shake. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution.
-For total volume less than or equal to 20 mL, prepare a syringe for infusion:
--All patients EXCEPT for pediatric patients who weigh less than 10 kg receiving 0.03 mg/kg and 0.1 mg/kg doses and patients who weigh between 10 and 20 kg receiving 0.03 mg/kg dose:
--Inject the required volume of the reconstituted olipudase alfa (4 mg/mL) solution slowly down the inside wall of the syringe.
-Add the quantity sufficient of 0.9% Sodium Chloride Injection slowly to obtain the required total infusion volume (avoid foaming within the syringe).
-Pediatric patients who weigh less than 10 kg receiving 0.03 or 0.1 mg/kg doses and patients who weigh between 10 and 20 kg receiving 0.03 mg/kg dose:
--Prepare an infusion solution diluted to a final concentration of 0.1 mg/mL with a quantity sufficient of 0.9% Sodium Chloride Injection.
-Gently invert the syringe to mix. Do not shake. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution.
-Storage: If the diluted solution is not administered immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours or at room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to 12 hours (including infusion time). Do not freeze.
Intravenous Infusion
-Olipudase alfa is for intravenous use only. Infuse in stepwise manner.
-Prior to administration, inspect the syringe or infusion bag for foaming. If foaming is present, let foam dissipate before administration.
-Use an in-line, low protein-binding, 0.2 micron in-line 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.
-Do not infuse olipudase alfa in the same intravenous line with other products.
-Monitor for signs and symptoms of infusion-associated reactions (IARs), such as headache, urticaria, fever, nausea and vomiting, and other signs of hypersensitivity during the infusion. If IARs occur, depending on the symptom severity, slow, pause, or discontinue the infusion and initiate appropriate medical treatment as needed.
-Increase the infusion rate incrementally only in the absence of IARs.
-Adults
--0.1 mg/kg/dose: Initiate infusion at 20 mL/hour for 20 minutes, followed by 60 mL/hour until completion.
-0.3 to 3 mg/kg/doses: Initiate infusion at 3.33 mL/hour for 20 minutes, followed by 10 mL/hour for 20 minutes, followed by 20 mL/hour for 20 minutes, followed by 33.33 mL/hour until completion.
-Pediatrics
--0.03 mg/kg/dose: Initiate infusion at 0.1 mg/kg/hour and continue for the full length of infusion.
-0.1 mg/kg/dose: Initiate infusion at 0.1 mg/kg/hour for 20 minutes, followed by 0.3 mg/kg/hour until completion.
-0.3 mg/kg/dose: Initiate infusion at 0.1 mg/kg/hour for 20 minutes, followed by 0.3 mg/kg/hour for 20 minutes, followed by 0.6 mg/kg/hour until completion.
-0.6 to 3 mg/kg/doses: Initiate infusion at 0.1 mg/kg/hour for 20 minutes, followed by 0.3 mg/kg/hour for 20 minutes, followed by 0.6 mg/kg/hour for 20 minutes, followed by 1 mg/kg/hour until completion.
-At the end of infusion (once the syringe or infusion bag is empty), flush infusion line with 0.9% Sodium Chloride Injection using the same infusion rate as the 1 used for the last part of the infusion.
Home infusion during maintenance phase
-Home administration under the supervision of a health care provider may be considered for patients on maintenance dose and who are tolerating their infusion well. The decision to have patients moved to home infusion should be made after evaluation and recommendation by a physician.
-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 a physician.
