Olipudase Alfa-Rpcp

1 INDICATIONS AND USAGE XENPOZYME is indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. XENPOZYME is a hydrolytic lysosomal sphingomyelin-specific enzyme indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important recommendations prior to XENPOZYME treatment initiation. ( 2.1 ) Adults: Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion. ( 2.2 ) Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion. ( 2.3 ) See Full Prescribing Information for the recommended dose escalation and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions. ( 2.2 , 2.3 , 2.5 , 2.6 , 2.7 ) 2.1 Important Recommendations Prior to XENPOZYME Treatment Initiation Therapy with XENPOZYME should be directed in consultation with physicians knowledgeable in the management of ASMD. In order to avoid dosing errors including overdosage [see Overdosage (10) ] , follow all instructions for dosage and administration. Laboratory Testing Before initiating XENPOZYME: Obtain baseline transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels in all patients within 1 month prior to treatment initiation [see Warnings and Precautions (5.3) ] . Verify pregnancy status in females of reproductive potential [see Use in Specific Populations (8.1 , 8.3) ] . Premedication Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 5.2) ] . Medical Support Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during XENPOZYME administration [see Warnings and Precautions (5.1) ] . Weight-Based Dosing Information The recommended adult and pediatric dosages of XENPOZYME for the dose escalation and maintenance phases [see Dosage and Administration (2.2 , 2.3) ] are based on body weight as follows for patients with a body mass index (BMI): Less than or equal to 30, the dosage is based on actual body weight (kg) Greater than 30, the dosage is based on adjusted body weight (kg). Calculate an adjusted body weight (kg) based on height in meters as described below: Adjusted body weight (kg) = (actual height in m) 2 × 30 2.2 Recommended Dosage in Adult Patients Dose Escalation Phase The recommended starting dose of XENPOZYME in adults is 0.1 mg/kg. In order to reduce the risk of infusion-associated reactions or elevated transaminase levels, follow the dose escalation regimen in Table 1 [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Administer XENPOZYME via intravenous infusion every 2 weeks. Table 1: XENPOZYME Dose Escalation Regimen for Adult Patients Use actual body weight for patients with a BMI less than or equal to 30. For patients with a BMI greater than 30, calculate adjusted body weight (kg) = (actual height in m) 2 × 30 [see Dosage and Administration (2.1) ] . Adult Patients (18 years and older) First dose (Day 1/Week 0) 0.1 mg/kg Second dose (Week 2) 0.3 mg/kg Third dose (Week 4) 0.3 mg/kg Fourth dose (Week 6) 0.6 mg/kg Fifth dose (Week 8) 0.6 mg/kg Sixth dose (Week 10) 1 mg/kg Seventh dose (Week 12) 2 mg/kg Eighth dose (Week 14) The dose escalation phase includes the first 3 mg/kg dose. 3 mg/kg (recommended maintenance dose) Maintenance Phase The recommended maintenance dosage of XENPOZYME in adults is 3 mg/kg via intravenous infusion every 2 weeks. 2.3 Recommended Dosage in Pediatric Patients Dose Escalation Phase The recommended starting dose of XENPOZYME in pediatric patients is 0.03 mg/kg. In order to reduce the risk of hypersensitivity and infusion-associated reactions or elevated liver enzyme elevations, follow the dose escalation regimen in Table 2 [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Administer XENPOZYME via intravenous infusion every 2 weeks. Table 2: XENPOZYME Dose Escalation Regimen for Pediatric Patients Use actual body weight for patients with a BMI less than or equal to 30. For patients with a BMI greater than 30, calculate adjusted body weight (kg) = (actual height in m) 2 × 30 [see Dosage and Administration (2.1) ] . Pediatric Patients (0 to 17 years) First dose (Day 1/Week 0) 0.03 mg/kg Second dose (Week 2) 0.1 mg/kg Third dose (Week 4) 0.3 mg/kg Fourth dose (Week 6) 0.3 mg/kg Fifth dose (Week 8) 0.6 mg/kg Sixth dose (Week 10) 0.6 mg/kg Seventh dose (Week 12) 1 mg/kg Eighth dose (Week 14) 2 mg/kg Ninth dose (Week 16) The dose escalation phase includes the first 3 mg/kg dose. 3 mg/kg (recommended maintenance dose) Maintenance Phase The recommended maintenance dosage of XENPOZYME in pediatric patients is 3 mg/kg via intravenous infusion every 2 weeks. 