XENPOZYME

Dosage and Administration, Missed Doses ( 2.4 ) 12/2024 Dosage and Administration, Administration Instructions ( 2.7 ) 12/2024

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 …

3 DOSAGE FORMS AND STRENGTHS For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a sterile, white to off white lyophilized powder in a single-dose vial for reconstitution. For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a lyophilized powder in a single-dose vial for reconstitution. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal harm when administered to a pregnant female. XENPOZYME dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations (see Data ) , [see Clinical Pharmacology (12.2) ] . However, the decision to continue or discontinue XENPOZYME maintenance dosing in pregnancy should consider the female's need for XENPOZYME, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal ASMD disease. 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-rpcp (see Data ) . There are no available data on XENPOZYME use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise the pregnant female of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant mice, olipudase alfa-rpcp was administered intravenously at doses of 3, 10, or 30 mg/kg daily from gestation day (GD) 6 through GD 15. Exencephaly was observed in 1 litter at each of the 10 and 30 mg/kg dose groups (2 and 3 fetuses, respectively). These data are consistent with published literature reports that brief embryonic exposures to sphingomyelin metabolites or a sphingosine-1-phosphate (S1P) receptor modulator produced neural tube defects, including exencephaly, in chicks and mice. The developmental No Observed Adverse Effect Level (NOAEL) is 3 mg/kg. The AUC associated with this dose is 0.14-fold the clinical exposure at the MRHD. The developmental Lowest-Observed-Adverse-Effect Level (LOAEL), 10 mg/kg, is also associated with an exposure that is less than the clinical exposure at the MRHD. In an embryo-fetal development study in pregnant rabbits, olipudase alfa-rpcp was administered intravenously at doses of 3, 10, or 30 mg/kg daily from GD 6 through GD 19. There was no maternal or developmental toxicity. The developmental NOAEL was 30 mg/kg; the AUC 0–24 at this dose is approximately 10.5-fold the exposure at the MRHD. In a study of pre- and postnatal development in mice, olipudase alfa-rpcp was administered intravenously every other day from GD 6 through GD 18; then resumed every other day after parturition, from Lactation Day (LD) 1 through LD 19. Olipudase alfa-rpcp did not induce any effect on maternal reproductive function or on developmental and reproductive parameters of male and female offspring. Therefore, the maternal and developmental NOAELs are 30 mg/kg. Exposures at this dose, based on the embryo-fetal development study, were estimated to be approximately 1.5-fold the MRHD of olipudase alfa-rpcp. 8.2 Lactation Risk Summary There are no data on the presence of olipudase alfa-rpcp in human milk, the effects on the breastfed infant, or the effects on milk production. Olipudase alfa-rpcp is present in animal milk. (see Data ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XENPOZYME and any potential adverse effects on the breastfed infant from XENPOZYME or from the underlying maternal condition. Data Olipudase alfa-rpcp was administered as a single …

12.1 Mechanism of Action 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. XENPOZYME provides an exogenous source of ASM. XENPOZYME is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD.

11 DESCRIPTION Olipudase alfa-rpcp is a hydrolytic lysosomal sphingomyelin-specific enzyme consisting of 570 amino acids produced in a Chinese hamster ovary cell line by recombinant DNA technology. The molecular weight of olipudase alfa-rpcp is approximately 76 kDa. XENPOZYME (olipudase alfa-rpcp) for injection is supplied as a sterile, preservative-free, white to off-white lyophilized powder for reconstitution and dilution to be administered via intravenous infusion. XENPOZYME is supplied in single-dose vials. Each 4 mg vial contains 4 mg olipudase alfa-rpcp, dibasic sodium phosphate (0.89 mg), methionine (14.92 mg), monobasic sodium phosphate (1.63 mg), and sucrose (50 mg). After reconstitution with 1.1 mL of Sterile Water for Injection, USP, the final concentration is 4 mg/mL [see Dosage and Administration (2.6) ] . Each 20 mg vial contains 20 mg olipudase alfa-rpcp, dibasic sodium phosphate (4.47 mg), methionine (74.6 mg), monobasic sodium phosphate (8.17 mg), and sucrose (250 mg). After reconstitution with 5.1 mL of Sterile Water for Injection, USP, the final concentration is 4 mg/mL [see Dosage and Administration (2.6) ] . The pH is 6.5 after reconstitution.

10 OVERDOSAGE Cases of overdosage with XENPOZYME have been reported in pediatric patients during dose escalation. Some patients experienced serious adverse reactions including death within 24 hours of initial dose [see Warnings and Precautions (5.2) ] . The clinical findings included fever, hypotension, gastrointestinal bleeding, marked elevation in liver tests, metabolic acidosis, respiratory failure, and vomiting. There is no known specific antidote for XENPOZYME overdosage. In the event of overdosage, immediately stop the infusion, and monitor the patient closely in a hospital setting for the development of hypersensitivity reactions and IARs including acute phase reactions. For the management of adverse reactions, see Warnings and Precautions (5.1 , 5.2 , 5.3) and Adverse Reactions (6.1) .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied XENPOZYME (olipudase alfa-rpcp) for injection is supplied as a sterile white to off-white lyophilized powder for reconstitution in a single-dose vial. XENPOZYME does not contain any preservatives. XENPOZYME is available supplied as: Carton containing one 20 mg single-dose vial (NDC 58468-0050-1) Carton containing one 4 mg single-dose vial (NDC 58468-0051-1) Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. For storage of reconstituted and diluted solution [see Dosage and Administration (2.6) ] .