Serious hypersensitivity reactions or anaphylaxis have occurred in patients treated with olipudase alfa. Some of these reactions have been life-threatening. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during olipudase alfa administration. Treatment related serious adverse reactions and hypersensitivity reactions, including anaphylaxis, occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than in adult patients. Prior to olipudase alfa administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids to decrease the risk of reactions. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue olipudase alfa immediately and initiate appropriate medical treatment. If a mild or moderate hypersensitivity reaction occurs, consider holding the infusion temporarily, slowing the infusion rate, and/or reducing the olipudase alfa dose. In patients with a severe hypersensitivity reaction, a desensitization procedure to olipudase alfa may be considered. Consider the risks and benefits of readministering olipudase alfa after severe hypersensitivity reactions (including anaphylaxis). If the decision is made to readminister olipudase alfa, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the approved recommended dosage. Consider testing for IgE ADA in olipudase alfa-treated patients who experience severe hypersensitivity reactions, including anaphylaxis. Testing for antibodies against olipudase alfa are available through Genzyme Corporation (at 1-800-745-4447). Consider other clinical laboratory testing such as serum tryptase and complement activation in patients who experience anaphylaxis. In clinical trials, 1 pediatric patient (18 months of age) experienced an anaphylactic reaction during the sixth infusion of olipudase alfa in the dose escalation period. Additionally, another pediatric patient (16 months of age) with acid sphingomyelinase deficiency (ASMD) type A, treated with a version of olipudase alfa manufactured from a different process, experienced 2 anaphylactic reactions during the fifth and sixth infusions in the dose escalation period; the patient received an immune tolerance induction therapy prior to treatment. In both of these pediatric patients who had anaphylaxis, anti-olipudase alfa IgE (IgE ADA) and IgG (IgG ADA) antibodies were detected. Hypersensitivity-related reactions that were mild to moderate in severity occurred in 10 (33%) adult patients and 4 (50%) pediatric patients who received olipudase alfa in clinical trials. Hypersensitivity reactions in adults included urticaria (8%), pruritus, erythema (8%), rash (including erythematous rash), eczema, angioedema, and erythema nodosum. Hypersensitivity reactions in pediatric patients included urticaria (50%), pruritus (25%), rash (38%), erythema (38%), and localized edema. Additional adverse reactions reported in adult and pediatric patients that could be signs of a hypersensitivity reaction include cough (31% adults, 75% pediatrics), dyspnea (8% adults), throat irritation (8% adults), papule (8% adults), hypotension (15% adults, 13% pediatrics), ocular or conjunctival hyperemia (15% adults), pharyngeal swelling (13% pediatrics), and sinus tachycardia (13% pediatrics).
Infusion-related reactions were reported in approximately 50% of adult patients and 75% of pediatric patients treated with olipudase alfa in clinical trials; a severe infusion-related reaction occurred in 1 pediatric patient. Infusion-related reactions occurred within 24 hours of infusion. The most common infusion-related reactions in adult patients (more than 10%) were headache (54%), pruritus, vomiting, and urticaria. The most common infusion-related reactions in pediatric patients (more than 20%) were urticaria, erythema, headache (50%), nausea (38%), fever (100%), and vomiting (50%). Injection site reaction or infusion site swelling was reported in 13% of pediatric patients. Antihistamines, antipyretics, and/or corticosteroids may be given prior to olipudase alfa administration to reduce the risk of infusion-related reactions; however, these reactions may still occur in patients after receiving pretreatment. If severe infusion-related reactions occur, discontinue olipudase alfa immediately and initiate appropriate medical treatment. Consider the risks and benefits of readministering olipudase alfa after severe infusion-related reactions. Once a patient tolerates the infusion, the dose may be increased to reach the recommended dose. If a mild or moderate infusion-related reaction occurs, consider holding the infusion temporarily, slowing the infusion rate, and/or reducing the olipudase alfa dosage. Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, was also observed in 1 adult and 1 pediatric patient receiving olipudase alfa in clinical trials. Most of the APRs occurred at 48 hours post infusion during the dose escalation period. Elevations of C-reactive protein, calcitonin, and IL-6, and reduction of serum iron were observed. The most common clinical symptoms associated with APRs were fever, vomiting, and diarrhea. These can be managed as other infusion-related reactions.
Elevated hepatic enzymes were reported in 4 (13%) olipudase alfa-treated adults and 1 (13%) olipudase alfa-treated pediatric patient during the dose escalation phase in clinical trials. At the time of the next scheduled infusion, these elevated transaminase concentrations generally returned to concentrations observed prior to the infusion. To manage the risk of elevated transaminase concentrations, assess ALT and AST within 1 month prior to initiation of olipudase alfa, within 72 hours prior to any infusion during dose escalation, which includes the first 3 mg/kg dose, or prior to the next scheduled infusion upon resuming treatment after a missed dose. If either the baseline or preinfusion transaminase concentration (during the dose escalation phase) is more than 2 times the ULN, repeat transaminase concentrations within 72 hours after the end of the infusion. If the preinfusion transaminase concentrations are elevated above baseline and more than 2 times the ULN prior to the next scheduled administration, the dose can be reduced (repeat prior lower dose or reduce the dose) or olipudase alfa can be temporarily withheld until the transaminase concentrations return to the patient's baseline value. Assess transaminase concentrations routinely when reaching the recommended maintenance dose.
Rhinitis (75% pediatrics), abdominal pain (63% pediatrics), diarrhea (15% adults, 75% pediatrics), arthralgia (38% pediatrics), myalgia (8% adults), fatigue (25% pediatrics), asthenia (8% adults), and pharyngitis (8% adults, 25% pediatrics) were reported in patients receiving olipudase alfa in adult (n = 13) and pediatric (n = 8) clinical trials.
