Posology : מינונים

4.2 Posology and method of administration

4.2.1 Administration instructions
Each injection must be administered only by a health care professional.
Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration, whenever product and container permit.
XEPLION® is intended for intramascular use only. Do not administer by any other route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the muscle.
The recommended needle size for administration of XEPLION® into the deltoid muscle is determined by the patient’s weight:
• For patients weighing 90 Kg or more, the 1 ½ -inch, the 22 gauge needle is recommended.
• For patients weighing less than 90 Kg, the 1 inch, the 23 gauge needle is recommended.
Deltoid injections should be alternated between the two deltoid muscles.
The recommended needle size for administration of XEPLION® into the gluteal muscle is the 1 ½ - inch, 22 gauge needle regardless of patient weight.
Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.

4.2.2 Schizophrenia and Schizoaffective Disorder

For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with XEPLION®.
The recommended dosing of XEPLION® for each approved indication is displayed in Table 1.
The recommended initiation of XEPLION® is with a dose of 150 mg on treatment day 1 and 100 mg one week later, both administered in the deltoid muscle.
Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.

Table 1. Recommended Dosing of XEPLION® for Adults with Schizophrenia or Schizoaffective Disorder Indication     Initiation Dosing (deltoid) Monthly Maintenance        Maximum Day 1      Day 8            Dosea (deltoid or gluteal) Monthly Dose
Schizophrenia  150mg 100mg                 50-150mg b                 150mg 
Schizoaffective      150mg       100mg                 50-150mg c              150mg disorder a
Administered 5 weeks after the first injection.
b The recommended monthly maintenance dose for treatment os schizophrenia is 75 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths ( 50mg, 100mg, and 150 mg).
c
Adjust dose based on tolerability and/or efficacy using available strengths.

Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of XEPLION® should be considered, as the full effect of the dose adjustment may not be evident for several months.

4.2.3 Missed Doses

Avoiding Missed Doses
It is recommended that the second initiation dose of XEPLION® be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one- week timepoint. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly timepoint.

Management of a Missed Second Initiation Dose
If the target date for the second XEPLION® injection (one week ±4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient’s first injection. In case of a missed second initiation dose follow the dosing instructions provided in Table 2.


Table 2. Management of a Missed Second Initiation Dose
TIMING OF MISSED           DOSING
SECOND
INITIATION DOSE

Less than 4 weeks          Administer the second initiation dose of 100 mg in the deltoid muscle as soon since first injection      as possible.
1. It is recommended to administer a third injection of 75 mg in either the deltoid or gluteal muscle 5 weeks after the first injection (regardless of the timing of the second injection).
2. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.
4 to 7 weeks since first   Resume dosing with two injections of 100 mg in the following manner: injection                  1. Administer a deltoid injection as soon as possible.
2. Administer a second deltoid injection 1 week later.
3. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.
More than 7 weeks          Restart dosing with recommended initiation (see Section 4.2.2, Table 1): since first injection      1. Administer a 150 mg deltoid injection on Day 1.
2. Administer a 100 mg deltoid injection 1 week later.
3. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.

Management of a Missed Maintenance Dose
In case of a missed maintenance dose follow the dosing instructions provided in Table 3.

Table 3. Management of a Missed Maintenance Dose
TIMING OF MISSED                     DOSING
MAINTENANCE
DOSE
4 to 6 weeks since last    Resume regular monthly dosing as soon as possible at the patient’s previously injection                  stabilized dose, followed by injections at monthly intervals.
More than 6 weeks to       Resume the same dose the patient was previously stabilized on (unless the 6 months since last        patient was stabilized on a dose of 150 mg, then the first 2 injections should injection                  each be 100 mg) in the following manner:
1. Administer a deltoid injection as soon as possible.
2. Administer a second deltoid injection 1 week later at the same dose.
3. Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.
More than 6 months         Restart dosing with recommended initiation (see Section 4.2.2, Table 1): since last injection       1. Administer a 150 mg deltoid injection on Day 1.
2. Administer a 100 mg deltoid injection 1 week later.
3. Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.


4.2.4 Use with Oral Paliperidone or with Risperidone
Since paliperidone is the major active metabolite of risperidone, caution should be exercised when xeplion is coadministered with risperidone or with oral paliperidone for extended periods of time.
Safety data involving concomitant use of xeplion with other antipsychotics is limited.

  4.2.5 Dosage Adjustments
Renal Impairment
XEPLION® has not been systematically studied in patients with renal impairment [see 5.2 Pharmacokinetic properties ]. For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate XEPLION® With a dose of 100 mg on treatment day 1 and 75 mg one week later, Administer both doses in the deltoid muscle. Thereafter, follow with monthly injections of 50 mg in either the deltoid or gluteal muscle.
XEPLION® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). [see 5.2 Pharmacokinetic properties].

Coadministration with Strong CYP3A4 /P-glycoprotein (P-gp) Inducers
It may be necessary to increase the dose of XEPLION® when strong inducer of both CYP3A4 and Pgp (e.g., carbamazepine, rifampin, St Jhon’s wort) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of XEPLION® [see 4.5 Interaction with other medicinal products and other forms of interaction and 5.2 Pharmacokinetic properties].

4.2.6 Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to XEPLION®, or concerning concomitant administration with other antipsychotics.

4.2.6.1 Switching from Oral Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with XEPLION®.
Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with XEPLION®. Recommended initiation of XEPLION® is with a dose of 150 mg on treatment day 1 and 100 mg one week later, both administered in the deltoid muscle [see sectiom 4.2.2]. Patients previously stabilized on different doses of Invega Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with XEPLION® monthly doses as depicted in Table 4

Table 4. Doses of INVEGA® and XEPLION® needed to attain similar steady-state paliperidone exposure during maintenance treatment
Formulation         INVEGA®                 XEPLION®
Extended-Release Tablet Injection
Dosing Frequency Once Daily                 Once every 4 weeks
12                      150
Dose (mg)           6                       75
3                       50

4.2.6.2 Switching from Long-Acting Injectable Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with XEPLION®.
When switching patients currently at steady-state on a long-acting injectable antipsychotics, initiate XEPLION® therapy in place of the next scheduled injection. XEPLION® should then be continued at monthly intervals. The one-week initiation dosing regimen as described in Section 2.2 is not required.
Based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the additional available strengths (50mg, 100mg, and 150mg). Monthly maintenance doses can be administered in either the deltoid or gluteal muscle [see sectiom 4.2.2].
If XEPLION® is discontinued, its prolonged-release characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.