XENPOZYME

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. 6 mg/kg, administer that dose twice as per Table 1 and 2.

1 mg/kg and follow Table 1. 03 mg/kg and follow Table 2. 3 mg/kg and follow Table 1 for adult patients or Table 2 for pediatric patients. 1 mg/kg and dose escalate according to Table 1. 03 mg/kg and dose escalate according to Table 2. 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. 2) ] . 3) ] . 6 Preparation Instructions Use aseptic technique during preparation.

Reconstitute and dilute XENPOZYME in the following manner:

Reconstitution and Dilution Instructions 1. 3) ] . 2. Remove XENPOZYME vials from refrigeration and set aside for approximately 20 to 30 minutes to allow vials to reach room temperature. 3. 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. 9% Sodium Chloride Injection, USP in a syringe or infusion bag depending on the volume of infusion (see Table 4 ).

1 mg/mL (see Table 4 ). 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.

9% Sodium Chloride Injection, USP to obtain the required total infusion volume (avoid foaming within the syringe). 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. 3) ] . 7 Administration Instructions Prior to administration, inspect the syringe or infusion bag for foaming.

If foaming is present, let foam dissipate before administering XENPOZYME. 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.

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.

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.

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.

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.

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. 1) ] .

Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during XENPOZYME administration. , anaphylaxis) occurs, discontinue XENPOZYME immediately and initiate appropriate medical treatment.

Consider the risks and benefits of re-administering XENPOZYME following a severe hypersensitivity reaction (including anaphylaxis). One patient has been rechallenged using slower infusion rates at a dosage lower than the recommended dosage.

In patients with a severe hypersensitivity reaction, a tailored desensitization procedure to XENPOZYME may be considered. If the decision is made to readminister XENPOZYME, 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 recommended dosage.

1) ]. Testing for antibodies against olipudase alfa-rpcp 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.

5) ] . 5%) of the pediatric patients. The most frequent IARs in: ≥10% of adult patients were headache, pruritus, vomiting, and urticaria >20% of pediatric patients were urticaria, erythema, headache, nausea, pyrexia, and vomiting Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, was observed in one XENPOZYME-treated adult and one XENPOZYME-treated pediatric patient.

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.

Acute phase reactions were managed similar to other IARs. In the postmarketing setting, 24 hours after receiving XENPOZYME at a higher than recommended initial dose, a 2-year-old male patient with ASMD, experienced fever, respiratory distress, hypotension, and death [see Overdosage (10) ] .

Prior to XENPOZYME administration, consider pre-medicating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pre-treatment.

3) ] . If a severe IAR occurs, discontinue XENPOZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering XENPOZYME following a severe IAR. One patient has been rechallenged using slower infusion rates at a dosage lower than the recommended dosage.

If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage. 5) ] . 3 Elevated Transaminase Levels XENPOZYME may be associated with elevated transaminases (ALT, AST, or both) within 24 to 48 hours after infusion.

Elevated transaminase levels were reported in 4 (13%) XENPOZYME-treated adults and 1 (13%) XENPOZYME-treated pediatric patient during the dose escalation phase in clinical trials. 1) ] . To manage the risk of elevated transaminase levels, assess ALT and AST within one month prior to initiation of XENPOZYME, within 72 hours prior to any infusion during dose escalation, which includes the first 3 mg/kg dose outlined in Tables 1 and 2, or prior to the next scheduled XENPOZYME infusion upon resuming treatment following a missed dose.

If either the baseline or pre-infusion transaminase level (during the dose escalation phase) is >2 times the ULN, repeat transaminase levels within 72 hours after the end of the infusion. If the pre-infusion transaminase levels are elevated above baseline and >2 times the ULN prior to the next scheduled administration, the XENPOZYME dose can be reduced (repeat prior lower dose or reduce the dose) or XENPOZYME can be temporarily withheld until the liver transaminases return to the patient's baseline value.

Upon reaching the recommended maintenance dose, transaminase testing is recommended to be continued as part of routine clinical management of ASMD. 4 Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy There is no evidence that olipudase alfa-rpcp crosses the human placenta.

However, published literature reports that early embryonic exposure to a metabolite of sphingomyelin (ceramide) or the S1P receptor modulator fingolimod can produce exencephaly in chicks and mice, respectively. In animal reproduction studies, exencephaly, a neural tube defect occurring in the first trimester of pregnancy, was observed in mouse fetuses at exposures less than the exposure at the maximum recommended human dose of olipudase alfa-rpcp.

2) ] . 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.

Verify the pregnancy status in females of reproductive potential prior to initiating XENPOZYME treatment. 3) ] .