Posology : מינונים

4.2   Posology and method of administration

Treatment with Vargatef should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Posology

The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle.

Vargatef must not be taken on the same day of docetaxel chemotherapy administration (= day 1).
If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded.

Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.

For posology, methods of administration, and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel.

Dose adjustments
As initial measure for the management of adverse reactions (see Tables 1 and 2) treatment with nintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline).
Nintedanib treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 1 and Table 2.
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with Vargatef should be permanently discontinued. In case of specific elevations of aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) values to > 3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥ 2 x ULN and alkaline phosphatase (ALKP) < 2 x ULN (see Table 2) treatment with Vargatef should be interrupted. Unless there is an alternative cause established, Vargatef should be permanently discontinued (see also section 4.4).


Table 1:        Recommended dose adjustments for Vargatef (nintedanib) in case of diarrhoea, vomiting and other non-haematological or haematological adverse reactions 
CTCAE* Adverse reaction                                       Dose adjustment Diarrhoea ≥ grade 2 for more than 7 consecutive days despite anti-diarrhoeal treatment
OR
Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment                                                After treatment interruption and recovery to grade 1 or baseline, dose reduction from 200 mg
Vomiting ≥ grade 2                                       twice daily to 150 mg twice daily and AND/OR                                                  - if a 2nd dose reduction is considered necessary - from 150 mg twice daily to 100 mg
Nausea ≥ grade 3                                         twice daily.
despite anti-emetic treatment
Other non-haematological or haematological adverse reaction of ≥ grade 3
* CTCAE: Common Terminology Criteria for Adverse Events

Table 2:        Recommended dose adjustments for Vargatef (nintedanib) in case of AST and/or ALT and bilirubin elevations

AST / ALT and bilirubin elevations                                 Dose adjustment Elevation of AST and/or ALT values                       After treatment interruption and recovery of to > 2.5 x ULN in conjunction with total bilirubin       transaminase-values to ≤ 2.5 x ULN in elevation to ≥ 1.5 x ULN                                 conjunction with bilirubin to normal, dose OR                                                      reduction from 200 mg twice daily to 150 mg Elevation of AST and/or ALT values                       twice daily and - if a 2nd dose reduction is to > 5 x ULN                                             considered necessary - from 150 mg twice daily to 100 mg twice daily.

Elevation of AST and/or ALT values                       Unless there is an alternative cause established, to > 3 x ULN in conjunction with an increase of          Vargatef should be permanently discontinued total bilirubin to ≥ 2 x ULN and
ALKP < 2 x ULN
AST: Aspartate aminotransferase; ALT: Alanine aminotransferase
ALKP: Alkaline phosphatase; ULN: Upper limit normal

Special populations
Paediatric population
The safety and efficacy of Vargatef in children aged 0-18 years have not been established. No data are available.

Elderly patients (≥ 65 years)
No overall differences in safety and efficacy were observed for elderly patients.
In the pivotal study 1199.13, 85 patients (12.9 % of the patients with adenocarcinoma histology) were ≥ 70 years of age (median age: 72 years, range: 70 - 80 years) (see section 5.1).
No adjustment of the initial dosing is required on the basis of a patient’s age (see section 5.2).

Race and body weight
Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of Vargatef are necessary (see section 5.2). Safety data for Black and African American patients are limited.
Renal impairment
Less than 1 % of a single dose of nintedanib is excreted via the kidney (see section 5.2). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 ml/min creatinine clearance).

Hepatic impairment
Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90 %). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B; see section 5.2). No adjustment of the starting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinical data. Limited safety data available from 9 patients with moderate hepatic impairment (Child Pugh B) are insufficient to characterize this population. The safety, efficacy and pharmacokinetics of nintedanib have not been investigated in patients with severe hepatic impairment (Child Pugh C).
Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Vargatef is not recommended (see sections 4.4 and 5.2).

Method of administration
Vargatef capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed The capsule should not be opened or crushed (see section 6.6).