Dosing and uses of Ofev (nintedanib)
Adult dosage forms and strengths
capsule
- 100mg
- 150mg
Idiopathic Pulmonary Fibrosis
Conduct liver function tests before initiating therapy (also see Dosage modifications and Cautions)
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 <5 x ULN without signs of severe liver damage: Interrupt treatment or reduce dose to 100 mg BID; once LFTs return to normal, may reintroduce at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage
- AST/ALT >5 x ULN or >3 times ULN with signs/symptoms of severe liver damage: Discontinue
Hepatic impairment
- Mild (Child Pugh A): Monitor for adverse reactions and consider dose modification or discontinuation as needed
- 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
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Ofev (nintedanib) adverse (side) 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%)
Warnings
Contraindications
None
Cautions
Conduct liver function tests (ALT, AST, and bilirubin) before initiating, monthly for 3 months, and then q3months thereafter and as clinically indicated; dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevation
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
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
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
Pregnancy and lactation
Pregnancy category: d
Lactation: Distributed in human breast milk is probable
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 of Ofev (nintedanib)
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
