Nintedanib is a medication used for the treatment of idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung disease characterized by scarring of the lung tissue. It belongs to a class of medications known as tyrosine kinase inhibitors. Nintedanib works by blocking multiple pathways involved in the formation of scar tissue in the lungs, thereby slowing down the progression of IPF and improving lung function.

Among tiny molecules, nintedanib (Ofev) is a powerful tyrosine kinase inhibitor (of the PDGF, FGF, and vascular endothelial growth factor receptors). Idiopathic pulmonary fibrosis is the condition for which it is suggested. Patients with non-small cell lung cancer can take it to slow the advancement of pulmonary fibrosis brought on by scleroderma.

Uses:

• Idiopathic pulmonary fibrosis:
  • Idiopathic pulmonary fibrosis therapy drug (IPF).

"See Pirfenidone for the treatment of idiopathic pulmonary fibrosis"

Nintedanib (Ofev) Dose in Adult

Nintedanib (Ofev) Dose in the treatment of idiopathic pulmonary fibrosis (IPF):

• For most people, the usual dose is 150 milligrams taken by mouth every 12 hours.
• That means you take it twice a day.
• The maximum dose you should take in a day is 300 milligrams.

Missed Dose:

• If you forget to take a dose, just take the next one at the scheduled time. Don't take extra doses to make up for the one you missed.

Nintedanib (Ofev) Dose in Children

Not indicated in children.

Nintedanib Pregnancy Risk Category: D

• Nintedanib can potentially harm a developing baby if taken during pregnancy, based on studies in animals.
• So, it's crucial for women who might get pregnant to have a pregnancy test before starting this medication.
• If a woman can become pregnant, she should use effective birth control while taking nintedanib and for at least 3 months after stopping it.
• This helps prevent pregnancy and reduce the risk of harm to the fetus.

Use of Nintedanib while breastfeeding

• Since it's uncertain whether nintedanib passes into breast milk, it's not recommended for breastfeeding mothers.
• The manufacturer advises against breastfeeding while taking this medication because of the potential for serious side effects in the nursing infant.

Nintedanib (Ofev) Dose in Kidney Disease:

• For individuals with a creatinine clearance (CrCl) of 30 milliliters per minute or higher, no initial dosage adjustment is needed when taking nintedanib.
• However, for those with a CrCl less than 30 milliliters per minute, or for those with end-stage renal disease (ESRD), there are no specific dosage adjustments recommended in the manufacturer's instructions. This is because nintedanib hasn't been studied extensively in these populations.

Nintedanib (Ofev) Dose in Liver disease:

For individuals with hepatic impairment at the beginning of treatment:

• Mild impairment (Child-Pugh class A): The initial dose is 100 milligrams every 12 hours. If the patient has difficulty tolerating this dose, the healthcare provider may consider interrupting treatment or discontinuing it to manage any adverse reactions.
• Moderate to severe impairment (Child-Pugh class B or C): Nintedanib use is not recommended in these cases. This is because exposure to the medication is increased in moderate impairment, and its use hasn't been studied in severe impairment.

In cases where hepatotoxicity (liver damage) occurs during treatment:

• If AST or ALT levels rise to more than 3 times but less than 5 times the upper limit of normal (ULN) without signs of liver damage, treatment should be interrupted or the dosage reduced to 100 milligrams every 12 hours. Once the liver enzymes return to their normal values after treatment interruption, therapy can be reintroduced at 100 milligrams every 12 hours. The dosage may then be increased to 150 milligrams every 12 hours if deemed appropriate.
• If AST or ALT levels rise to more than 5 times the ULN or more than 3 times the ULN with signs or symptoms of liver damage, nintedanib therapy should be discontinued.

Common Side Effects of Nintedanib (Ofev):

• Hepatic:
  • Increased Liver Enzymes
• Gastrointestinal:
  • Abdominal Pain
  • Vomiting
  • Diarrhea
  • Nausea
  • Decreased Appetite

Less Common Side Effects Of Nintedanib (Ofev):

• Endocrine & Metabolic:
  • Weight Loss
  • Hypothyroidism
• Cardiovascular:
  • Arterial Thrombosis
  • Hypertension
  • Myocardial Infarction
• Central Nervous System:
  • Headache
• Respiratory:
  • Bronchitis
• Hematologic And Oncologic:
  • Hemorrhage

Contraindications to Nintedanib (Ofev):

In the manufacturer's labeling, there are typically no contraindications listed for the use of nintedanib.

