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Nintedanib Esylate

Class: Antifibrotic Agents
Chemical Name: (3Z) - 2,3 - Dihydro - 3 - [[[4 - [methyl[2 - (4 - methyl - 1 - piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene] - 2 - oxo - 1H - indole - 6 - carboxylic acid, methyl ester ethanesulfonate (1:1)
Molecular Formula: C31H33N5O4•2C2H6O3S
CAS Number: 656247-18-6
Brands: Ofev

Introduction

An inhibitor of multiple tyrosine kinases; reduces fibroblast activity in idiopathic pulmonary fibrosis (IPF).1 2 3 7 10

Uses for Nintedanib Esylate

Idiopathic Pulmonary Fibrosis

Treatment of idiopathic pulmonary fibrosis (IPF) (designated an orphan drug by FDA for this use).1 4

Nintedanib Esylate Dosage and Administration

General

  • Monitor liver function tests prior to initiation, monthly for the first 3 months, then every 3 months, and as clinically indicated.1

Restricted Distribution Program

  • Obtain through a limited network of specialty pharmacies.11 Consult the Ofev website () for specific ordering and availability information.11

Administration

Oral Administration

Administer orally twice daily (approximately 12 hours apart) with food.1

Swallow capsules whole with liquid; do not chew or crush.1

If a dose is missed, take the next dose at the regularly scheduled time.1 Do not double the dose or take extra doses.1

Dosage

Available as nintedanib esylate; dosage expressed in terms of nintedanib.1

Adults

Idiopathic Pulmonary Fibrosis
Oral

150 mg twice daily.1

Dosage Modification for Toxicity
Hepatic Toxicity

ALT or AST elevations >3 times but <5 times the ULN without signs or symptoms of severe liver damage: Temporarily interrupt therapy or reduce dosage to 100 mg twice daily.1 When liver function tests return to baseline values, may resume nintedanib at 100 mg twice daily and may subsequently increase dosage to 150 mg twice daily.1

ALT or AST elevations >5 times the ULN, or >3 times the ULN with signs or symptoms of severe liver damage: Discontinue therapy.1 (See Hepatic Toxicity under Cautions.)

Other Adverse Effects

If adverse reactions occur and are intolerable, despite symptomatic treatment, temporarily interrupt therapy or reduce dosage to 100 mg twice daily until the adverse reaction improves or resolves.1

May resume nintedanib 150 mg twice daily; alternatively, initially reduce dosage to 100 mg twice daily and may subsequently increase dosage to 150 mg twice daily.1

Discontinue therapy if intolerable adverse reactions occur or persist at a dosage of 100 mg twice daily.1

Prescribing Limits

Adults

Idiopathic Pulmonary Fibrosis
Oral

300 mg daily.1

Special Populations

Hepatic Impairment

No initial dosage adjustment required in patients with mild hepatic impairment (Child-Pugh class A); monitor closely and reduce dosage or temporarily interrupt therapy if not tolerated.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Not studied in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1

Renal Impairment

No initial dosage adjustment required in patients with mild to moderate renal impairment (Clcr 30–90 mL/minute).1

Not studied in patients with severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Nintedanib Esylate

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hepatic Toxicity

Abnormal liver function test results reported.1 If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Perform liver function tests prior to initiation, monthly for the first 3 months, then every 3 months, and as clinically indicated.1

GI Effects

Diarrhea, nausea, and vomiting may occur.1 In clinical studies, diarrhea reported frequently in patients receiving nintedanib and generally occurred within first 3 months of therapy.1 Nausea and vomiting reported less frequently.1

Treat adverse GI effects as necessary with appropriate supportive therapy.1 If diarrhea occurs or if nausea or vomiting persists despite appropriate supportive care, temporary interruption and/or dosage reduction may be necessary.1

Discontinue nintedanib if diarrhea persists despite symptomatic treatment or if severe nausea or vomiting does not resolve.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity and teratogenicity demonstrated in animals.1 Avoid pregnancy during therapy and for at least 3 months after drug discontinuance.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Arterial Thromboembolic Events

Arterial thromboembolic events (e.g., MI) reported.1 Use with caution in patients with cardiovascular risks, including coronary artery disease.1 Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.1

Hemorrhage

May increase the risk of bleeding based on mechanism of action.1 Use in patients with risk factors for bleeding only if the potential benefit outweighs the risk.1

