Posology : מינונים

4.2    Posology and method of administration

Xenpozyme treatment should be supervised by a healthcare professional experienced in the management of ASMD or other inherited metabolic disorders. Xenpozyme infusion should be administered by a healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious systemic hypersensitivity reactions.

Posology

The rapid metabolism of accumulated sphingomyelin (SM) by olipudase alfa generates pro-inflammatory breakdown products, which may induce infusion-associated reactions and/or transient liver enzyme elevations. A dose escalation regimen can minimise the majority of these adverse events (see section 5.3).
Xenpozyme dose is based on the actual body weight for patient with a body mass index (BMI) ≤ 30 or an optimal body weight for patient with a BMI > 30 (see section for patients with a BMI > 30).

Adults

Dose escalation phase
The recommended starting dose of Xenpozyme is 0.1 mg/kg* for adults (also see missed doses subsection for additional guidance) and subsequently, the dose should be increased according to the dose escalation regimen presented in Table 1:

Table 1: Dose escalation regimen in adults
Adult patients (≥18 years old)
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)           3 mg/kg* (recommended maintenance dose)
*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Maintenance phase
The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.
*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Paediatric population

Dose escalation phase
The recommended starting dose of Xenpozyme is 0.03 mg/kg* for paediatric patients, and the dose should be subsequently increased according to the dose escalation regimen presented in Table 2: 
Table 2: Dose escalation regimen in paediatric patients
Paediatric patients (0 to <18 years old)
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)          3 mg/kg* (recommended maintenance dose)
*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Maintenance phase
The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.


*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Patients with BMI> 30

In adult and paediatric patients with a body mass index (BMI) > 30, the body weight that is used to calculate the dose of Xenpozyme is estimated via the following method (for dose escalation and maintenance phases).
Body weight (kg) to be used for dose calculation = 30 × (actual height in m)2 
Example:
For a patient with:
BMI of 38 body weight of 110 kg height of 1.7 m.
The dose to be administered will be calculated using a body weight of 30 × 1.72 = 86.7 kg.

Missed doses
A dose is considered missed when not administered within 3 days of the scheduled date. When a dose of Xenpozyme is missed, the next dose should be administered as described below as soon as possible.
Thereafter, administrations should be scheduled every 2 weeks from the date of the last administration.

During the dose escalation phase
•      If 1 infusion is missed: the last tolerated dose should be administered, before resuming dose escalation according to the regimen in adults (Table 1) or in paediatric patients (Table 2).
•      If 2 consecutive infusions are missed: 1 dose level lower than the last tolerated dose (using a minimal dose of 0.3 mg/kg) should be administered, before resuming dose escalation according to Table 1 or Table 2.
•      If 3 or more consecutive infusions are missed: dose escalation should be resumed at 0.3 mg/kg according to Table 1 or Table 2.
At the next scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg, that dose should be administered twice as per Table 1 and Table 2.

During the maintenance phase
•      If 1 maintenance infusion is missed: the maintenance dose should be administered and the treatment schedule adjusted accordingly.
•      If 2 consecutive maintenance infusions are missed: 1 dose below the maintenance dose (i.e.
2 mg/kg) should be administered. Then for subsequent infusions, the maintenance dose (3 mg/kg) every 2 weeks should be administered.
•      If 3 or more consecutive maintenance infusions are missed: dose escalation should be resumed at 0.3 mg/kg according to Table 1 or Table 2.

Monitoring of transaminase level

Transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels should be obtained prior to treatment initiation and monitored during any dose escalation phases (see section 4.4). If the pre-infusion transaminase levels are elevated above baseline and >2 times the upper limit of normal (ULN), the Xenpozyme dose can be adjusted (prior dose repeated or reduced) or treatment can be temporarily withheld in accordance with the degree of transaminase elevation. If a patient requires a dose adjustment or treatment interruption, treatment re-initiation should follow the dose escalation regimen described in Table 1 and Table 2 for adult and paediatric patients, respectively, and recommendations in case of missed doses (see missed doses section).

Special populations

Elderly patients
No dose adjustment is recommended for patients over the age of 65 (see section 5.2).

Hepatic impairment
No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

Renal impairment
No dose adjustment is recommended in patients with renal impairment (see section 5.2).
Method of administration

Xenpozyme is for intravenous use only. Infusions should be administered in a stepwise manner preferably using an infusion pump.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

After reconstitution and dilution, the solution is administered as an intravenous infusion. The infusion rates must be incrementally increased during the infusion only in the absence of infusion-associated reactions (in case of infusion-associated reactions, see section 4.4.). The infusion rate and duration of infusion (+/- 5 min) for each step of infusion are detailed in Table 3 and Table 4: 
Table 3: Infusion rates and duration of infusion in adult patients

Approximate
Dose                               Infusion rate duration of
(mg/kg)                          Duration of infusion infusion step 1         step 2            step 3          step 4
20 mL/hr       60 mL/hr
0.1                                            NA              NA               35 min for 20 min     for 15 min
3.33 mL/hr       10 mL/hr          20 mL/hr      33.33 mL/hr
0.3 to 3                                                                         220 min for 20 min     for 20 min        for 20 min     for 160 min hr: hour; min: minute; NA: Not applicable

Table 4: Infusion rates and duration of infusion in paediatric patients 
Infusion rate                              Approximate
Dose                             Duration of infusion                           duration of (mg/kg)                                                                           infusion step 1          step 2           step 3          step 4
0.1 mg/kg/hr for the full
0.03                              NA               NA             NA             18 min length of the infusion
0.1 mg/kg/hr     0.3 mg/kg/hr
0.1                                                NA             NA             35 min for 20 min        onwards
0.1 mg/kg/hr     0.3 mg/kg/hr     0.6 mg/kg/hr
0.3                                                               NA             60 min for 20 min       for 20 min        onwards
0.6                                                                             80 min 1         0.1 mg/kg/hr   0.3 mg/kg/hr       0.6 mg/kg/hr     1 mg/kg/hr        100 min        2          for 20 min     for 20 min         for 20 min       onwards          160 min
3                                                                              220 min hr: hour; min: minute; NA: Not applicable

Signs and symptoms of infusion-associated reactions (IARs), such as headache, urticaria, pyrexia, nausea and vomiting, and other signs or symptoms of hypersensitivity should be monitored during the 

infusion. Depending on the symptom severity, the infusion may be slowed, paused or discontinued and appropriate medical treatment initiated as needed.

In case of severe hypersensitivity and/or anaphylactic reaction, treatment with Xenpozyme should be discontinued immediately (see section 4.4).

At the end of infusion (once the syringe or infusion bag is empty), the infusion line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection using the same infusion rate as the one used for the last part of the infusion.

Home infusion during maintenance phase

Home infusion under the supervision of a healthcare professional may be considered for patients on maintenance dose and who are tolerating their infusions well. The decision to have patients moved to home infusion should be made after evaluation and recommendation by the prescribing physician.
Appropriate medical support, including personnel trained in emergency measures, should be readily available when Xenpozyme is administered. If anaphylactic or other acute reactions occur, immediately discontinue the Xenpozyme infusion, initiate appropriate medical treatment and seek the attention of a physician. If severe hypersensitivity reactions occur, subsequent infusions should only occur in a setting where resuscitation measures are available. Dose and infusion rates should remain constant while at home, and should not be changed without supervision of the prescribing physician.
In case of missed doses or delayed infusion, the prescribing physician should be contacted.