Nintedanib Esylate (nintedanib esylate)

Dosage of nintedanib esylate is expressed in terms of nintedanib.

Nintedanib esylate is administered orally twice daily, approximately 12 hours apart, with food. The capsules should be swallowed whole with liquid and should not be chewed or crushed because of a bitter taste. Wash hands thoroughly if contact with the content of the capsule occurs.

If a dose is missed, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time; the recommended maximum daily dosage of 300 mg should not be exceeded.

Store at 20-25degreesC (excursions permitted between 15-30degreesC).

Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, cytochrome P-450 (CYP) 3A4.

In vitro studies indicate that nintedanib and its metabolites do not inhibit or induce CYP isoenzymes.

In vitro studies indicate that nintedanib does not inhibit organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 2, or multidrug resistance protein (MRP) 2. In vitro, the drug has a weak inhibitory potential on OCT1, breast cancer resistance protein (BCRP), and P-gp; these findings are not expected to be clinically important.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Nintedanib/P-Gp And Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong P-gp or CYP3A4 inducers may decrease absorption, increase elimination rate, or increase the metabolism of nintedanib.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong P-gp or CYP3A4 inducers may result in decreased levels and effectiveness of nintedanib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends avoiding concomitant use of nintedanib with agents which are inducers of both P-gp and CYP3A4 as coadministration may decrease nintedanib exposure by 50%.(1)

DISCUSSION: In an interaction study, concurrent rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of nintedanib by 50.3% and 60.3%, respectively.(1) Inducers of both P-gp and CYP3A4 linked to this monograph are apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Nintedanib/Dual Cyp3a4 & P-Gp Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nintedanib is a substrate for the P-glycoprotein (P-gp) transporter and is metabolized to a minor extent by CYP3A4.

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and CYP3A4 may result in elevated levels of and clinical effects of nintedanib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nintedanib recommends close monitoring for nintedanib patients receiving drugs which are both P-gp and CYP3A4 inhibitors. In an interaction study ketoconazole increased exposure to nintedanib by 60%. Nintedanib therapy may need to be interrupted or the dose may need to be reduced.(1)

DISCUSSION: In an interaction study coadministration with ketoconazole, a P-gp and CYP3A4 inhibitor, increased nintedanib exposure (area-under-curve, AUC) and maximum concentration (Cmax) by 1.61-fold and 1.83 fold respectively.(1) Strong CYP3A4 & P-gp inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib. Moderate CYP3A4 & P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, schisandra, and verapamil. Weak CYP3A4 & P-gp inhibitors include: amiodarone, azithromycin, cimetidine, cyclosporine, daclatasvir, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, ivacaftor, lapatinib, mavorixafor, ranolazine, and vepdegestrant.(2)

None.

• Arterial aneurysm
• Arterial dissection
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Posterior reversible encephalopathy syndrome

• Arterial thrombosis
• Child-pugh class A hepatic impairment
• Coronary artery disease
• Disease of liver
• Gastrointestinal perforation
• Increased risk of bleeding
• Ischemic colitis
• Pregnancy
• Proteinuria
• Tobacco smoker

• Dehydration
• Pulmonary hypertension

Adverse effects reported in >=5% of patients receiving nintedanib include diarrhea, nausea, abdominal pain, vomiting, elevated concentrations of hepatic enzymes (e.g., ALT, AST, alkaline phosphatase), decreased appetite, headache, decreased weight, and hypertension.

More Frequent

• Abnormal hepatic function tests

Less Frequent

• Acute arterial thromboembolism
• Acute myocardial infarction
• Hemorrhage
• Hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Malignant neoplasm of lung

Rare or Very Rare

• Arterial aneurysm
• Arterial dissection
• Drug-induced hepatitis
• Gastrointestinal perforation
• Glomerular microangiopathy
• Hepatitis
• Hyperbilirubinemia
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Pancreatitis
• Pneumonia
• Posterior reversible encephalopathy syndrome
• Proteinuria
• Thrombocytopenic disorder

More Frequent

• Acute abdominal pain
• Anorexia
• Diarrhea
• Headache disorder
• Nausea
• Vomiting
• Weight loss

Less Frequent

• Bronchitis
• Hypothyroidism

Rare or Very Rare

• Pruritus of skin
• Skin rash

No enhanced messaging available.

Safety and efficacy of nintedanib have not been established in pediatric patients.

May cause fetal harm based on animal studies and its mechanism of action.

Nintedanib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to nintedanib in nursing infants, breastfeeding is not recommended during treatment.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In phase 2 and 3 IPF clinical studies, 61% of patients were >=65 years of age and 16% were >=75 years of age. In the chronic fibrosing ILDs with a progressive phenotype study, 61% of patients were >=65 years of age, and 19% were >=75 years of age . In the systemic sclerosis-ILD study, 21.4% were >=65 years of age, and 1.9% were >=75 years of age.

No overall differences in safety and efficacy were observed between geriatric patients and younger adults in phase 3 studies; however, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.