Antibody formation can occur with olipudase alfa use. After 0.4 to 3.7 years of olipudase alfa treatment in adult patients, 9 out of 30 (30%) patients with acid sphingomyelinase deficiency (ASMD) developed anti-olipudase alfa IgG antibodies (referred to as IgG ADA). The median time to seroconversion from first infusion was approximately 8 weeks. One out of these 9 (11%) adult patients had neutralizing antibodies (NAb) that inhibited the olipudase alfa enzyme activity; none of these 9 patients had NAb that inhibit the cellular uptake of olipudase alfa. After 2.5 to 3.2 years of olipudase alfa treatment in pediatric patients, 6 out of 8 (75%) patients with ASMD developed IgG ADA. The median time to seroconversion from first infusion was 10 weeks. One out of the 6 (17%) pediatric patients developed NAb that inhibited olipudase alfa enzyme activity; none of these 6 patients had NAb that inhibited the cellular uptake of olipudase alfa. Infusion-associated reactions (including hypersensitivity reactions) occurred in a higher percentage in olipudase alfa-treated patients who developed ADA compared to those who did not develop ADA. In the adult study, infusion-associated reactions occurred in 73% of patients who developed IgG ADA compared to 44% of patients who did not develop IgG ADA. In the pediatric study, 1 olipudase alfa-treated patient (18 months of age) experienced an anaphylactic reaction during the sixth infusion and developed IgE ADA and the highest IgG ADA titers (ADA peak titer 1,600) of the patients in this trial. After treatment discontinuation, olipudase alfa was resumed 4 months later using a diluted drug solution and a desensitization procedure. One pediatric patient (16 months of age) with ASMD type A, treated with a version of olipudase alfa manufactured from a different process, experienced anaphylactic reactions (both during the fifth and sixth infusions) and developed IgG ADA (highest titer 1,600) and IgE ADA.
Serious hypersensitivity reactions or anaphylaxis have been reported in patients treated with olipudase alfa. Some of these reactions have been life-threatening. Olipudase alfa therapy requires an experienced clinician in the treatment of acid sphingomyelinase deficiency. Administration requires a specialized care setting where appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, are readily available during administration. Prior to administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids to decrease the risk of reactions. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue olipudase alfa immediately and initiate appropriate medical treatment. If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily withheld, and/or the olipudase alfa dose reduced. In patients with a severe hypersensitivity reaction, a desensitization procedure to olipudase alfa may be considered. Consider the risks and benefits of readministering olipudase alfa after severe hypersensitivity reactions (including anaphylaxis). If the decision is made to readminister olipudase alfa, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the approved recommended dosage. Consider testing for IgE antidrug antibodies (ADA) in olipudase alfa-treated patients who experience severe hypersensitivity reactions, including anaphylaxis. Testing for antibodies against olipudase alfa are available through Genzyme Corporation (at 1-800-745-4447). Consider other clinical laboratory testing such as serum tryptase and complement activation in patients who experience anaphylaxis.
Infusion-related reactions (i.e., headache, pruritus, urticaria, erythema, vomiting, fever) have been reported with olipudase alfa administration. Antihistamines, antipyretics, and/or corticosteroids may be given prior to administration to reduce the risk of infusion-related reactions; however, these reactions may still occur in patients after receiving pretreatment. If severe infusion-related reactions occur, discontinue olipudase alfa immediately and initiate appropriate medical treatment. Consider the risks and benefits of readministering olipudase alfa after severe infusion-related reactions. Once a patient tolerates the infusion, the dose may be increased to reach the recommended dose. If a mild or moderate infusion-related reaction occurs, consider temporarily withholding the infusion, slowing the infusion rate, and/or reducing the dosage. Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, was also observed in patients receiving olipudase alfa. Most of the APRs occurred at 48 hours post infusion during the dose escalation period. Elevations of C-reactive protein, calcitonin, and IL-6, and reduction of serum iron were observed. The most common clinical symptoms associated with APRs were pyrexia, vomiting, and diarrhea. These can be managed as other infusion-related reactions.
There are no available data on olipudase alfa use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. However, based on findings from animal reproduction studies, olipudase alfa may cause embryo-fetal harm when administered during the first trimester of pregnancy. In an embryo-fetal toxicity study in pregnant mice, a rare malformation (exencephaly) was observed in offspring at an exposure less than the exposure at the maximum recommended human dose (MRHD) of olipudase alfa. Olipudase alfa dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite concentrations that may increase the risk of fetal malformations. Consider the need for olipudase alfa, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal acid sphingomyelinase deficiency (ASMD) disease when deciding whether to continue or discontinue olipudase alfa maintenance dosing in pregnancy. Advise the pregnant female of the potential risk to the fetus if olipudase alfa is administered during pregnancy.
