Posology : מינונים

4.2    Posology and method of administration

Odomzo 200 mg should only be prescribed by or under the supervision of a specialist physician experienced in the management of the approved indication.

Posology

The recommended dose is 200 mg sonidegib taken orally.
Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity develops.


Dose modifications for creatine phosphokinase (CK) elevations and muscle-related adverse reactions
Temporary dose interruption and/or dose reduction of Odomzo therapy may be required for CK elevations and muscle-related adverse reactions.

Table 1 summarises recommendations for dose interruption and/or dose reduction of Odomzo therapy in the management of symptomatic CK elevations and muscle-related adverse reactions (such as myalgia, myopathy, and/or spasm).

Table 1          Recommended dose modifications and management for symptomatic CK elevations and muscle-related adverse reactions

Severity of CK elevation                 Dose modifications* and management recommendations
•     Continue treatment at the same dose and monitor CK levels weekly until resolution to baseline level and then monthly thereafter. Monitor muscle
Grade 1 symptoms for changes until resolution
[CK elevation >ULN - 2.5 x ULN] to baseline.
•     Check renal function (serum creatinine) regularly and ensure that patient is adequately hydrated.
•     Interrupt treatment and monitor CK levels weekly until resolution to baseline level.
•     Monitor muscle symptoms for changes until resolution to baseline. Upon resolution, resume treatment at the same dose level and measure CK monthly thereafter.
Grade 2 without renal impairment                 •     Check renal function (serum creatinine) (serum Cr ≤ ULN)                                       regularly and ensure that the patient is [CK elevation >2.5 x ULN - 5 x ULN]                    adequately hydrated.
•     If symptoms re-occur, interrupt treatment until resolution to baseline.
Re-introduce sonidegib at 200 mg every other day and follow the same monitoring recommendations. If symptoms persist despite alternate-day dosing, consider discontinuing treatment.


•       Interrupt treatment and monitor CK levels weekly until resolution to baseline. Monitor muscle symptoms for changes until resolution to baseline.
•       Check renal function (serum creatinine)
Grade 3 or 4 without renal impairment regularly and ensure that patient is
(serum Cr ≤ ULN) adequately hydrated.
[Grade 3 (CK elevation >5 x ULN - 10 x
ULN)]                                             •       If renal function is not impaired and [Grade 4 (CK elevation >10 x ULN)]                        CK resolves to baseline, consider resuming treatment at 200 mg every other day. CK levels should be measured weekly for 2 months after re-administration of sonidegib and monthly thereafter.
•       If renal function is impaired, interrupt treatment and ensure that the patient is adequately hydrated and evaluate other secondary causes of renal impairment.
•       Monitor CK and serum creatinine levels weekly until resolution to baseline.
Grade 2, 3 or 4 with renal impairment                     Monitor muscle symptoms for changes (serum Cr > ULN)                                          until resolution to baseline.
•       If CK and serum creatinine levels return to baseline consider resuming treatment at 200 mg every other day and measure
CK levels weekly for 2 months and monthly thereafter; otherwise discontinue treatment permanently.

*     The above recommendations for dose modifications are based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, developed by the National Cancer Institute (USA). The CTCAE is a standardised classification of adverse events used in assessing medicinal products for cancer therapy.
Cr: creatinine; ULN: upper limit of normal

Other dose modifications
Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a subsequent dose reduction) or discontinuation.

When dose interruption is required, consider resuming Odomzo at the same dose after resolution of the adverse reaction to ≤ grade 1.

If dose reduction is required, then the dose should be reduced to 200 mg every other day. If the same adverse drug reaction occurs following the switch to alternate daily dosing and does not improve, consider discontinuing treatment with Odomzo.

Due to the long half-life of sonidegib the full effect of a dose interruption or dose adjustment of sonidegib on several adverse reactions is expected to generally occur after a few weeks (see section 5.2).


Duration of treatment
In clinical studies, treatment with Odomzo was continued until disease progression or until unacceptable toxicity. Treatment interruptions of up to 3 weeks were allowed based on individual tolerability.

Benefit of continued treatment should be regularly assessed, with the optimal duration of therapy varying for each individual patient.

Special populations
Patients with renal impairment
Sonidegib has not been studied in a dedicated pharmacokinetic study in patients with renal impairment. Based on the available data, sonidegib elimination via the kidney is negligible. A population pharmacokinetic analysis found that mild or moderate renal impairment did not have a significant effect on the apparent clearance (CL/F) of sonidegib, suggesting that dose adjustment is not necessary in patients with renal impairment (see section 5.2). No efficacy and safety data are available in patients with severe renal impairment.

Patients with hepatic impairment
No dose adjustment is necessary in patients with hepatic impairment (see section 5.2).

Elderly (≥65 years)
Safety and efficacy data in patients aged 65 years and older do not suggest that a dose adjustment is required in these patients (see section 5.2).

Paediatric population
The safety and efficacy of Odomzo in children and adolescents aged below 18 years with basal cell carcinoma have not been established. No data are available.

Method of administration

Odomzo is for oral use. The capsules must be swallowed whole. They must not be chewed or crushed. The capsules must not be opened due to risk of teratogenicity (see section 5.3).

Odomzo must be taken at least two hours after a meal and at least one hour before the following meal to prevent increased risk of adverse reactions due to higher exposure of sonidegib when taken with a meal (see section 5.2). If vomiting occurs during the course of the treatment, then no re-dosing of the patient is allowed before the next scheduled dose.

If a dose is missed, it should be taken as soon as this is realised, unless more than six hours have passed since it was scheduled to be taken; in this case, the patient should wait and take the next scheduled dose.