2.4 Missed Doses A dose is considered missed when it is not administered within 3 days of the scheduled date. When a dose of XENPOZYME is missed, refer to Table 3. Follow the instructions in the "Escalation Phase" or "Maintenance Phase" depending on which phase the patient misses the dose. Table 3: Dosing Recommendations for XENPOZYME Missed Doses At scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg, administer that dose twice as per Table 1 and 2. Consecutive Missed Doses In: Escalation Phase Maintenance Phase 1 missed dose First dose after a missed dose: Administer last tolerated dose Second and subsequent doses after missed dose: Resume dose escalation at next infusion according to Table 1 for adult patients or Table 2 for pediatric patients First and subsequent doses after missed dose: Administer maintenance dose 2 consecutive missed doses First dose after missed dose: Administer 1 dose below last tolerated dose Second and subsequent doses after missed dose: Resume dose escalation according to Table 1 for adults or Table 2 for pediatric patients First dose after missed dose: Administer 1 dose below the maintenance dose Second and subsequent doses after missed dose: Resume the maintenance dose 3 or more consecutive missed doses For adult patients who have not completed the dose escalation phase: Reinitiate dose escalation regimen starting at 0.1 mg/kg and follow Table 1. For pediatric patients who have not completed the dose escalation phase: Reinitiate dose escalation regimen starting at 0.03 mg/kg and follow Table 2. First and subsequent doses after missed doses: Restart dosing at 0.3 mg/kg and follow Table 1 for adult patients or Table 2 for pediatric patients. For adult patients who have missed 3 or more consecutive doses in the mainenance phase during which sphingomyelin could have reaccumulated: The treating physician may consider resuming dosing at 0.1 mg/kg and dose escalate according to Table 1. For pediatric patients who have missed 3 or more consecutive doses in the maintenance phase during which sphingomyelin could have reaccumulated: The treating physician may consider resuming dosing at 0.03 mg/kg and dose escalate according to Table 2. 2.5 Dosage and Administration Modifications and Monitoring In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe infusion-associated reaction (IAR), immediately discontinue XENPOZYME administration and initiate appropriate medical treatment [see Warnings and Precautions (5.1 , 5.2) ] . In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding or slowing the infusion rate, and/or reducing the XENPOZYME dose. If dose is reduced, re-escalate following dose escalation described in Tables 1 and 2 for adult and pediatric patients, respectively [see Warnings and Precautions (5.1 , 5.2) ] . If transaminase levels are elevated above baseline and >2 times the ULN prior to the next scheduled administration, the XENPOZYME dose can be adjusted (prior dose repeated or reduced) or treatment can be temporarily withheld until the liver transaminases return to the patient's baseline value [see Warnings and Precautions (5.3) ] . 2.6 Preparation Instructions Use aseptic technique during preparation. Reconstitute and dilute XENPOZYME in the following manner: Reconstitution and Dilution Instructions 1. Determine the number of XENPOZYME vials to be reconstituted based on the calculated dose [see Dosage and Administration (2.2 , 2.3) ] . 2. Remove XENPOZYME vials from refrigeration and set aside for approximately 20 to 30 minutes to allow vials to reach room temperature. 3. Reconstitute each vial with: 1.1 mL of Sterile Water for Injection, USP into the 4 mg vial 5.1 mL of Sterile Water for Injection, USP into the 20 mg vial by directing the diluent flow to the inside wall of the vial to avoid foaming. 4. Gently roll and tilt vial(s) to reconstitute XENPOZYME and avoid foaming. Each reconstituted vial will yield a 4 mg/mL clear, colorless solution. 5. Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The solution should be clear and colorless. Discard if the solution is discolored or if visible particulate matter is present. 6. Withdraw the required volume of XENPOZYME from the vial(s) and dilute the XENPOZYME solution for infusion with 0.9% Sodium Chloride Injection, USP in a syringe or infusion bag depending on the volume of infusion (see Table 4 ). For patients who weigh less than 10 kg receiving 0.03 mg/kg and 0.1 mg/kg and patients who weigh between 10 to 20 kg receiving 0.03 mg/kg dose, the volume of infusion will vary to achieve a fixed final concentration of 0.1 mg/mL (see Table 4 ). Prepare the required dose diluted to a final concentration of 0.1 mg/mL in a syringe for infusion. For all other patient weights and doses, the final concentration will vary to achieve a fixed total volume (see Table 4 ). - For total volume less than or equal to 20 mL prepare a syringe for infusion: Inject the required volume of the reconstituted XENPOZYME solution (4 mg/mL) from step 3 slowly down the inside wall of the syringe. Add slowly the quantity sufficient of 0.9% Sodium Chloride Injection, USP to obtain the required total infusion volume (avoid foaming within the syringe). - For a total volume of greater than or equal to 50 mL prepare an infusion bag : Add slowly the required volume of the reconstituted XENPOZYME solution (4 mg/mL) from step 3 into the appropriate size 0.9% Sodium Chloride Injection, USP infusion bag (avoid foaming within the bag) to achieve a fixed total volume per Table 4. 