Dosing & Uses
Dosage Forms & Strengths
capsule
- 100mg
- 150mg
Idiopathic Pulmonary Fibrosis
150 mg PO q12hr with food
Dosage Modifications
Diarrhea, nausea, and/or vomiting
- Temporarily interrupt treatment if symptoms persist despite hydration or antidiarrheal/antiemetic medication
- If unable to resume at full dose, decrease dose to 100 mg PO BID, which subsequently may be increased to the full dosage
- Discontinue if patient does not tolerate 100 mg BID
Elevated liver enzymes
- AST/ALT >3 to <5x ULN without signs of severe liver damage: Interrupt treatment or reduce to 100 mg BID; once LFTs return to normal, may reintroduce at 100 mg BID, which subsequently may be increased to 150 mg BID
- AST/ALT >5x ULN or >3x ULN with signs/symptoms of severe liver damage: Discontinue
Hepatic impairment
- Mild (Child Pugh A): Consider treatment interruption, or discontinuation for management of adverse reactions
- Moderate-to-severe (Child Pugh B or C): Not recommended (not studied)
Renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe (CrCl <30 mL/min) or ESRD: Not studied
Dosing Considerations
Conduct liver function tests and a pregnancy test prior to initiating drug (see Cautions and Pregnancy)
Systemic Sclerosis (Orphan)
Orphan designation for treatment of systemic sclerosis (including the associated interstitial lung disease)
Sponsor
- Boehringer Ingelheim Pharmaceuticals, Inc; 900 Ridgebury Rd, Box 368; Ridgefield, CT 06877
Mesothelioma (Orphan)
Orphan designation for treatment of mesothelioma
Sponsor
- Boehringer Ingelheim Pharmaceuticals, Inc; 900 Ridgebury Rd, Box 368; Ridgefield, CT 06877
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Diarrhea (62%)
Nausea (24%)
Abdominal pain (15%)
Elevated liver enzymes (14%)
Vomiting (12%)
Decreased appetite (11%)
1-10%
Decreased weight (10%)
Bleeding events (10%)
Headache (8%)
Hypertension (5%)
Arterial thromboembolic events (2.5%)
Myocardial infarction (1.5%)
Hypothyroidism (1.1%)
<1%
Gastrointestinal perforation (0.3%)
Postmarketing Reports
Pancreatitis
Thrombocytopenia
Drug-induced liver injury
Rash
Pruritus
Warnings
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 (see Dosage Modifications)
Diarrhea, nausea, and/or vomiting may occur; treat with adequate hydration and antidiarrheal/antiemetic medications; if persists, treatment interruption and dose reduction may be needed (see Adult Dosing, Dosage Modifications)
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
Pregnancy & Lactation
Pregnancy
Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women
In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose
Verify the pregnancy status of females of reproductive potential prior to treatment
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
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.
Pharmacology
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
Administration
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
If a dose is missed, the next dose should be taken at the next scheduled time; advise the patient to not make up for a missed dose
Not to exceed 300 mg/day
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Patient Handout
Formulary
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