Posology : מינונים

4.2   Posology and method of administration
Therapy with CABOMETYX should be initiated by a physician experienced in the administration of anticancer medicinal products.

Posology

CABOMETYX as monotherapy
For RCC, HCC and DTC, the recommended dose of CABOMETYX is 60 mg once daily.
Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

CABOMETYX in combination with nivolumab in first-line advanced RCC
The recommended dose of CABOMETYX is 40 mg once daily in combination with nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks. The treatment should continue until disease progression or unacceptable toxicity. Nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression (see the Summary of Product Characteristics (SmPC) for posology of nivolumab).

Treatment modification
Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction (see Table 1). When dose reduction is necessary in monotherapy, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.

When CABOMETYX is administered in combination with nivolumab, it is recommended to reduce the dose to 20 mg of CABOMETYX once daily, and then to 20 mg every other day (refer to the nivolumab SmPC for recommended treatment modification for nivolumab).

Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, could become serious or intolerable.

If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.
Table 1: Recommended CABOMETYX dose modifications for adverse reactions Adverse reaction and severity              Treatment modification
Grade 1 and grade 2 adverse reactions      Dose adjustment is usually not required.
which are tolerable and easily managed
Add supportive care as indicated.
Grade 2 adverse reactions which are        Interrupt treatment until the adverse reaction resolves to intolerable and cannot be managed with     grade ≤1.
a dose reduction or supportive care
Add supportive care as indicated.
Consider re-initiating at a reduced dose.
Grade 3 adverse reactions (except          Interrupt treatment until the adverse reaction resolves to clinically nonrelevant laboratory          grade ≤1.
abnormalities)
Add supportive care as indicated.
Re-initiate at a reduced dose.
Grade 4 adverse reactions (except          Interrupt treatment.
clinically nonrelevant laboratory
Institute appropriate medical care.
abnormalities)
If adverse reaction resolves to grade ≤1, re-initiate at a reduced dose.
If adverse reaction does not resolve, permanently discontinue the treatment.
Liver enzymes elevations for RCC patients treated with CABOMETYX in combination with nivolumab
ALT or AST > 3 times ULN but ≤10           Interrupt CABOMETYX and nivolumab until these adverse times ULN without concurrent total         reactions resolves to Grade≤1 bilirubin ≥ 2 times ULN
Corticosteroid therapy may be considered if immune-mediated reaction is suspected (refer to nivolumab SmPC).
Re-initiate with a single medicine or sequential re-initiating with both medicines after recovery may be considered. If re- initiating with nivolumab, refer to nivolumab SmPC.
ALT or AST > 10 times ULN or > 3           Permanently discontinue CABOMETYX and nivolumab.
times ULN with concurrent total
Corticosteroid therapy may be considered if immune-mediated bilirubin ≥ 2 times ULN reaction is suspected (refer to nivolumab SmPC).
Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4)

Concomitant medicinal products
Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided (see sections 4.4 and 4.5).

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.

Special populations

Elderly
No specific dose adjustment for the use of cabozantinib in elderly patients (≥ 65 years) is recommended.
Race
No dose adjustment is necessary based on ethnicity (see section 5.2).
Renal impairment
Cabozantinib should be used with caution in patients with mild or moderate renal impairment.
Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.

Hepatic impairment
In patients with mild hepatic impairment no dose adjustment is required. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2).
There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients (see section 5.2).

Cardiac impairment
There are limited data in patients with cardiac impairment. No specific dosing recommendations can be made.

Paediatric population
The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet been established. Currently available data are described in sections 4.8,5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration
CABOMETYX is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking CABOMETYX.