Nintedanib

Introduction Overview

Generic Name

nintedanib

Brand Name

Ofev

Dosage Form

capsules (150 mg, 100 mg)

Drug Class

Multikinase inhibitors

Pharmacokinetics

Absorption: Nintedanib is administered orally and exhibits moderate absorption after oral dosing. The recommended dose of Ofev capsules is 150 mg twice daily taken approximately every 12 hours. Food intake affects its absorption; for patients with normal hepatic function, it is recommended to take Ofev apart from food to optimize absorption, whereas for mild hepatic impairment, administration with food is advised. Peak plasma concentrations are typically reached within 2 to 4 hours post-dose. The absolute bioavailability is approximately 4.7%, highlighting extensive first-pass metabolism and low bioavailability. Clinical studies have shown that plasma concentrations are dose proportional.

Distribution: Nintedanib exhibits a high volume of distribution, indicating extensive tissue penetration. It is highly protein-bound (>97%), which contributes to its pharmacokinetic profile. The drug distributes widely into tissues, including lung tissue, which is therapeutically relevant for its use in idiopathic pulmonary fibrosis and other interstitial lung diseases. Because of its high protein binding, displacement interactions can influence its free plasma concentrations.

Metabolism: Nintedanib undergoes predominant hepatic metabolism via hydrolytic cleavage mediated by esterases, which bypass cytochrome P450 pathways, minimizing common CYP-mediated drug interactions. Minor metabolism follows oxidative pathways catalyzed by CYP3A4, but this plays a less critical role. The drug’s metabolites are pharmacologically inactive. Due to this metabolic profile, nintedanib has a relatively low potential for CYP450-mediated interactions. Hepatic impairment affects metabolism and clearance, necessitating dose adjustments in mild impairment and contraindication in moderate to severe impairment.

Elimination: Excretion of nintedanib occurs primarily via the fecal route, with about 93% eliminated through biliary/fecal pathways and roughly 2% in urine. The elimination half-life is approximately 9.5 hours, supporting twice-daily dosing. Impairment in liver function delays elimination and increases systemic exposure, heightening risk for adverse effects. Renal impairment does not significantly affect elimination due to fecal clearance predominance. Routine monitoring of liver function tests is recommended during therapy to prevent accumulation and toxicity.

Dosage Forms

Available Dosage Forms:
- Oral capsules: 100 mg and 150 mg strengths.

Dosages for Adults and Adolescents:
- The usual recommended adult dose is 150 mg orally twice daily, taken approximately every 12 hours apart from food.
- For patients with mild hepatic impairment (Child-Pugh A), dosage should be reduced to 100 mg twice daily, administered approximately every 12 hours with food.
- Maximum total daily dose should not exceed 300 mg.
- Not approved for use in pediatric patients under 18 years old.

Specific Patient Populations:
- Not recommended for patients with moderate or severe hepatic impairment due to increased exposure and risk of toxicity.
- Use with caution in patients with pre-existing liver disease; frequent monitoring of liver enzymes is mandated.
- Dose adjustments, treatment interruptions, or discontinuation may be necessary based on tolerability and side effects.
- Pregnant patients must avoid use due to risks of fetal harm; effective contraception is essential during therapy and for at least three months after discontinuation.

Clinical Guidelines:
- Capsules should be swallowed whole with a full glass of water; do not crush, chew, or open capsules due to risk of exposure to the active ingredient.
- For patients without hepatic impairment, administer apart from food; for those with mild hepatic impairment, administer with food to improve tolerability.
- Close clinical and laboratory monitoring is necessary during therapy, including liver function tests and symptom assessments.

Mechanism Of Action

Nintedanib, the active ingredient in Ofev, exerts its pharmacological effect by acting as a potent inhibitor of multiple receptor tyrosine kinases (RTKs) and several non-receptor tyrosine kinases (nRTKs). Its molecular mechanism centers on blocking the activity of key tyrosine kinase receptors involved in pathological fibrosis, including platelet-derived growth factor receptor (PDGFR) alpha and beta, fibroblast growth factor receptor (FGFR) types 1-3, and vascular endothelial growth factor receptor (VEGFR) types 1-3. These receptors play central roles in mediating profibrotic signaling, angiogenesis, and fibroblast proliferation.

By inhibiting these kinases, nintedanib interrupts downstream signaling pathways that drive cellular proliferation, migration, differentiation, and fibrotic tissue remodeling commonly observed in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. The blockade of PDGFR and FGFR pathways reduces fibroblast proliferation and differentiation into myofibroblasts, key effector cells responsible for excessive extracellular matrix deposition leading to lung scarring.

Moreover, inhibition of VEGFR signaling decreases aberrant angiogenesis associated with fibrotic lung lesions, potentially mitigating disease progression. Additional inhibition of non-receptor tyrosine kinases, such as Lck, Lyn, and Src kinases, contributes to the modulation of inflammatory and fibrotic responses at the cellular level.

