Xenpozyme Drug Information

XENPOZYME is indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.

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, follow all instructions for dosage and administration. Laboratory Testing Before initiating XENPOZYME: Obtain baseline transaminase (alanine aminotransferase and aspartate aminotransferase ) levels in all patients within 1 month prior to treatment initiation.

Verify pregnancy status in females of reproductive potential. Premedication Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids. Medical Support Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during XENPOZYME administration.

Weight-Based Dosing Information The recommended adult and pediatric dosages of XENPOZYME for the dose escalation and maintenance phases 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

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. 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. The recommended maintenance dosage of XENPOZYME in adults is 3 mg/kg via intravenous infusion every 2 weeks.

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.

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.

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. 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.

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.

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. 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 ). 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.

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 Home Infusion Home administration under the supervision of a healthcare 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. 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.

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. 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. Adverse reactions that occurred in at least 7% of XENPOZYME-treated adult patients during the PAP are described in Table 7. 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. All patients continued into Trial 3. and Trial 3 for an Overall Observation Period of 2.5 to 3.2 Years 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. 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%).

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.

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 ),. 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 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. 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.

Pediatric Use The safety and effectiveness of XENPOZYME for the treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) have been established in pediatric patients down to birth. Use of XENPOZYME for this indication is supported by evidence from an adequate, and well-controlled trial (Trial 1) in adults with supportive efficacy, safety, and tolerability data in pediatric patients (Trial 2 and Trial 3). Compared to 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.

Two pediatric patients, an 18 month old receiving XENPOZYME and a 16 month old with ASMD type A that received a version of olipudase alfa manufactured from a different process developed anaphylaxis.

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. 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 and Adverse Reactions.