GI Perforation

May increase the risk of GI perforation based on mechanism of action.1 Use caution in patients with recent abdominal surgery.1 Use in patients with risk factors for GI perforation only if the potential benefit outweighs the risk.1 Discontinue nintedanib if GI perforation develops.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Not formally studied in patients with hepatic impairment.1 Monitor closely in patients with mild hepatic impairment (Child-Pugh class A).1 Safety and efficacy not established in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure to nintedanib not affected by mild or moderate renal impairment (Clcr 30–90 mL/minute); no initial dosage adjustment necessary.1 Safety and efficacy not established in patients with severe renal impairment or end-stage renal disease.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 nausea,1 abdominal pain,1 elevated concentrations of hepatic enzymes (e.g., ALT, AST, alkaline phosphatase),1 vomiting,1 decreased appetite,1 decreased weight,1 headache,1 hypertension.1

Interactions for Nintedanib Esylate

Substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4.1

Does not inhibit or induce CYP isoenzymes in vitro.1

Has weak potential to inhibit P-gp, organic cation transporter (OCT) 1, and breast cancer resistance protein (BCRP); clinically important interaction unlikely.1

Does not inhibit organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, OATP2B1, OCT2, or multidrug resistance protein (MRP) 2 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes and the P-glycoprotein (P-gp) Transport System

Inhibitors of both P-gp and CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure of nintedanib).1 Monitor closely and reduce dosage or temporarily interrupt therapy if not tolerated.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Inducers of P-gp and CYP3A4: Potential pharmacokinetic interaction (decreased systemic exposure of nintedanib).1 Avoid concomitant use.1

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility of nintedanib) with drugs that increase gastric pH.1 Clinically important pharmacokinetic interactions unlikely.1

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decreased solubility of nintedanib; clinically important interaction unlikely1

Anticoagulants

Potential increased risk of bleeding1

Monitor patients receiving full-dose anticoagulation; dosage adjustment of anticoagulant may be necessary1

Antifungals, azoles (e.g., ketoconazole)

Possible increased nintedanib concentrations with P-gp and CYP3A4 inhibitors1

Ketoconazole increased peak concentrations and AUC of nintedanib by 1.8- and 1.6-fold, respectively1

Monitor closely; reduce dosage or temporarily interrupt nintedanib therapy if not tolerated1

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers1

Rifampin decreased nintedanib exposure by 50%1

Avoid concomitant use1

Carbamazepine

Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers1

Avoid concomitant use1

Carboplatin

Concomitant use of nintedanib with carboplatin and paclitaxel in patients with non-small cell lung cancer (NSCLC) did not substantially alter carboplatin pharmacokinetics7

Cigarette smoking

Decreased nintedanib exposure1

Dosage adjustment not necessary; encourage smoking cessation1

Docetaxel

Concomitant use of nintedanib with docetaxel in patients with prostate cancer did not substantially alter docetaxel pharmacokinetics7

Erythromycin

Possible increased nintedanib concentrations with P-gp and CYP3A4 inhibitors1

Monitor closely; reduce dosage or temporarily interrupt nintedanib therapy if not tolerated1

Histamine H2-receptor antagonists

Possible decreased solubility of nintedanib; clinically important interaction unlikely1

Paclitaxel

Concomitant use of nintedanib with paclitaxel and carboplatin in patients with NSCLC did not substantially alter paclitaxel pharmacokinetics7

Pemetrexed

Concomitant use of nintedanib with pemetrexed in patients with NSCLC did not substantially alter pemetrexed pharmacokinetics7

Phenytoin

Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers1

Avoid concomitant use1

Pirfenidone

Decreased systemic exposure to nintedanib1 8

No effect on pirfenidone pharmacokinetics1 8

Proton-pump inhibitors

Possible decreased solubility of nintedanib; clinically important interaction unlikely1

St. John's wort (Hypericum perforatum)

Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers1

Avoid concomitant use1

Nintedanib Esylate Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics following oral administration of 50–450 mg once daily and 150–300 mg twice daily.1

Peak plasma concentrations attained within 2–4 hours after oral administration with food.1

Steady-state concentrations achieved within 1 week.1

Absolute oral bioavailability of a 100-mg dose of nintedanib is 4.7%.1

Food

Administration with food increases systemic exposure by 20% and delays absorption by approximately 2 hours compared with fasting state.1

Special Populations

Not studied in hepatic impairment; hepatic impairment expected to increase plasma nintedanib concentrations.1