7. Gently invert the syringe or 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. 8. Vials are for single dose only. Discard any unused solution. Storage and Handling of the Reconstituted and Diluted Solutions If the reconstituted XENPOZYME vials are not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at controlled room temperature at 20°C to 25°C (68°F to 77°F) for up to 6 hours. Discard the unused XENPOZYME reconstituted solution after 24 hours if stored refrigerated or 6 hours if stored at controlled room temperature. If the diluted solution is not used immediately, refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours or store at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours (inclusive of infusion time), or discard. Do not freeze. Table 4: XENPOZYME Infusion Volumes for Pediatric and Adult Patients Based on Body Weight Use actual or adjusted body weight per patient BMI. Refer to section 2. [see Dosage and Administration (2.2 , 2.3) ] . Pediatric Patients (0 to 17 years) Adult patients (18 years and older) Body Weight ≥2 kg and <10 kg Body Weight ≥10 kg and <20 kg Body Weight ≥20 kg Body Weight ≥20 kg XENPOZYME Dose Total Infusion Volume 0.03 mg/kg Actual volume will vary Volume will vary to achieve a final concentration of 0.1 mg/mL (0.6 mL to 3 mL) Actual volume will vary (3 mL to 6 mL) 5 mL NA 0.1 mg/kg Actual volume will vary (2 mL to 10 mL) 5 mL 10 mL 20 mL 0.3 mg/kg 5 mL 10 mL 20 mL 100 mL 0.6 mg/kg 10 mL 20 mL 50 mL 100 mL 1 mg/kg 20 mL 50 mL 100 mL 100 mL 2 mg/kg 50 mL 75 mL 200 mL 100 mL 3 mg/kg 50 mL 100 mL 250 mL 100 mL 2.7 Administration Instructions Prior to administration, inspect the syringe or infusion bag for foaming. If foaming is present, let foam dissipate before administering XENPOZYME. Use a 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. Infuse XENPOZYME using the infusion rates described in Table 5 and Table 6. In absence of infusion-associated reactions, increase infusion rate per the steps of infusion as indicated (+/- 5 minutes). Each step of infusion will last for 20 minutes with the exception of the final step which should last until completion of the infusion volume. At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection, USP using the same infusion rate as the one used for the last part of the infusion. Do not infuse XENPOZYME in the same intravenous line with other products. Table 5: XENPOZYME Infusion Rates for Adult Patients Dose Infusion Rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion. 0.1 mg/kg 20 mL/hour 60 mL/hour NA NA 0.3 to 3 mg/kg 3.33 mL/hour 10 mL/hour 20 mL/hour 33.33 mL/hour Table 6: XENPOZYME Infusion Rates for Pediatric Patients Dose Infusion rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reactions increase infusion rate sequentially per the steps of infusion. 0.03 mg/kg 0.1 mg/kg/hour for the full length of the infusion NA NA NA 0.1 mg/kg 0.1 mg/kg/hour 0.3 mg/kg/hour NA NA 0.3 mg/kg 0.1 mg/kg/hour 0.3 mg/kg/hour 0.6 mg/kg/hour NA 0.6 mg/kg 0.1 mg/kg/hour 0.3 mg/kg/hour 0.6 mg/kg/hour 1 mg/kg/hour 1 mg/kg 2 mg/kg 3 mg/kg Home Infusion Home administration under the supervision of a healthcare provider may be considered for patients on maintenance dose [see Dosage and Administration (2.2 , 2.3) ] 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. The dose and infusion rate used in the home setting should remain the same as were used in the supervised clinical setting and should not be changed without supervision of a physician. In case of missed dose(s) or delayed infusion, contact a physician as subsequent infusions may occur in a supervised clinical setting.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions (IARs) [see Warnings and Precautions (5.2) ] Elevated Transaminase Levels [see Warnings and Precautions (5.3) ] Most common adverse reactions in adult patients (incidence ≥10%) are headache, cough, diarrhea, hypotension, and ocular hyperemia. ( 6.1 ) Most common adverse reactions in pediatric patients (incidence ≥20%) are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety analysis from 3 clinical trials included a total of 38 XENPOZYME-treated patients (30 adult and 8 pediatric patients) with age range from 1.5 to 59 years old receiving intravenous doses up to 3 mg/kg every 2 weeks [see Clinical Studies (14) ] . The median exposure duration was 2.5 years (range: 0.4 to 3.7 years) in adult patients and 2.7 years (range: 2.5 to 3.2 years) in pediatric patients. Serious adverse reactions of anaphylactic