VARGATEF

What it is

VARGATEF is available as soft capsules containing 100 mg or 150 mg of nintedanib as the esilate salt. Nintedanib is a tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptors (VEGFR 1–3), platelet-derived growth factor receptors (PDGFR α and β), and fibroblast growth factor receptors (FGFR 1–3).

Approved indications

— Treatment in combination with docetaxel for patients with locally advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after failure of first line chemotherapy. — Treatment of Idiopathic Pulmonary Fibrosis (IPF). — Treatment of other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype. — Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

Dosing overview

For NSCLC, the recommended dose of VARGATEF 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 as docetaxel chemotherapy administration (day 1). For IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD, the recommended dose of VARGATEF is 150 mg twice daily administered approximately 12 hours apart. VARGATEF capsules should be taken orally, preferably with food, and swallowed whole with water.

Key safety warnings

Diarrhoea is the most frequently reported gastrointestinal event in NSCLC, with the majority of patients experiencing mild to moderate diarrhoea; 6.3% of patients had grade ≥3 diarrhoea in combination treatment compared to 3.6% treated with docetaxel alone. In IPF and other chronic fibrosing ILDs, diarrhoea was the most frequent gastrointestinal event reported, and in most patients the event was mild to moderate intensity occurring within the first 3 months of treatment. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products and may require dose interruption, dose reduction or discontinuation of therapy with VARGATEF. Due to the mechanism of action, nintedanib patients might have an increased risk of gastrointestinal perforations and ischaemic colitis, with cases of gastrointestinal perforations and ischaemic colitis, some of which were fatal, reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. VARGATEF should only be initiated at least 4 weeks after abdominal surgery. Cases of drug-induced liver injury have been observed with nintedanib treatment, and in the post-marketing period, severe liver injury with fatal outcome has been reported in NSCLC; administration of nintedanib was associated with elevation of liver enzymes (ALT, AST, ALP, gamma-glutamyltransferase) and bilirubin. Liver related adverse events of grade ≥3 were reported in 15.3% of patients treated with the combination of VARGATEF and docetaxel compared to 1.8% of patients treated with docetaxel alone. Female and Asian patients have a higher risk of elevations in liver enzymes. In NSCLC, a higher frequency of grade >3 neutropenia was observed with VARGATEF plus docetaxel compared to docetaxel alone, with subsequent complications such as sepsis or febrile neutropenia; febrile neutropenia was reported in 7.5% of patients in the combination arm compared to 4.5% treated with docetaxel alone, and fatal sepsis was reported in 0.9% of patients treated with VARGATEF in combination with docetaxel.

Contraindications

VARGATEF is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya, or to any of the excipients listed in the product information. VARGATEF is contraindicated during pregnancy.

PBS listing

VARGATEF nintedanib 150 mg and 100 mg soft capsules are registered on the ARTG (Australian Register of Therapeutic Goods) in the RE (restricted export) licence category, first listed 1 September 2015. Specific PBS listing details including item numbers, restriction type, and ex-manufacturer price are not provided in the available source documents.

Regulatory history

VARGATEF nintedanib soft capsules were registered on the ARTG on 1 September 2015 for both the 100 mg and 150 mg strengths. The TGA approved the extension of indications for VARGATEF (nintedanib) for the treatment of other chronic fibrosing interstitial lung diseases with a progressive phenotype on 23 December 2020. The TGA's evaluation found that the pivotal INBUILD study demonstrated a statistically significant and clinically meaningful reduction in the annual rate of decline in forced vital capacity in patients with progressive fibrosing ILDs treated with nintedanib compared to placebo.