However, in Canadian labeling, there are additional contraindications that are not present in US labeling. These include:

• Hypersensitivity to nintedanib, peanut, or soya, or any component of the formulation.
• Pregnancy.

It's important for individuals in Canada to be aware of these contraindications when considering the use of nintedanib.

Warnings and precautions

Bleeding

• Nintedanib use may heighten the risk of bleeding.
• It should be utilized in patients with a known risk of bleeding only if the potential benefits outweigh the risks.
• There have been reports, including fatal cases, of both serious and non-serious bleeding events in the postmarketing period.

Cardiovascular effects

• Nintedanib has been associated with arterial thromboembolic events, including myocardial infarction (MI).
• It's important to exercise caution when prescribing nintedanib to patients at high cardiovascular risk, such as those with known coronary artery disease.
• If patients develop signs or symptoms of acute myocardial ischemia, it may be necessary to interrupt treatment.
• This underscores the importance of close monitoring for cardiovascular effects during nintedanib therapy, with prompt intervention as needed.

GI effects

• Nintedanib can cause gastrointestinal (GI) side effects like diarrhea, nausea, and vomiting, with diarrhea being the most common, occurring in more than half of patients treated with nintedanib.
• These symptoms usually appear within the first 3 months of treatment and are typically mild to moderate.
• Treatment involves supportive care such as staying hydrated and using anti-diarrheal or anti-nausea medications if needed.
• In some cases, reducing the dose or temporarily stopping treatment might be necessary.
• If GI symptoms persist, discontinuing nintedanib may be required.
• Additionally, there's a risk of GI perforation, which can be fatal.
• Caution should be exercised, especially in patients with recent abdominal surgery, a history of diverticular disease, or those taking corticosteroids or NSAIDs concurrently.
• Nintedanib should only be used in these patients if the potential benefits outweigh the risks, and treatment should be discontinued if perforation occurs.
• It's advisable to wait at least 4 weeks after abdominal surgery before starting nintedanib therapy.

Hepatic effects

• Nintedanib can lead to serious liver problems, including drug-induced liver injury, some of which have been fatal.
• These effects often occur within the first 3 months of treatment.
• Liver function tests should be conducted before starting treatment, regularly during the initial 3 months, and periodically thereafter, or as needed based on clinical signs.
• Elevations in liver enzymes like ALT, AST, GGT, alkaline phosphatase, and bilirubin are usually reversible with dose adjustments or treatment interruption.
• Patients with a low body weight (<65 kg), as well as Asian and female patients, may have an increased risk of hepatic effects.
• Therefore, dosage modifications or interruptions may be necessary to manage these risks effectively.

Nintedanib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Anticoagulants	might make Nintedanib's harmful or hazardous effects worse. In particular, there may be an elevated risk of bleeding.
Combined Inhibitors of CYP3A4 and P-glycoprotein	The serum levels of nitedanib can increase.
Erdafitinib	Serum levels of P-glycoprotein/ABCB1 Substrates can increase.
Lumacaftor	may reduce the serum concentration of P-glycoprotein/ABCB1 Substrates. After utilizing lumacaftor, the level of P-glycoprotein/ABCB1 Substrates in the serum can increase.
P-glycoprotein/ABCB1 Inhibitors	Serum levels of P-glycoprotein/ABCB1 Substrates can increase. P-glycoprotein inhibitors could also make it simpler for certain cells, tissues, and organs where p-glycoprotein is plentiful to receive p-glycoprotein substrates (e.g., brain, T-lymphocytes, testes, etc.).
Ranolazine:	Serum levels of P-glycoprotein/ABCB1 Substrates can increase.
Risk Factor X (Avoid combination)
Combined Inducers of CYP3A4 and P-glycoprotein	The level of nintedanib in the serum might decline.

Monitoring parameters:

• Liver Function Tests: Before starting treatment with nintedanib, and regularly during the first 3 months of treatment, as well as periodically afterward or as needed based on clinical signs, liver function tests should be conducted.
• Pregnancy Test: Prior to initiating treatment, it's important to obtain a pregnancy test.
• GI Events: Keep an eye out for gastrointestinal events such as diarrhea, nausea, vomiting, and GI perforation.
• Arterial Thromboembolic Events: Monitor for signs of arterial thromboembolic events.
• Bleeding: Watch for any signs of bleeding.

How to administer Nintedanib (Ofev)?

• Oral Administration: Take nintedanib with food.
• Swallow Whole: Swallow the capsules whole with a drink of liquid. Do not chew or crush them, as they may have a bitter taste.

Mechanism of action of Nintedanib (Ofev):

• Targets: Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs), including platelet-derived growth factor (PDGFR alpha and PDGFR beta), fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3), vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), and Fms-like tyrosine kinase-3 (FLT3).
• Blocking Signaling: By competitively binding to the adenosine triphosphate (ATP) binding pocket of these receptors, nintedanib blocks intracellular signaling critical for the proliferation, migration, and transformation of fibroblasts.

Absorption

• Food: Consumption with food increases exposure by approximately 20% and delays absorption.

Distribution

• Volume of Distribution (V): Approximately 1050 liters.
• Protein Binding: Nintedanib is highly bound to proteins, with approximately 98% binding.

Metabolism

• Metabolism Pathway: Nintedanib undergoes hydrolytic cleavage by esterases to form the free acid moiety BIBF 1202. This moiety is then glucuronidated by enzymes such as UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to produce BIBF 1202 glucuronide. A minor pathway involves metabolism by CYP 3A4.

Bioavailability

• Bioavailability: Nintedanib's bioavailability is approximately 5%.

Elimination

• Half-life: The elimination half-life of nintedanib is approximately 9.5 hours.
• Time to Peak Plasma Levels: It takes around 2 hours for nintedanib to reach peak plasma levels (4 hours with food).

Excretion

• Excretion Routes: Nintedanib is primarily eliminated via the feces (approximately 93%), with a minor portion excreted in the urine (less than 1%).

International Brands of Nintedanib:

• Ofev
• Vargatef

Nintedanib Brand Names in Pakistan:

No Brands Available in Pakistan.

Nintedanib is a medication used for the treatment of idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung disease characterized by scarring of the lung tissue. It belongs to a class of medications known as tyrosine kinase inhibitors. Nintedanib works by blocking multiple pathways involved in the formation of scar tissue in the lungs, thereby slowing down the progression of IPF and improving lung function.

Among tiny molecules, nintedanib (Ofev) is a powerful tyrosine kinase inhibitor (of the PDGF, FGF, and vascular endothelial growth factor receptors). Idiopathic pulmonary fibrosis is the condition for which it is suggested. Patients with non-small cell lung cancer can take it to slow the advancement of pulmonary fibrosis brought on by scleroderma.

Uses:

• Idiopathic pulmonary fibrosis:
  • Idiopathic pulmonary fibrosis therapy drug (IPF).

"See Pirfenidone for the treatment of idiopathic pulmonary fibrosis"

Nintedanib (Ofev) Dose in Adult

Nintedanib (Ofev) Dose in the treatment of idiopathic pulmonary fibrosis (IPF):

• For most people, the usual dose is 150 milligrams taken by mouth every 12 hours.
• That means you take it twice a day.
• The maximum dose you should take in a day is 300 milligrams.

Missed Dose:

• If you forget to take a dose, just take the next one at the scheduled time. Don't take extra doses to make up for the one you missed.

Nintedanib (Ofev) Dose in Children

Not indicated in children.

Nintedanib Pregnancy Risk Category: D

• Nintedanib can potentially harm a developing baby if taken during pregnancy, based on studies in animals.
• So, it's crucial for women who might get pregnant to have a pregnancy test before starting this medication.
• If a woman can become pregnant, she should use effective birth control while taking nintedanib and for at least 3 months after stopping it.
• This helps prevent pregnancy and reduce the risk of harm to the fetus.

Use of Nintedanib while breastfeeding

• Since it's uncertain whether nintedanib passes into breast milk, it's not recommended for breastfeeding mothers.
• The manufacturer advises against breastfeeding while taking this medication because of the potential for serious side effects in the nursing infant.

Nintedanib (Ofev) Dose in Kidney Disease:

• For individuals with a creatinine clearance (CrCl) of 30 milliliters per minute or higher, no initial dosage adjustment is needed when taking nintedanib.
• However, for those with a CrCl less than 30 milliliters per minute, or for those with end-stage renal disease (ESRD), there are no specific dosage adjustments recommended in the manufacturer's instructions. This is because nintedanib hasn't been studied extensively in these populations.

Nintedanib (Ofev) Dose in Liver disease:

For individuals with hepatic impairment at the beginning of treatment:

• Mild impairment (Child-Pugh class A): The initial dose is 100 milligrams every 12 hours. If the patient has difficulty tolerating this dose, the healthcare provider may consider interrupting treatment or discontinuing it to manage any adverse reactions.
• Moderate to severe impairment (Child-Pugh class B or C): Nintedanib use is not recommended in these cases. This is because exposure to the medication is increased in moderate impairment, and its use hasn't been studied in severe impairment.

In cases where hepatotoxicity (liver damage) occurs during treatment:

• If AST or ALT levels rise to more than 3 times but less than 5 times the upper limit of normal (ULN) without signs of liver damage, treatment should be interrupted or the dosage reduced to 100 milligrams every 12 hours. Once the liver enzymes return to their normal values after treatment interruption, therapy can be reintroduced at 100 milligrams every 12 hours. The dosage may then be increased to 150 milligrams every 12 hours if deemed appropriate.
• If AST or ALT levels rise to more than 5 times the ULN or more than 3 times the ULN with signs or symptoms of liver damage, nintedanib therapy should be discontinued.

Common Side Effects of Nintedanib (Ofev):

• Hepatic:
  • Increased Liver Enzymes
• Gastrointestinal:
  • Abdominal Pain
  • Vomiting
  • Diarrhea
  • Nausea
  • Decreased Appetite

Less Common Side Effects Of Nintedanib (Ofev):

• Endocrine & Metabolic:
  • Weight Loss
  • Hypothyroidism
• Cardiovascular:
  • Arterial Thrombosis
  • Hypertension
  • Myocardial Infarction
• Central Nervous System:
  • Headache
• Respiratory:
  • Bronchitis
• Hematologic And Oncologic:
  • Hemorrhage

Contraindications to Nintedanib (Ofev):

In the manufacturer's labeling, there are typically no contraindications listed for the use of nintedanib.

However, in Canadian labeling, there are additional contraindications that are not present in US labeling. These include:

• Hypersensitivity to nintedanib, peanut, or soya, or any component of the formulation.
• Pregnancy.

It's important for individuals in Canada to be aware of these contraindications when considering the use of nintedanib.

Warnings and precautions

Bleeding

• Nintedanib use may heighten the risk of bleeding.
• It should be utilized in patients with a known risk of bleeding only if the potential benefits outweigh the risks.
• There have been reports, including fatal cases, of both serious and non-serious bleeding events in the postmarketing period.

Cardiovascular effects

• Nintedanib has been associated with arterial thromboembolic events, including myocardial infarction (MI).
• It's important to exercise caution when prescribing nintedanib to patients at high cardiovascular risk, such as those with known coronary artery disease.
• If patients develop signs or symptoms of acute myocardial ischemia, it may be necessary to interrupt treatment.
• This underscores the importance of close monitoring for cardiovascular effects during nintedanib therapy, with prompt intervention as needed.

GI effects

• Nintedanib can cause gastrointestinal (GI) side effects like diarrhea, nausea, and vomiting, with diarrhea being the most common, occurring in more than half of patients treated with nintedanib.
• These symptoms usually appear within the first 3 months of treatment and are typically mild to moderate.
• Treatment involves supportive care such as staying hydrated and using anti-diarrheal or anti-nausea medications if needed.
• In some cases, reducing the dose or temporarily stopping treatment might be necessary.
• If GI symptoms persist, discontinuing nintedanib may be required.
• Additionally, there's a risk of GI perforation, which can be fatal.
• Caution should be exercised, especially in patients with recent abdominal surgery, a history of diverticular disease, or those taking corticosteroids or NSAIDs concurrently.
• Nintedanib should only be used in these patients if the potential benefits outweigh the risks, and treatment should be discontinued if perforation occurs.
• It's advisable to wait at least 4 weeks after abdominal surgery before starting nintedanib therapy.