reaction were reported in 2 (25%) XENPOZYME-treated pediatric patients. Most frequently reported adverse drug reactions in adults (incidence ≥10%) were headache, cough, diarrhea, hypotension, and ocular hyperemia. Most frequently reported adverse drug reactions in pediatric patients (incidence ≥20%) were pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis. Adult patients with ASMD type B and type A/B (Trial 1) In Trial 1, 13 adult patients received XENPOZYME once every 2 weeks for 52 weeks (primary analysis period (PAP)) at dosages escalating from 0.1 mg/kg to a target dose of 3 mg/kg [see Clinical Studies (14.2) ] . Adverse reactions that occurred in at least 7% of XENPOZYME-treated adult patients during the PAP are described in Table 7. Table 7: Adverse Reactions Occurring at >7% in Adult Patients with ASMD During the 52-Week Primary Analysis Period in Trial 1 Adverse Reaction XENPOZYME N=13 Placebo N=18 Headache 7 (54%) 8 (44%) Cough 4 (31%) 2 (11%) Diarrhea 2 (15%) 2 (11%) Hypotension 2 (15%) 2 (11%) Ocular hyperemia 2 (15%) 1 (6%) Erythema 1 (8%) 1 (6%) Asthenia 1 (8%) 1 (6%) Pharyngitis 1 (8%) 1 (6%) Dyspnea 1 (8%) 0 Urticaria 1 (8%) 0 Papule 1 (8%) 0 Myalgia 1 (8%) 0 Throat irritation 1 (8%) 0 C-reactive protein abnormal 1 (8%) 0 Pediatric Patients with ASMD type B and type A/B (Trial 2 and Trial 3) In Trial 2, 8 pediatric patients less than or equal to 17 years of age received XENPOZYME intravenously once every 2 weeks for 64 weeks [see Clinical Studies (14.3) ] . After 64 weeks, all pediatric patients entered into Trial 3. Adverse reactions that occurred in at least 13% of pediatric patients are described in Table 8. Table 8: Adverse Reactions Occurring at ≥13% in XENPOZYME-Treated Pediatric Patients with ASMD in Trial 2 Duration of treatment in Trial 2 was 64 weeks. All patients continued into Trial 3. and Trial 3 for an Overall Observation Period of 2.5 to 3.2 Years Adverse Reactions XENPOZYME N=8 Abdominal pain includes abdominal pain and abdominal pain upper Fatigue includes fatigue and asthenia Rash includes rash and erythema Pyrexia 8 (100%) Cough 6 (75%) Diarrhea 6 (75%) Rhinitis 6 (75%) Abdominal pain 5 (63%) Vomiting 4 (50%) Headache 4 (50%) Urticaria 4 (50%) Nausea 3 (38%) Rash 3 (38%) Arthralgia 3 (38%) Pruritus 2 (25%) Fatigue 2 (25%) Pharyngitis 2 (25%) C-reactive protein increased 1 (13%) Hypotension 1 (13%) Anaphylactic reaction 1 (13%) Hypersensitivity 1 (13%) Infusion site swelling 1 (13%) Tachycardia 1 (13%) Pharyngeal swelling 1 (13%) Treatment related serious adverse reactions, hypersensitivity reactions including anaphylaxis, and IARs occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than in adult patients. Laboratory Adverse Reaction Elevated transaminase levels ranging from 3 times to 14 times the upper limit of normal (ULN) were reported in 4 (13%) adults and 1 (13%) pediatric patient during the XENPOZYME dose escalation phase in clinical trials. Immunogenicity: Antidrug Antibody-Associated Adverse Reactions In Trial 1, infusion-associated reactions (including hypersensitivity reactions) occurred in a higher percentage in XENPOZYME-treated patients who developed IgG ADA compared to those who did not develop IgG ADA (73% versus 44%) [see Clinical Pharmacology (12.6) and Clinical Studies (14.2) ] . In Trial 2, one XENPOZYME-treated pediatric patient (18-months old) 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, XENPOZYME was resumed four months later using a diluted drug solution and a desensitization procedure. One pediatric patient (16-months old) 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 [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics In adult patients with ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration (C max ) and area under the concentration-time curve (AUC) at steady state were 30 (5) mcg/mL and 607 (120) mcg∙h/mL, respectively, at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks. Olipudase alfa-rpcp C max and AUC increase proportionally over a dose range of 0.1 to 3 mg/kg (0.03 to 1 times the approved recommended maintenance dose). Distribution The mean (SD) volume of distribution of olipudase alfa-rpcp was 13 (2) L in adult patients with ASMD. Elimination The mean (SD) clearance of olipudase alfa-rpcp was 0.33 (0.07) L/h and the mean half-life (t 1/2 ) ranged from 32 to 38 hours in adult patients with ASMD. Metabolism The metabolic pathway of olipudase alfa-rpcp has not been characterized. Olipudase alfa-rpcp is expected to be metabolized into small peptides and amino acids via catabolic pathways. Specific Populations Pediatric Patients In pediatric patients (1.5 to 17.5 years of age) with ASMD, the mean (SD) C max was 24.3 (2.8) mcg/mL and the mean (SD) AUC was 449 (70) mcg∙h/mL at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks.