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NINTEDANIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nintedanib is a small molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis in adult patients.

Specific Substances

    1) BIBF 1120
    2) Nintedanib esylate
    3) CAS 656247-17-5 (Nintedanib)
    1.2.1) MOLECULAR FORMULA
    1) C31H33N5O4.C2H6O3S (nintedanib esylate) (Prod Info OFEV(R) oral capsules, 2014)

Available Forms Sources

    A) FORMS
    1) Nintedanib is available in 100 mg and 150 mg capsules (Prod Info OFEV(R) oral capsules, 2014).
    B) USES
    1) Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis in adult patients (Prod Info OFEV(R) oral capsules, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis in adult patients.
    B) PHARMACOLOGY: Nintedanib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3), fibroblast growth factor receptor (FGFR1, FGFR2, and FGFR3), and platelet-derived growth factor receptor (PDGFR) alpha and beta. By binding to these receptors. nintedanib blocks intracellular signaling and prevents proliferation, migration, and transformation of fibroblasts implicated in idiopathic pulmonary fibrosis pathogenesis. Nintedanib is also shown to inhibit Fms-like tyrosine kinase-3 (FLT3) and other non-receptor tyrosine kinases (ie, Lck, Lyn, and Src), but the role of these receptors in the treatment of idiopathic pulmonary fibrosis is unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported, with an incidence of at least 5%, include nausea, vomiting, diarrhea, abdominal pain, decreased appetite, decreased weight, elevated liver enzymes, hypertension, and headache.
    2) INFREQUENT: Other adverse effects that occurred less frequently, but had an incidence greater than placebo, included arterial thromboembolic events, myocardial infarction, hypothyroidism, bleeding, gastrointestinal perforation, pneumonia, and bronchitis.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. One patient, who received a dose of 600 mg daily (twice the recommended daily dose) for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect. Two other patients, who received 600 mg twice daily (four times the recommended daily dose) for up to 8 days during oncology studies, reported clinical effects that were consistent with adverse effects that have been reported with therapeutic doses. Both patients recovered.
    0.2.20) REPRODUCTIVE
    A) Nintedanib can cause fetal harm when administered during pregnancy. Although there are no adequate or well-controlled studies in human pregnancy, embryofetal death and teratogenicity have occurred in animal studies at doses less than and approximately 5 times the maximum recommended human dose. Due to the mechanism of action and the potential for serious adverse effects, this drug is not recommended for use in pregnant women.
    0.2.21) CARCINOGENICITY
    A) Malignant lung neoplasms were reported in patients treated with nintedanib during placebo-controlled clinical trials, and were more likely to cause death than in patients in the placebo group.