Hepatic effects

• Nintedanib can lead to serious liver problems, including drug-induced liver injury, some of which have been fatal.
• These effects often occur within the first 3 months of treatment.
• Liver function tests should be conducted before starting treatment, regularly during the initial 3 months, and periodically thereafter, or as needed based on clinical signs.
• Elevations in liver enzymes like ALT, AST, GGT, alkaline phosphatase, and bilirubin are usually reversible with dose adjustments or treatment interruption.
• Patients with a low body weight (<65 kg), as well as Asian and female patients, may have an increased risk of hepatic effects.
• Therefore, dosage modifications or interruptions may be necessary to manage these risks effectively.

Nintedanib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Anticoagulants	might make Nintedanib's harmful or hazardous effects worse. In particular, there may be an elevated risk of bleeding.
Combined Inhibitors of CYP3A4 and P-glycoprotein	The serum levels of nitedanib can increase.
Erdafitinib	Serum levels of P-glycoprotein/ABCB1 Substrates can increase.
Lumacaftor	may reduce the serum concentration of P-glycoprotein/ABCB1 Substrates. After utilizing lumacaftor, the level of P-glycoprotein/ABCB1 Substrates in the serum can increase.
P-glycoprotein/ABCB1 Inhibitors	Serum levels of P-glycoprotein/ABCB1 Substrates can increase. P-glycoprotein inhibitors could also make it simpler for certain cells, tissues, and organs where p-glycoprotein is plentiful to receive p-glycoprotein substrates (e.g., brain, T-lymphocytes, testes, etc.).
Ranolazine:	Serum levels of P-glycoprotein/ABCB1 Substrates can increase.
Risk Factor X (Avoid combination)
Combined Inducers of CYP3A4 and P-glycoprotein	The level of nintedanib in the serum might decline.

Monitoring parameters:

• Liver Function Tests: Before starting treatment with nintedanib, and regularly during the first 3 months of treatment, as well as periodically afterward or as needed based on clinical signs, liver function tests should be conducted.
• Pregnancy Test: Prior to initiating treatment, it's important to obtain a pregnancy test.
• GI Events: Keep an eye out for gastrointestinal events such as diarrhea, nausea, vomiting, and GI perforation.
• Arterial Thromboembolic Events: Monitor for signs of arterial thromboembolic events.
• Bleeding: Watch for any signs of bleeding.

How to administer Nintedanib (Ofev)?

• Oral Administration: Take nintedanib with food.
• Swallow Whole: Swallow the capsules whole with a drink of liquid. Do not chew or crush them, as they may have a bitter taste.

Mechanism of action of Nintedanib (Ofev):

• Targets: Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs), including platelet-derived growth factor (PDGFR alpha and PDGFR beta), fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3), vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), and Fms-like tyrosine kinase-3 (FLT3).
• Blocking Signaling: By competitively binding to the adenosine triphosphate (ATP) binding pocket of these receptors, nintedanib blocks intracellular signaling critical for the proliferation, migration, and transformation of fibroblasts.

Absorption

• Food: Consumption with food increases exposure by approximately 20% and delays absorption.

Distribution

• Volume of Distribution (V): Approximately 1050 liters.
• Protein Binding: Nintedanib is highly bound to proteins, with approximately 98% binding.

Metabolism

• Metabolism Pathway: Nintedanib undergoes hydrolytic cleavage by esterases to form the free acid moiety BIBF 1202. This moiety is then glucuronidated by enzymes such as UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to produce BIBF 1202 glucuronide. A minor pathway involves metabolism by CYP 3A4.

Bioavailability

• Bioavailability: Nintedanib's bioavailability is approximately 5%.

Elimination

• Half-life: The elimination half-life of nintedanib is approximately 9.5 hours.
• Time to Peak Plasma Levels: It takes around 2 hours for nintedanib to reach peak plasma levels (4 hours with food).

Excretion

• Excretion Routes: Nintedanib is primarily eliminated via the feces (approximately 93%), with a minor portion excreted in the urine (less than 1%).

International Brands of Nintedanib:

• Ofev
• Vargatef

Nintedanib Brand Names in Pakistan:

No Brands Available in Pakistan.