Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Vargatef is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy.
Treatment with Vargatef should be initiated and supervised by a physician experienced in the use of anticancer therapies.
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.
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 × upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥2 × ULN and alkaline phosphatase (ALKP) <2 × 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 twice daily to 150 mg twice daily and – if a 2nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily. |
| Vomiting ≥ grade 2 AND/OR Nausea ≥ grade 3 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 to >2.5 × ULN in conjunction with total bilirubin elevation to ≥1.5 × ULN OR Elevation of AST and/or ALT values to >5 × ULN | After treatment interruption and recovery of transaminase-values to ≤2.5 × ULN in conjunction with bilirubin to normal, dose reduction from 200 mg twice daily to 150 mg twice daily and – if a 2nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily. |
| Elevation of AST and/or ALT values to >3 × ULN in conjunction with an increase of total bilirubin to ≥2 × ULN and ALKP <2 × ULN | Unless there is an alternative cause established, Vargatef should be permanently discontinued |
AST: Aspartate aminotransferase; ALT: Alanine aminotransferase
ALKP: Alkaline phosphatase; ULN: Upper limit normal
The safety and efficacy of Vargatef in children aged 0-18 years have not been established.
No overall differences in safety and efficacy were observed for elderly patients. In the pivotal trial 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 in elderly patients (see section 5.2).
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.
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).
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).
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).
There is no specific antidote or treatment for nintedanib overdose. The highest single dose of nintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients had an overdose of maximum 600 mg twice daily (b.i.d.) up to eight days. Observed adverse events were consistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinal symptoms. Both patients recovered from these adverse reactions. In case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.
3 years.
Do not store above 25°C.
Store in the original package in order to protect from moisture.
Aluminium/aluminium blisters containing 10 capsules each.
Pack-sizes: 60 or 120 capsules, or multipack of 120 (2 × 60) capsules (2 cartons of 60 capsules each, wrapped in plastic foil).
Pack-size: 60 capsules.
Not all pack-sizes may be marketed.
In the event of coming in contact with the content of the capsule, hands should be washed off immediately with plenty of water (see section 4.2).
Any unused product or waste material should be disposed of in accordance with local requirements.
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