Advise patients about the reproductive risk and contraception requirements during olipudase alfa treatment. Olipudase alfa can cause fetal harm if administered during pregnancy. Advise females to avoid pregnancy and use effective contraception during and for at least 2 weeks after the last dose of olipudase alfa. Females of reproductive potential should undergo pregnancy testing prior to initiation of olipudase alfa.
There are no data on the presence of olipudase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. Olipudase alfa is present in animal milk (1.3% of the estimated maximal maternal plasma concentration). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for olipudase alfa and any potential adverse effects on the breastfed infant from olipudase alfa or from the underlying maternal condition.
General Dosing Information
-Obtain baseline transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) concentrations in all patients within 1 month prior to treatment initiation.
-Consider pretreating with antihistamines, antipyretics, and/or corticosteroids prior to olipudase alfa administration to decrease the risk of hypersensitivity and infusion-related reactions.
-Use actual body weight to calculate the dose for patients with a BMI of 30 or less. For patients with a BMI more than 30, use adjusted body weight using the following formula: Adjusted body weight (kg) = 30 x (actual height in meters)2.
For the treatment of acid sphingomyelinase deficiency (ASMD):
NOTE: Olipudase alfa is designated as an orphan drug by the FDA for this indication.
-for the treatment of ASMD during dose escalation and maintenance phase:
Intravenous dosage:
Adults: 0.1 mg/kg/dose IV initially. Titrate dose according to the following schedule every 2 weeks: 0.3 mg/kg/dose IV on weeks 2 and 4, 0.6 mg/kg/dose IV on weeks 6 and 8, 1 mg/kg/dose IV on week 10, 2 mg/kg/dose IV on week 12, and 3 mg/kg/dose IV on week 14. The recommended maintenance dose is 3 mg/kg/dose IV every 2 weeks.
Infants, Children, and Adolescents: 0.03 mg/kg/dose IV initially. Titrate dose according to the following schedule every 2 weeks: 0.1 mg/kg/dose IV on week 2, 0.3 mg/kg/dose IV on weeks 4 and 6, 0.6 mg/kg/dose IV on weeks 8 and 10, 1 mg/kg/dose IV on week 12, 2 mg/kg/dose IV on week 14, and 3 mg/kg/dose IV on week 16. The recommended maintenance dose is 3 mg/kg/dose IV every 2 weeks.
Neonates: 0.03 mg/kg/dose IV initially. Titrate dose according to the following schedule every 2 weeks: 0.1 mg/kg/dose IV on week 2, 0.3 mg/kg/dose IV on weeks 4 and 6, 0.6 mg/kg/dose IV on weeks 8 and 10, 1 mg/kg/dose IV on week 12, 2 mg/kg/dose IV on week 14, and 3 mg/kg/dose IV on week 16. The recommended maintenance dose is 3 mg/kg/dose IV every 2 weeks.
-for missed doses during dose escalation phase:
Intravenous dosage:
Adults: If 1 dose is missed: administer last tolerated dose before resuming dose escalation according to the recommended regimen. If 2 consecutive doses are missed: administer 1 dose level lower than the last tolerated dose, before resuming dose escalation according to the recommended regimen. If 3 or more consecutive doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen. At the next scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg/dose IV, that dose should be administered twice according to recommended regimen.
Infants, Children, and Adolescents: If 1 dose is missed: administer last tolerated dose before resuming dose escalation according to the recommended regimen. If 2 consecutive doses are missed: administer 1 dose level lower than the last tolerated dose, before resuming dose escalation according to the recommended regimen. If 3 or more consecutive doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen. At the next scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg/dose IV, that dose should be administered twice according to recommended regimen.
Neonates: If 1 dose is missed: administer last tolerated dose before resuming dose escalation according to the recommended regimen. If 2 consecutive doses are missed: administer 1 dose level lower than the last tolerated dose, before resuming dose escalation according to the recommended regimen. If 3 or more consecutive doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen. At the next scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg/dose IV, that dose should be administered twice according to recommended regimen.
-for missed doses during maintenance phase:
Intravenous dosage:
Adults: If 1 maintenance dose is missed: administer the maintenance dose and adjust the treatment schedule accordingly. If 2 consecutive maintenance doses are missed: administer 1 dose below the maintenance dose (i.e., 2 mg/kg/dose IV). Then for subsequent infusions, administer the maintenance dose (3 mg/kg/dose IV) every 2 weeks. If 3 or more consecutive maintenance doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen.
Infants, Children, and Adolescents: If 1 maintenance dose is missed: administer the maintenance dose and adjust the treatment schedule accordingly. If 2 consecutive maintenance doses are missed: administer 1 dose below the maintenance dose (i.e., 2 mg/kg/dose IV). Then for subsequent infusions, administer the maintenance dose (3 mg/kg/dose IV) every 2 weeks. If 3 or more consecutive maintenance doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen.
Neonates: If 1 maintenance dose is missed: administer the maintenance dose and adjust the treatment schedule accordingly. If 2 consecutive maintenance doses are missed: administer 1 dose below the maintenance dose (i.e., 2 mg/kg/dose IV). Then for subsequent infusions, administer the maintenance dose (3 mg/kg/dose IV) every 2 weeks. If 3 or more consecutive maintenance doses are missed: resume dose escalation at 0.3 mg/kg/dose IV according to the recommended regimen.
Therapeutic Drug Monitoring:
Dose Modifications for Treatment-Related Toxicity
Elevated Transaminase Concentrations
If either the baseline or preinfusion transaminase concentration (during the dose escalation phase) is more than 2 times the ULN, repeat transaminase concentrations within 72 hours after the end of the infusion. If the preinfusion transaminase concentrations are elevated above baseline and more than 2 times the ULN prior to the next scheduled administration, the olipudase alfa dose can be reduced (repeat prior lower dose or reduce the dose) or olipudase alfa can be temporarily withheld until the liver transaminases return to the patient's baseline value.
Hypersensitivity or Infusion-Related Reactions
Severe reactions: Discontinue olipudase alfa immediately and initiate appropriate medical treatment. Consider the risks and benefits of readministering olipudase alfa.
Mild or moderate reactions: The infusion rate may be slowed or temporarily withheld, and/or the olipudase dosage may be reduced. If dose is reduced, re-escalate following dose escalation recommendations.
Maximum Dosage Limits:
-Adults
3 mg/kg/dose IV every 2 weeks.
-Geriatric
3 mg/kg/dose IV every 2 weeks.
-Adolescents
3 mg/kg/dose IV every 2 weeks.
-Children
3 mg/kg/dose IV every 2 weeks.
-Infants
3 mg/kg/dose IV every 2 weeks.
-Neonates
3 mg/kg/dose IV every 2 weeks.
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 Olipudase Alfa products.
Acid sphingomyelinase deficiency (ASMD) 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. The deficiency of ASM causes an intra-lysosomal accumulation of sphingomyelin (as well as cholesterol and other cell membrane lipids) in various tissues. Olipudase alfa provides an exogenous source of ASM. Olipudase alfa is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD.
Plasma ceramide concentrations
Ceramide is elevated in the plasma of patients with ASMD. During clinical trials, plasma ceramide concentrations showed a transient increase after each administration (post infusion) of olipudase alfa. In the dose escalation phase, plasma ceramide concentrations were substantially increased compared to the baseline concentration. Plasma ceramide concentrations gradually decreased after repeated administration of olipudase alfa and the pre-infusion concentrations were generally lower than the baseline concentration during the maintenance phase of treatment.
Plasma lyosphingomyelin concentrations
Lysosphingomyelin is substantially elevated in the plasma of patients with ASMD. Plasma lysosphingomyelin concentrations decreased after repeated administration of olipudase alfa.
Liver sphingomyelin content
In adult patients, the liver sphingomyelin content, as assessed by histopathology, decreased from baseline to Week 52 in the olipudase alfa treatment group compared to an increase in the placebo group.
Olipudase alfa is administered intravenously. The mean Vd of olipudase alfa was 13 L in adult patients with acid sphingomyelinase deficiency (ASMD). The metabolic pathway of olipudase alfa has not been determined. Olipudase alfa is expected to be metabolized into small peptides and amino acids via catabolic pathways. The mean clearance and half-life of olipudase alfa were 0.33 L/hour and 32 to 38 hours, respectively, in adult patients with ASMD.
Affected cytochrome P450 isoenzymes and transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
In adult patients with ASMD, the mean Cmax and AUC of olipudase alfa at steady state were 30 mcg/mL and 607 mcg x hour/mL, respectively, at the recommended maintenance dose of 3 mg/kg/dose IV every 2 weeks. The Cmax and AUC of olipudase alfa increased proportionally over a dose range of 0.1 to 3 mg/kg (0.03 to 1 times the approved recommended maintenance dose).
-Special Populations
Pediatrics
In pediatric patients (1 to 17 years of age) with ASMD, the mean Cmax and AUC of olipudase alfa were 24.3 mcg/mL and 449 mcg x hour/mL, respectively, at the recommended maintenance dose of 3 mg/kg/dose IV every 2 weeks.