Nintedanib

Nintedanib is a drug indicated for the treatment of idiopathic pulmonary fibrosis (IPF) that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, Nintedanib inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease characterized by a progressive loss of lung function with worsening dyspnoea and cough. Development is thought to be instigated by repetitive lung injury (such as by cigarette smoke, industrial dusts, gastrooesophageal reflux and viral infection) leading to destruction of epithelial alveolar cells. Subsequent dysregulation of the repair process results in the proliferation/migration of fibroblasts and their differentiation into myofibroblasts, abnormal extracellular matrix deposition and excessive collagen accumulation in the lung interstitium and alveolar space, leading to progressive fibrosis and stiffening of the lungs. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) mediate various processes, including fibrogenesis and angiogenesis, and are implicated in the pathogenesis of IPF. By blocking substrate binding and downstream signalling cascades, Nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of extracellular matrix.

Nintedanib 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.

Nintedanib is indicated for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

Nintedanib (Nintedanib) is used to treat a lung disease called idiopathic pulmonary fibrosis (IPF). IPF causes scar tissue to form deep within your lungs. The scar tissue thickens and becomes stiff over time, which can make it harder for your lungs to work. Decreased lung function can make it hard for you to breathe. Other medical problems can occur when your brain, heart, and other organs do not get enough oxygen.

The cause of IPF is often unknown, but this condition is a progressive disease that can be fatal. Nintedanib is not a cure for IPF, but this medicine may slow the progress of this disease.

Nintedanib may also be used for purposes not listed in this medication guide.

Testing Prior to Nintedanib Administration

​Conduct liver function tests and a pregnancy test prior to initiating treatment with Nintedanib.

Recommended Dosage

The recommended dosage of Nintedanib is 150 mg twice daily administered approximately 12 hours apart.

Nintedanib capsules should be taken with food and swallowed whole with liquid. Nintedanib capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of Nintedanib is not known.

If a dose of Nintedanib is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.

​In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of Nintedanib is 100 mg twice daily approximately 12 hours apart taken with food.

Dosage Modification due to Adverse Reactions

In addition to symptomatic treatment, if applicable, the management of adverse reactions of Nintedanib may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with Nintedanib.

Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe liver damage, interrupt treatment or reduce Nintedanib to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with Nintedanib may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily). Discontinue Nintedanib for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.

​In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.

See also:
What is the most important information I should know about Nintedanib?

Nintedanib is contraindicated in patients with known hypersensitivity to Nintedanib, peanut or soya, or to any of the excipients.

Nintedanib is contraindicated during pregnancy (Use in Pregnancy & Lactation and Toxicology under Actions).

NSCLC: For contraindications of docetaxel please refer to the corresponding product information for docetaxel.

Use Nintedanib as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Nintedanib. Talk to your pharmacist if you have questions about this information.
• Take Nintedanib by mouth with food and liquid.
• Swallow Nintedanib whole. Do not break, crush, or chew before swallowing.
• Take Nintedanib on a regular schedule to get the most benefit from it.
• If you miss a dose of Nintedanib, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Nintedanib.

Use: Labeled Indications

Chronic fibrosing interstitial lung diseases with a progressive phenotype: Treatment of chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype.

Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis.

Systemic sclerosis-associated interstitial lung disease: Indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated ILD.

See also:
What other drugs will affect Nintedanib?

P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to Nintedanib 1.61-fold based on AUC and 1.83-fold based on C_max in a dedicated drug-drug interaction study.

In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to Nintedanib decreased to 50.3% based on AUC and to 60.3% based on C_max upon co-administration with rifampicin compared to administration of Nintedanib alone.

If co-administered with Nintedanib, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) may increase exposure to Nintedanib. In such cases, patients should be monitored closely for tolerability of Nintedanib. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with Nintedanib.

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John's Wort) may decrease exposure to Nintedanib. Selection of an alternate concomitant medication with no or minimal P-gp induction potential should be considered.

Food: Nintedanib is recommended to be taken with food.

Cytochrome (CYP) Enzymes: Only a minor extent of the biotransformation of Nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies. The likelihood of drug-drug interactions with Nintedanib based on CYP metabolism is therefore considered to be low.

Co-administration with Other Drugs: The potential for interactions of Nintedanib with hormonal contraceptives was not explored.

NSCLC: Co-administration of Nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of either drug to a relevant extent.

See also:
What are the possible side effects of Nintedanib?

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Liver Enzyme and Bilirubin Elevations
• Gastrointestinal Disorders
• Embryo-Fetal Toxicity
• Arterial Thromboembolic Events
• Risk of Bleeding
• Gastrointestinal Perforation

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Nintedanib was evaluated in over 1000 IPF patients with over 200 patients exposed to Nintedanib for more than 2 years in clinical trials.

Nintedanib was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 3) trials, 723 patients with IPF received Nintedanib 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with Nintedanib and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).

The most frequent serious adverse reactions reported in patients treated with Nintedanib, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with Nintedanib, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEVtreated patients and 1.8% of placebo-treated patients.

Adverse reactions leading to permanent dose reductions were reported in 16% of Nintedanib-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with Nintedanib was diarrhea (11%).

Adverse reactions leading to discontinuation were reported in 21% of Nintedanib-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in Nintedanib-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).

The most common adverse reactions with an incidence of ≥ 5% and more frequent in the Nintedanib than placebo treatment group are listed in Table 1.

Table 1 : Adverse Reactions Occurring in ≥ 5% of Nintedanib-treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3

In addition, hypothyroidism was reported in patients treated with Nintedanib, more than placebo (1.1% vs. 0.6%).