Mild or moderate renal impairment (Clcr 30–90 mL/minute) does not affect exposure to nintedanib.1 Not studied in severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1

Distribution

Extent

Not known whether nintedanib is distributed into milk.1

Plasma Protein Binding

97.8% (mainly albumin).1

Elimination

Metabolism

Principally metabolized by esterases to the carboxylate metabolite, BIBF 1202, which then undergoes glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A7, 1A8, and 1A10; CYP isoenzymes, mainly CYP3A4, play a minor role.1 10

Elimination Route

Eliminated in feces (93.4%) and urine (0.65%).1

Half-life

9.5 hours.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1 Protect from excessive humidity and heat.1

Actions

  • Inhibits several receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, VEGFR-3; fibroblast growth factor receptors (FGFR)-1, FGFR-2, FGFR-3; and platelet-derived growth factor receptors (PDGFR)-α, PDGFR-β.1 2 3 7 10

  • VEGFR, FGFR, and PDGFR signaling pathways involved in proliferation, migration, and differentiation of fibroblasts in the lungs; these kinases implicated in pathogenesis of IPF.1 2 7 10 Inhibition of these receptors reduces fibroblast activity in IPF.1 2 3 7 10

  • Also inhibits Fms-like tyrosine kinase (FLT)-3, and nonreceptor tyrosine kinases Lck, Lyn, and Src; inhibitory effect of these kinases in IPF unknown.1

Advice to Patients

  • Importance of reading the manufacturer’s patient information prior to beginning nintedanib therapy and each time the prescription is refilled.1

  • Importance of taking with food.1 Importance of swallowing capsules whole with liquid; do not chew or crush the capsules.1

  • If a dose is missed, skip the missed dose and take the next dose at the regularly scheduled time; do not double the dose to make up for a missed dose.1

  • Risk of hepatotoxicity and importance of periodic liver function test monitoring.1 Importance of immediately reporting any manifestations of hepatotoxicity to clinician.1

  • Importance of clinician informing patients that diarrhea, nausea, and vomiting are most common adverse effects and recommending supportive treatment.1 Importance of informing clinician at first sign of diarrhea or if severe or persistent diarrhea, nausea, or vomiting occurs.1

  • Risk of arterial thromboembolic events.1 Importance of advising patients to seek emergency help and to contact clinician if any symptoms suggestive of acute myocardial ischemia or other thromboembolic event occur.1

  • Risk of GI perforation; importance of immediately informing clinician of any manifestations of GI perforation (e.g., abdominal pain, swelling).1

  • Increased risk of bleeding.1 Importance of promptly informing clinician of any unusual bleeding.1

  • Risk of fetal harm.1 Necessity of women of childbearing potential to avoid pregnancy and to use effective contraception while receiving nintedanib and for at least 3 months after drug is discontinued.1 Importance of patients informing their clinicians if they are pregnant or think they may be pregnant.1

  • Importance of advising women to avoid breast-feeding while receiving therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., anticoagulants, aspirin, laxatives, St. John's wort), as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Nintedanib Esylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg (of nintedanib)

Ofev

Boehringer Ingelheim

150 mg (of nintedanib)

Ofev

Boehringer Ingelheim

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Boehringer Ingelheim Pharmaceuticals, Inc. Ofev (nintedanib) capsules prescribing information. Ridgefield, CT; 2014 Oct.

2. Richeldi L, Costabel U, Selman M et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011; 365:1079-87. [PubMed 21992121]

3. Richeldi L, du Bois RM, Raghu G et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370:2071-82. [PubMed 24836310]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Jul 13.

5. Raghu G, Collard HR, Egan JJ et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011; 183:788-824. [PubMed 21471066]

6. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014; 9:157-79. [PubMed 24050627]

7. McCormack PL. Nintedanib: first global approval. Drugs. 2015; 75:129-39. [PubMed 25430078]

8. Ogura T, Taniguchi H, Azuma A et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2015; 45:1382-92. [PubMed 25504994]

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205832Orig1s000: Summary review. From FDA website.

10. Roth GJ, Binder R, Colbatzky F et al. Nintedanib: from discovery to the clinic. J Med Chem. 2015; 58:1053-63. [PubMed 25474320]

11. Boehringer Ingelheim. Start your appropriate patients with IPF on Ofev today. Ridgefield, CT. Accessed 2015 Jul 20.

12. King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011; 378:1949-61. [PubMed 21719092]

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