Laboratory Monitoring

    A) Monitor fluid and electrolyte levels in patients with significant vomiting and/or diarrhea.
    B) Monitor vital signs and liver enzymes.
    C) Bleeding has been reported with nintedanib therapy. Monitor CBC with differential and platelet count periodically following overdose.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Serum nintedanib levels are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Nitroglycerin and phentolamine are alternatives. There may be an increased risk of bleeding with this agent. Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, who remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected nintedanib overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) The absolute bioavailability of a 100 mg dose was 4.7% in healthy subjects. Protein binding and volume of distribution are 97.8% and 1050 L, respectively. Primarily metabolized by hydrolytic cleavage via esterases followed by glucuronidation; minor metabolism via cytochrome P450 enzymes. Following oral administration, 93.4% of radiolabeled nintedanib was completely excreted via the fecal/biliary route primarily as the metabolite (BIBF 1202) within 4 days. Urinary excretion of unchanged drug was 0.05% within 48 hours following oral administration. Half-life was 9.5 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension, elevated liver enzyme concentrations, and gastrointestinal effects (eg, nausea, vomiting, diarrhea, abdominal pain).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. One patient, who received a nintedanib dose of 600 mg daily for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect. Two other patients, who received 600 mg twice daily for up to 8 days during oncology studies, reported clinical effects that were consistent with adverse effects that have been reported with therapeutic doses. Both patients recovered.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 150 mg every 12 hours. The maximum daily dose is 300 mg. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis in adult patients.
    B) PHARMACOLOGY: Nintedanib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3), fibroblast growth factor receptor (FGFR1, FGFR2, and FGFR3), and platelet-derived growth factor receptor (PDGFR) alpha and beta. By binding to these receptors. nintedanib blocks intracellular signaling and prevents proliferation, migration, and transformation of fibroblasts implicated in idiopathic pulmonary fibrosis pathogenesis. Nintedanib is also shown to inhibit Fms-like tyrosine kinase-3 (FLT3) and other non-receptor tyrosine kinases (ie, Lck, Lyn, and Src), but the role of these receptors in the treatment of idiopathic pulmonary fibrosis is unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported, with an incidence of at least 5%, include nausea, vomiting, diarrhea, abdominal pain, decreased appetite, decreased weight, elevated liver enzymes, hypertension, and headache.
    2) INFREQUENT: Other adverse effects that occurred less frequently, but had an incidence greater than placebo, included arterial thromboembolic events, myocardial infarction, hypothyroidism, bleeding, gastrointestinal perforation, pneumonia, and bronchitis.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. One patient, who received a dose of 600 mg daily (twice the recommended daily dose) for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect. Two other patients, who received 600 mg twice daily (four times the recommended daily dose) for up to 8 days during oncology studies, reported clinical effects that were consistent with adverse effects that have been reported with therapeutic doses. Both patients recovered.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, hypertension, including hypertensive crisis and hypertensive cardiomyopathy, was reported in 5% of patients treated with nintedanib (n=723) compared to 4% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) During clinical trials, arterial thromboembolic events occurred in 2.5% of patients treated with nintedanib compared to 0.8% of patients receiving placebo, with myocardial infarction as the most common arterial thromboembolic event, reported in 1.5% of patients treated with nintedanib (n=723) compared to 0.4% of patients who received placebo (n=508). Myocardial infarction was more likely to cause death in patients treated with nintedanib (0.3%) over placebo (0.2%) (Prod Info OFEV(R) oral capsules, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, bronchitis was reported in 1.2% of patients treated with nintedanib (n=723) compared to 0.8% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).
    B) NASOPHARYNGITIS
    1) WITH POISONING/EXPOSURE
    a) During a clinical trial, one patient, who received a nintedanib dose of 600 mg daily for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect(Prod Info OFEV(R) oral capsules, 2014) .
    C) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Pneumonia was more likely to cause death in patients treated with nintedanib (0.7%) over placebo (0.6%) (Prod Info OFEV(R) oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, headaches were reported in 8% of patients treated with nintedanib (n=723) compared to 5% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, nausea and vomiting were reported in 24% and 12%, respectively, of patients treated with nintedanib (n=723) compared to 7% and 3%, respectively, of patients who received placebo (n=508). Nausea and vomiting resulted in the discontinuation of nintedanib in 2% and 1% of patients, respectively (Prod Info OFEV(R) oral capsules, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, diarrhea was the most commonly reported adverse effect, occurring in 62% of patients treated with nintedanib (n=723) compared to 18% of patients who received placebo (n=508). Diarrhea was also the most frequent reason for permanent dose reduction, occurring in 11% of patients (Prod Info OFEV(R) oral capsules, 2014).
    b) Diarrhea resulted in the discontinuation of nintedanib in 5% of patients as compared to less than 1% of patients who received placebo (Prod Info OFEV(R) oral capsules, 2014).
    c) Diarrhea typically occurred within the first 3 months of treatment and was mild to moderate in intensity in the majority of patients (Prod Info OFEV(R) oral capsules, 2014).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, abdominal pain, including upper and lower abdominal pain, gastrointestinal pain, and abdominal tenderness, was reported in 15% of patients treated with nintedanib (n=723) compared to 6% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).
    D) DECREASE IN APPETITE
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, decreased appetite was reported in 11% of patients treated with nintedanib (n=723) compared to 5% of patients who received placebo (n=508). Decreased appetite resulted in the discontinuation of nintedanib in 2% of patients (Prod Info OFEV(R) oral capsules, 2014).
    E) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) During clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with nintedanib compared to no patients who received placebo (Prod Info OFEV(R) oral capsules, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, elevated liver enzyme concentrations, including gamma-glutamyl transferase, alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) concentrations, were reported in 14% of patients treated with nintedanib (n=723) compared to 3% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).
    b) Of the patients with elevated ALT or AST concentrations, 94% had elevations less than 5 times the upper limit of normal (Prod Info OFEV(R) oral capsules, 2014).
    c) During clinical trials, elevated bilirubin concentrations also occurred with nintedanib therapy. Approximately 95% of the patients, with elevated bilirubin concentrations, had elevations less than 2 times the upper limit of normal (Prod Info OFEV(R) oral capsules, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) During clinical trials, bleeding events were reported in 10% of patients treated with nintedanib compared to 7% of patients who received placebo (Prod Info OFEV(R) oral capsules, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) According to 3 randomized, double-blind, placebo-controlled trials, hypothyroidism was reported in 1.1% of patients treated with nintedanib (n=723) compared to 0.6% of patients who received placebo (n=508) (Prod Info OFEV(R) oral capsules, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Nintedanib can cause fetal harm when administered during pregnancy. Although there are no adequate or well-controlled studies in human pregnancy, embryofetal death and teratogenicity have occurred in animal studies at doses less than and approximately 5 times the maximum recommended human dose. Due to the mechanism of action and the potential for serious adverse effects, this drug is not recommended for use in pregnant women.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal reproduction studies, administration of nintedanib resulted in embryofetal death and teratogenicity at exposures less than and approximately 5 times the maximum recommended human dose (MRHD), respectively. Malformations included urogenital, skeletal, and vasculature abnormalities, including missing urogenital organs and missing or additional major blood vessels. Skeletal abnormalities included abnormalities in the thoracic, lumbar, and caudal vertebrae, ribs and sternebrae (Prod Info OFEV(R) oral capsules, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Nintedanib can cause fetal harm when administered during pregnancy. There are no adequate or well controlled studies of nintedanib use in human pregnancy. However, due to the lack of human safety data and the potential for serious adverse effects, this drug is not recommended for use in pregnant women. Use of adequate contraception is recommended in women of childbearing potential during treatment with nintedanib and for at least 3 months after discontinuation. If nintedanib is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus (Prod Info OFEV(R) oral capsules, 2016).
    B) ANIMAL STUDIES
    1) A decrease in postnatal viability was reported in the offspring of mothers exposed to nintedanib at concentrations less than the maximum recommended human dose (MRHD) (Prod Info OFEV(R) oral capsules, 2016).
    2) Administration of nintedanib at doses approximately 15 times the MRHD resulted in a sex ratio change in fetuses (female:male ratio of approximately 71%:29%) (Prod Info OFEV(R) oral capsules, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether nintedanib is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined. It is recommended to either discontinue nursing or nintedanib, because excretion of nintedanib and/or its metabolites in human milk are probable and the potential for serious adverse reactions from nintedanib exists in nursing infants (Prod Info OFEV(R) oral capsules, 2016).
    B) ANIMAL STUDIES
    1) Nintedanib and its metabolites were excreted into the milk of lactating animals. Similar concentrations of nintedanib and its metabolites have been found in milk and plasma (Prod Info OFEV(R) oral capsules, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Female fertility in animals was reduced with nintedanib at exposure levels approximately 3 times the maximum recommended human dose (MRHD) (an oral dose of 100 mg/kg/day). Effects included increased resorption and postimplantation loss, and an increase in the gestation index. During chronic toxicity studies in animals, a change in the number and size of the corpora lutea in the ovaries was noted. There appeared to be no effect on male fertility given nintedanib at exposure levels approximately 3 times the MRHD (Prod Info OFEV(R) oral capsules, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Malignant lung neoplasms were reported in patients treated with nintedanib during placebo-controlled clinical trials, and were more likely to cause death than in patients in the placebo group.
    3.21.3) HUMAN STUDIES
    A) PULMONARY NEOPLASM
    1) Malignant lung neoplasms were reported in patients treated with nintedanib during placebo-controlled clinical trials, and were more likely to cause death in patients treated with nintedanib (0.3%) over placebo (0%) (Prod Info OFEV(R) oral capsules, 2014).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity in rats and mice given nintedanib for 2 years at doses up to 10 and 30 mg/kg/day, respectively (less than and approximately 4 times the maximum recommended human dose, respectively, on a plasma drug AUC basis) (Prod Info OFEV(R) oral capsules, 2014).

Genotoxicity

    A) According to the negative results of the in vitro bacterial reverse mutation assay, the mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus assay, nintedanib is not genotoxic (Prod Info OFEV(R) oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte levels in patients with significant vomiting and/or diarrhea.
    B) Monitor vital signs and liver enzymes.
    C) Bleeding has been reported with nintedanib therapy. Monitor CBC with differential and platelet count periodically following overdose.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Serum nintedanib levels are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.2) SERUM/BLOOD
    A) Monitor fluid and electrolyte levels in patients with significant vomiting and/or diarrhea.
    B) Monitor vital signs and liver enzymes.
    C) Bleeding has been reported with nintedanib therapy (Prod Info OFEV(R) oral capsules, 2014). Monitor CBC with differential and platelet count periodically following overdose.
    D) Serum nintedanib levels are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Myocardial infarction has been reported in patients treated with nintedanib during clinical trials (Prod Info OFEV(R) oral capsules, 2014). Obtain an ECG, and institute continuous cardiac monitoring.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, who remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.

Monitoring

    A) Monitor fluid and electrolyte levels in patients with significant vomiting and/or diarrhea.
    B) Monitor vital signs and liver enzymes.
    C) Bleeding has been reported with nintedanib therapy. Monitor CBC with differential and platelet count periodically following overdose.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Serum nintedanib levels are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Nitroglycerin and phentolamine are alternatives. There may be an increased risk of bleeding with this agent. Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte levels in patients with significant vomiting and/or diarrhea.
    2) Monitor vital signs and liver enzymes.
    3) Bleeding has been reported with nintedanib therapy. Monitor CBC with differential and platelet count periodically following overdose.
    4) Serum nintedanib levels are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    D) BLEEDING
    1) If necessary, blood loss and reversal of bleeding tendency can be managed with packed red blood cells and cryoprecipitate or fresh frozen plasma.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (97.8%) and large volume of distribution (1050 L) (Prod Info OFEV(R) oral capsules, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. One patient, who received a nintedanib dose of 600 mg daily for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect. Two other patients, who received 600 mg twice daily for up to 8 days during oncology studies, reported clinical effects that were consistent with adverse effects that have been reported with therapeutic doses. Both patients recovered.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 150 mg every 12 hours. The maximum daily dose is 300 mg. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 150 mg every 12 hours. The maximum daily dose is 300 mg (Prod Info OFEV(R) oral capsules, 2014).
    B) Due to the bitter taste, the capsule should be swallowed whole and not chewed or crushed. The pharmacokinetics of nintedanib, following chewing or crushing of the capsule, is unknown (Prod Info OFEV(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info OFEV(R) oral capsules, 2014).

Maximum Tolerated Exposure

    A) During a clinical trial, one patient, who received a nintedanib dose of 600 mg daily for 21 days, experienced nasopharyngitis that resolved without an onset of any other reported clinical effect. Two other patients, who received 600 mg twice daily for up to 8 days during oncology studies, reported clinical effects that were consistent with adverse effects that have been reported with therapeutic doses. Both patients recovered (Prod Info OFEV(R) oral capsules, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nintedanib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3), fibroblast growth factor receptor (FGFR1, FGFR2, and FGFR3), and platelet-derived growth factor receptor (PDGFR) alpha and beta. By binding to these receptors, nintedanib blocks intracellular signaling and prevents proliferation, migration, and transformation of fibroblasts implicated in idiopathic pulmonary fibrosis pathogenesis. Nintedanib is also shown to inhibit Fms-like tyrosine kinase-3 (FLT3) and other non-receptor tyrosine kinases (ie, Lck, Lyn, and Src), but the role of these receptors in the treatment of idiopathic pulmonary fibrosis is unknown (Prod Info OFEV(R) oral capsules, 2014).

Physicochemical

Physical Characteristics

    A) Nintedanib esylate is a bright yellow powder (Prod Info OFEV(R) oral capsules, 2014).

Molecular Weight

    A) 649.76 g/mol (nintedanib esylate) (Prod Info OFEV(R) oral capsules, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    8) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    9) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    10) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    11) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    12) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    13) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    14) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    15) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    16) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    17) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    18) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    19) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    20) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    21) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    22) Product Information: OFEV(R) oral capsules, nintedanib oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 2014.
    23) Product Information: OFEV(R) oral capsules, nintedanib oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield, CT, 2016.
    24) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    25) Rasch DK & Lancaster L: Successful use of nitroglycerin to treat postoperative pulmonary hypertension. Crit Care Med 1987; 15(6):616-617.
    26) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    27) Rhoney D & Peacock WF: Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm 2009; 66(15):1343-1352.
    28) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
    29) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    30) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    31) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.