nintedanib (Rx)

>10%

Idiopathic pulmonary fibrosis

• Diarrhea (62%)
• Nausea (24%)
• Abdominal pain (15%)
• Elevated liver enzymes (14%)
• Vomiting (12%)
• Decreased appetite (11%)

SSc-ILD

• Diarrhea (76%)
• Nausea (32%)
• Vomiting (25%)
• Skin ulcer (18%)
• Abdominal pain (18%)
• Liver enzyme elevation (13%)
• Decreased weight (12%)
• Fatigue (11%)

1-10%

Idiopathic pulmonary fibrosis

• Decreased weight (10%)
• Bleeding events (10%)
• Headache (8%)
• Hypertension (5%)
• Arterial thromboembolic events (2.5%)
• Myocardial infarction (1.5%)
• Bronchitis (1.5%)
• Hypothyroidism (1.1%)

SSc-ILD

• Decreased appetite (9%)
• Headache (9%)
• Pyrexia (6%)
• Back pain (6%)
• Dizziness (6%)
• Hypertension (5%)

<1%

Idiopathic pulmonary fibrosis

• Pneumonia (0.7%)
• Lung neoplasm malignant (0.3%)
• Gastrointestinal perforation (0.3%)

Postmarketing Reports

Pancreatitis

Thrombocytopenia

Drug-induced liver injury

Rash

Pruritus

Alopecia

Contraindications

None

Cautions

Severe liver injury with fatal outcome reported; majority of hepatic events occur within first 3 months of treatment; conduct liver function tests (ALT, AST, and bilirubin) before initiating, monthly for 3 months, and then q3months thereafter and as clinically indicated

Not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C); reduced dose for patients with mild hepatic impairment (Child Pugh A)

Nausea, and/or vomiting may occur; treat with adequate hydration and antidiarrheal/antiemetic medications; if persists, treatment interruption and dose reduction may be needed

Diarrhea may occur; treat at first signs with adequate hydration and antidiarrheal medication (eg, loperamide); consider treatment interruption if diarrhea continues; treatment may be resumed at full dosage (150 mg twice daily), or at reduced dosage (100 mg twice daily); may subsequently increase to full dosage; if severe diarrhea persists despite symptomatic treatment, discontinue treatment

Arterial thromboembolic events reported, including myocardial infarction; caution when treatment patients at higher cardiovascular risk

May increased risk of bleeding or gastrointestinal perforation (based on mechanism of action [VEGFR inhibition]); monitor for bleeding if on full anticoagulant therapy and adjust anticoagulation treatment as needed

Smoking associated with decreased systemic exposure; encourage patients to quit smoking

Can cause fetal harm; use adequate contraception during treatment and for at least 3 months after the last dose

In postmarketing period non-serious and serious bleeding events reported; use therapy in patients with known risk of bleeding only if anticipated benefit outweighs potential risk

In postmarketing period, cases of gastrointestinal perforations reported; use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs; discontinue therapy in patients who develop gastrointestinal perforation; only use in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk

Drug interaction overview

• Nintedanib is a substrate of CYP3A4 and P-gp transporter
• Coadministration with potent P-gp or CYP3A4 inhibitors may increase systemic exposure of nintedanib (monitor closely)
• Coadministration with P-gp or CYP3A4 inducers may decrease systemic exposure to nintedanib by 50%; avoid coadministration
• Nintedanib is a VEGFR inhibitor and may increase bleeding risk; monitor patients on full anticoagulation for bleeding and adjust anticoagulation treatment if needed

Pregnancy

Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women; counsel patients on pregnancy prevention and planning

Verify pregnancy status of females of reproductive potential prior to treatment and during treatment as appropriate

Animal data

• In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryofetal deaths and structural abnormalities at less than (rats) and ~5 times (rabbits) the maximum recommended human dose

Contraception

• Advise females of reproductive potential to avoid becoming pregnant while receiving nintedanib
• Use effective contraception during treatment, and for at least 3 months after taking the last dose
• Drug does not change exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD; however, efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where drug absorption may be reduced

Infertility

• Based on animal data, may reduce fertility in females of reproductive potential

Lactation

There is no information on the presence of nintedanib in human milk, the effects on the breast-fed infant or the effects on milk production

Nintedanib and/or its metabolites are present in the milk of lactating rats

Because of the potential for serious adverse effects in breastfed infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tyrosine kinase inhibitor; targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF])

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

Absorption

Bioavailability: 4.7%; undergoes substantial first-pass metabolism

Peak plasma concentration: 2-4 hr

Food increases systemic exposure by ~20% and delays peak level to ~4 hr

Distribution

Protein bound: 97.8%

Vd: 1050 L

Metabolism

Hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202 is the prevalent metabolic pathway (~25%); BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide

Only a minor extent of the biotransformation consists of CYP pathways (~5%), with CYP3A4 being the predominant enzyme involved

Elimination

Excretion: 93.4% feces/biliary; 0.65% urine

Oral Administration

Take with food

Swallow capsule whole with liquid; do not chew or crush (bitter taste); effect of crushing on the pharmacokinetics is unknown

Missed dose: Take next dose at next scheduled time; advise patient to not make up for a missed dose

Storage

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

Protect from exposure to high humidity and avoid excessive heat

If repackaged, use USP tight container

Keep out of reach of children