Clinically, these molecular actions translate into a slowing of lung function decline by reducing fibrosis progression in affected patients. Comparative studies with other antifibrotic agents, like pirfenidone, highlight nintedanib’s unique multikinase inhibition as a targeted approach addressing multiple profibrotic pathways simultaneously. Clinical trials demonstrate that nintedanib stabilizes forced vital capacity (FVC) by attenuating fibrotic remodeling, thereby preserving lung function and improving patient outcomes in chronic fibrosing interstitial lung diseases.

Pharmacological Actions

Inhibits receptor tyrosine kinases PDGFR α/β, FGFR 1-3, VEGFR 1-3, attenuating profibrotic signaling pathways.
Blocks non-receptor tyrosine kinases including Lck, Lyn, and Src involved in inflammation and fibrosis.
Reduces fibroblast proliferation and differentiation into myofibroblasts, limiting extracellular matrix deposition.
Suppresses angiogenesis in fibrotic tissues by inhibition of VEGF receptor-mediated pathways.
Slows progressive lung scarring in idiopathic pulmonary fibrosis and other interstitial lung diseases.
Modulates inflammatory responses contributing to fibrotic disease activity.
Decreases rate of forced vital capacity decline in patients with IPF and systemic sclerosis-associated ILD.
Acts as an antifibrotic agent by targeting multiple growth factor receptors simultaneously.
Lowers lung tissue remodeling and stiffness, improving respiratory function over time.
Exerts antiproliferative effects on pathological fibrotic cells while sparing normal cells.
Minimal cytochrome P450 metabolism reduces risk of metabolic drug interactions.
Demonstrates dose-proportional pharmacokinetics supporting flexible dosing in mild hepatic impairment.
May reduce progression of fibrosis in chronic fibrosing interstitial lung diseases with a progressive phenotype.

Therapeutic Or Clinical Uses

Treatment of idiopathic pulmonary fibrosis (IPF) to slow lung function decline.
Management of chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype.
Treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) to slow progression.
Used in adults to minimize respiratory deterioration caused by lung fibrosis.
Helps preserve forced vital capacity (FVC) over long-term therapy in fibrotic lung diseases.
Adjunct therapy to delay disease progression in patients with worsening lung fibrosis.
Not a cure but an effective antifibrotic agent to prolong lung function.
Therapeutic option for patients ineligible or intolerant to other antifibrotic therapies.
Indicated for long-term use with safety demonstrated for up to four years or more.
May be considered in combination with other antifibrotics in clinical trials with caution.
Prevention of rapid clinical deterioration from interstitial lung disease progression.
Slows worsening in pulmonary fibrosis caused by various etiologies, including systemic sclerosis.
Improves quality of life by preserving respiratory capacity and reducing symptom burden.

Side Or Adverse Effects

Nausea and vomiting, leading to potential nutritional compromise.
Diarrhea, which can be severe and cause dehydration requiring supportive care.
Loss of appetite and consequent weight loss during prolonged therapy.
Abdominal pain and stomach discomfort reported in some patients.
Increased blood pressure (hypertension) necessitating monitoring.
Elevated liver enzymes indicating hepatic toxicity; requires regular monitoring.
Headache of mild to moderate intensity reported during treatment.
Easy bruising and bleeding tendency, especially when combined with anticoagulants.
Rare cases of allergic reactions including hives, swelling, and respiratory distress.
Potential for severe rectal bleeding and non-healing wounds in vulnerable patients.
Risk of liver injury, particularly in women, low body weight individuals, and Asians.
Possible stroke symptoms such as numbness, weakness, and slurred speech in rare cases.
Fatigue and tiredness secondary to drug effects or liver dysfunction.
Diarrhea-associated dehydration may become life-threatening if untreated.
Elevated risk of serious infections due to underlying lung disease compounded by therapy.

Precautions

Pregnancy prevention is critical due to risk of fetal harm; use effective contraception plus barrier methods.
Avoid breastfeeding while taking Ofev as drug may pass into breast milk and harm the infant.
Regular liver function testing is required to detect hepatotoxicity early.
Use cautiously in patients with pre-existing liver disease or hepatic impairment.
Monitor blood pressure and manage hypertension during treatment.
Avoid coadministration with strong CYP3A4 inducers or inhibitors that may alter drug levels.
Use care in patients with bleeding risk or those on anticoagulants due to bleeding potential.
Patients should avoid smoking, which may diminish therapeutic effectiveness.
Administer capsules whole without crushing or opening to prevent exposure to active drug.
Patients with history of diverticulitis should be monitored carefully due to GI risks.
Discontinue or reduce dose if severe GI symptoms such as diarrhea or nausea occur.
Avoid St. John's wort as it may reduce nintedanib plasma concentrations via enzyme induction.
Consider dose adjustments or interruption in case of adverse reactions or toxicity.
Not approved for pediatric use; safety and efficacy have not been established in this population.
Frequent clinical assessments for pulmonary function and symptom progression are advised.

Warnings

May cause severe birth defects or fetal death; contraindicated in pregnancy.
Risk of severe diarrhea leading to dehydration and potential hospitalization.
Potential hepatotoxicity necessitating close liver enzyme monitoring.
Bleeding events including gastrointestinal bleeding may occur, more so with anticoagulants.
Allergic reactions ranging from mild hypersensitivity to life-threatening anaphylaxis have been reported.
Avoid use in moderate or severe hepatic impairment due to increased toxicity risk.
May increase risk of arterial thromboembolic events; monitor cardiac symptoms.
Smoking can reduce efficacy; cessation is recommended prior to and during therapy.
Liver function abnormalities more frequent in women, patients under 65 kg, and Asians.
Prompt medical attention required for any neurological symptoms indicative of stroke.
Dose modifications may be necessary for managing adverse events to maintain safety.
Concomitant use with NSAIDs should be approached cautiously due to increased bleeding risk.
Use of Ofev requires baseline and periodic pregnancy testing in women of childbearing potential.
Store medication properly to avoid degradation and maintain efficacy.
Patients should be educated on side effects and the importance of adherence and monitoring.

Contraindication

Known hypersensitivity to nintedanib or any component of the formulation.
Pregnancy, due to teratogenicity and potential fetal mortality.
Moderate or severe hepatic impairment (Child-Pugh B and C), owing to increased risk of toxicity.
Active bleeding or high risk of bleeding disorders without appropriate medical management.
Concomitant use with strong CYP3A4 inducers that substantially reduce nintedanib plasma levels.
Patients unable to swallow capsules whole or with gastrointestinal conditions precluding oral therapy.
Known severe allergic reactions to any excipients such as gelatin or coloring agents.
Use in pediatric patients under 18 years old due to lack of safety and efficacy data.
Patients with recent major surgery with increased risk of bleeding or wound healing complications.
Severe uncontrolled hypertension or significant cardiovascular instability without stabilization.
Pregnancy planning without adequate contraception during and for three months after treatment.
Concomitant use with St. John's wort or other potent CYP inducers causing subtherapeutic levels.

Drug Interactions

Coadministration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) reduces nintedanib levels.
CYP3A4 inhibitors (e.g., ketoconazole) can increase nintedanib plasma exposure, increasing toxicity risk.
Concomitant use with anticoagulants (e.g., warfarin) may increase bleeding risk; monitor coagulation parameters.
NSAIDs (aspirin, ibuprofen, naproxen) coadministration increases bleeding risk when combined with nintedanib.
Use with P-glycoprotein modulators can affect absorption and drug plasma levels.
Herbal supplements, especially St. John's wort, may reduce nintedanib efficacy through enzyme induction.
No significant CYP450 metabolism minimizes interactions, but hepatic impairment alters pharmacokinetics.
Potential pharmacodynamic interactions with other drugs causing hypertension or liver toxicity.
Co-administration with pirfenidone requires careful side effect monitoring due to overlapping toxicity.
Drugs that impair liver function may necessitate dose adjustments or close monitoring on Ofev.
Medications that cause diarrhea or GI irritation may potentiate gastrointestinal side effects.
Altered absorption with food or antacids is minimal; however, adherence to dosing recommendations is important.
No major interactions reported with common vitamins or mineral supplements.
Drugs influencing platelet function or coagulation cascade require caution when used with Ofev.
Interact with inhibitors or inducers of drug efflux transporters such as P-gp or BCRP may occur.

Preparations Of The Drug

Ofev is available as oral capsules formulated in strengths of 100 mg and 150 mg of nintedanib.
Each capsule contains the active ingredient nintedanib accompanied by inactive ingredients including triglycerides, hard fat, lecithin, gelatin, glycerol, titanium dioxide, red ferric oxide, yellow ferric oxide, and black ink for capsule shell color.
Capsules are manufactured to be swallowed whole without crushing or opening to prevent exposure and ensure complete delivery.
The formulation is designed for twice-daily oral administration with stability maintained at room temperature between 68°F to 77°F (20°C to 25°C).
Packaging includes protective measures against moisture and heat to preserve drug integrity.
The capsule shell colors assist in dose differentiation with 100 mg and 150 mg capsules distinctly identifiable.
No intravenous or alternative formulations are currently approved.
Ofev capsules must be stored in the original container with a secure lid to maintain stability.
Inactive ingredients facilitate bioavailability and manufacturing consistency.
The drug preparation undergoes rigorous quality control to meet pharmaceutical standards.
Dispensing includes patient instructions emphasizing the importance of taking the capsules as whole, and adherence to dosing intervals.
Prescribing information provides guidance on dose adjustments and management of adverse effects in clinical use.
No liquid or pediatric formulations of Ofev are commercially available as of current approvals.
Overdose management guidelines include symptomatic and supportive care, with no specific antidote available.
Distribution is handled by Boehringer Ingelheim Pharmaceuticals, ensuring consistent pharmaceutical quality and supply.