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GEFITINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. It has limited use and is only indicated for patients with metastatic non-small cell lung cancers whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 substitution mutations as determined by an FDA-approved test.

Specific Substances

    1) Iressa
    2) ZD 1839
    3) ZD-1839
    4) ZD1839
    5) 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin)propoxy]
    1.2.1) MOLECULAR FORMULA
    1) C22-H24-Cl-F-N4-O3

Available Forms Sources

    A) FORMS
    1) Gefitinib is available in the United States as 250 mg tablets (Prod Info IRESSA(R) oral tablets, 2015).
    B) USES
    1) Gefitinib is used as a first-line therapy for patients with metastatic non-small cell lung cancers whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 substitution mutations as determined by an FDA-approved test (Prod Info IRESSA(R) oral tablets, 2015).
    2) LIMITATION OF USE: The safety and efficacy of gefitinib have not been established in patients with tumors other than exon 19 deletions or exon 21 (L858R) substitution mutations (Prod Info IRESSA(R) oral tablets, 2015).
    3) In September 2011, AstraZeneca had withdrawn the Accelerated Approval New Drug Application (NDA) for Iressa (R) (gefitinib). At that time the manufacturer did not plan to pursue approval for Iressa(R) in the US (AstraZeneca, 2011).

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: Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. It has limited use and is only indicated for patients as a first-line therapy with metastatic non-small cell lung cancers whose tumors have EGFR receptor exon 19 deletions or exon 21 substitution mutations as determined by an FDA-approved test.
    B) PHARMACOLOGY: It reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, that can prevent autophosphorylation of tyrosine residues associated with the receptor, and can thereby, inhibit further downstream signaling and blocking EGFR-dependent proliferation.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Predominant adverse effects are an acne-like skin rash, diarrhea, nausea, vomiting, anorexia, and eye disorders (eg, conjunctivitis, blepharitis, dry eye). Infrequently, increases in transaminases and alkaline phosphatase have occurred. Potentially severe bullous, blistering or exfoliating skin conditions, including toxic epidermal necrolysis, Stevens Johnson syndromes and erythema multiforme, have developed with gefitinib therapy. Fatal interstitial pneumonia and acute lung damage have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Data limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects such as increases in transaminases and alkaline phosphatase, rash, diarrhea, nausea and vomiting. Potentially severe events, may include hepatotoxicity and interstitial lung disease.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with gefitinib therapy.
    0.2.20) REPRODUCTIVE
    A) Avoid using gefitinib during pregnancy. A pregnant woman who was treated with gefitinib for lung adenocarcinoma delivered a healthy male infant at 35 weeks gestation (gefitinib treatment duration was 55 days) via a planned cesarean section. It is not known whether gefitinib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Breastfeeding is not recommended.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of gefitinib in humans.

Laboratory Monitoring

    A) Monitor liver function as indicated in symptomatic patients.
    B) Monitor fluid and electrolyte status in patients with significant diarrhea and/or vomiting.
    C) Monitor chest radiograph, pulse oximetry and/or arterial blood gases in patients with acute respiratory signs or symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) No overdose information. Treatment is symptomatic supportive. Monitor vital signs. Monitor fluid status in patients that develop significant diarrhea and/or vomiting. Treat with IV fluids as necessary. Monitor liver enzymes as indicated. Stomatitis may occur.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs. Monitor electrolytes following a significant overdose. Patients with a new onset of dyspnea, cough and fever should be monitored closely for interstitial lung disease (ie, lung infiltration, pneumonitis, acute respiratory distress syndrome or pulmonary fibrosis). Monitor liver enzymes and bilirubin closely following a significant exposure. Severe skin disorders (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) have occurred with therapy.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is unlikely to be necessary following an inadvertent minor exposure. Administer activated charcoal following a significant recent overdose if the patient is alert and not vomiting, and is able to maintain their airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients that develop significant respiratory dysfunction (ie, new onset of dyspnea, respiratory distress secondary to interstitial lung disease).
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Due to the extensive distribution of gefitinib and a high degree of protein binding (90%), hemodialysis is unlikely to be effective.
    G) PHARMACOKINETICS
    1) ORAL: Time to peak concentration: 3 to 7 hours. It is absorbed slowly. Protein binding of gefitinib to serum albumin and alpha1-acid glycoprotein in vitro is 90% and independent of drug concentration. Primary mode of excretion is via the feces (86%) (unchanged drug and metabolites). Renal excretion is less than 4%.
    2) INTRAVENOUS: Extensively distributed with a mean steady state volume of distribution of 1400 L following IV administration. Elimination half-life is 48 hours.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion (a single extra dose) can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance, interstitial lung disease (ie, pneumonitis, acute respiratory distress syndrome or pulmonary fibrosis) or hepatotoxicity should be admitted.
    4) CONSULT CRITERIA: Contact a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult an intensivist or pulmonologist in any patient that develops a new onset of respiratory (eg, interstitial lung disease) dysfunction.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. In a clinical trial, 23 patients were treated weekly with doses from 1500 to 3500 mg and exposure did not appear to be dose-dependent. Adverse events were mild to moderate and were similar to events reported with therapeutic use. THERAPEUTIC: ADULT: ORAL: 250 mg once daily; PEDIATRIC: The safety and efficacy of gefitinib in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. It has limited use and is only indicated for patients as a first-line therapy with metastatic non-small cell lung cancers whose tumors have EGFR receptor exon 19 deletions or exon 21 substitution mutations as determined by an FDA-approved test.
    B) PHARMACOLOGY: It reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, that can prevent autophosphorylation of tyrosine residues associated with the receptor, and can thereby, inhibit further downstream signaling and blocking EGFR-dependent proliferation.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Predominant adverse effects are an acne-like skin rash, diarrhea, nausea, vomiting, anorexia, and eye disorders (eg, conjunctivitis, blepharitis, dry eye). Infrequently, increases in transaminases and alkaline phosphatase have occurred. Potentially severe bullous, blistering or exfoliating skin conditions, including toxic epidermal necrolysis, Stevens Johnson syndromes and erythema multiforme, have developed with gefitinib therapy. Fatal interstitial pneumonia and acute lung damage have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Data limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects such as increases in transaminases and alkaline phosphatase, rash, diarrhea, nausea and vomiting. Potentially severe events, may include hepatotoxicity and interstitial lung disease.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with gefitinib therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Ocular disorders, including keratitis, corneal erosion, aberrant eyelash growth, conjunctivitis, blepharitis and dry eyes, have been reported infrequently with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung disease or interstitial lung disease-like (eg, lung infiltration, pneumonitis, acute respiratory distress syndrome or pulmonary fibrosis) has been reported in about 1% of gefitinib-treated patients (n=2462). Of those patients, 0.7% of the cases were grade 3 or higher and 3 cases were fatal (Prod Info IRESSA(R) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea, sometimes severe, is one of the most common (greater than 20%) adverse events reported during therapy. Across all clinical trials, grade 3 or 4 diarrhea has occurred in 3% of gefitinib treated-patients (n=2462) (Prod Info IRESSA(R) oral tablets, 2015).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, nausea and vomiting are relatively common adverse effects reported during gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).
    C) GASTROINTESTINAL COMPLICATION
    1) WITH THERAPEUTIC USE
    a) Decreased appetite, stomatitis, and dry mouth have developed during gefitinib therapy. Pancreatitis has rarely been reported (Prod Info IRESSA(R) oral tablets, 2015).
    D) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) During clinical trials, gastrointestinal perforation was a rare adverse event (Prod Info IRESSA(R) oral tablets, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) During clinical trials, increases in liver enzymes have been reported. Alanine aminotransferase (ALT) was increased in 11.4% of patients, 7.9% had an increased aspartate aminotransferase (AST) and 2.7% had an increased bilirubin. In addition, grade 3 or higher liver test abnormalities occurred in ALT (5.1%), AST (3%) and bilirubin (0.7%). Fatal hepatotoxicity is rare (0.04%) (Prod Info IRESSA(R) oral tablets, 2015).
    b) CASE REPORT: A 75-year-old man with hepatitis-C-related liver cirrhosis of Child-Pugh class B and adenocarcinoma of the lung developed hypoalbuminemia (serum albumin level of 21 g/L), prolonged PT, decreased serum cholinesterase concentration, and severe ascites a week after completing 12 days of gefitinib therapy. In 30 patients who received gefitinib who had serum albumin assessed before and after therapy, 6 patients had a drop in serum albumin of more than 4 g/L (Mitsui et al, 2003).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CYSTITIS
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, cystitis and hemorrhagic cystitis have been reported with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Hemorrhage, including epistaxis and hematuria, have occurred infrequently with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin reactions are one of the most common (greater than 20%) adverse events reported with gefitinib therapy. Reactions can include, but are not limited to, rash (various types), acne, dermatitis, drug eruption, dry skin, erythema, and pruritus (Prod Info IRESSA(R) oral tablets, 2015).
    B) BULLOUS DERMATOSIS
    1) WITH THERAPEUTIC USE
    a) Potentially severe bullous, blistering or exfoliating skin conditions, including toxic epidermal necrolysis, Stevens Johnson syndromes and erythema multiforme have developed with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).
    C) SECONDARY CUTANEOUS VASCULITIS
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, cutaneous vasculitis has been reported with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reaction, including angioedema and urticaria, has been reported infrequently with gefitinib therapy (Prod Info IRESSA(R) oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Avoid using gefitinib during pregnancy. A pregnant woman who was treated with gefitinib for lung adenocarcinoma delivered a healthy male infant at 35 weeks gestation (gefitinib treatment duration was 55 days) via a planned cesarean section. It is not known whether gefitinib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Breastfeeding is not recommended.
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) Gefitinib can cause fetal harm when administered to a pregnant woman, based on its mechanism of action and animal data (Prod Info IRESSA(R) oral tablets, 2015).
    B) DISEASE-ASSOCIATED MATERNAL/FETAL RISK
    1) CASE REPORT: A 33-year-old pregnant woman, with a past history of smoking, began treatment with gefitinib 250 mg/day at 28 weeks gestation for treatment of lung adenocarcinoma. The patient experienced dramatic improvement within 8 days of treatment initiation and ceased supplemental oxygen. Fetal growth, morphology, and amniotic fluid index were evaluated twice monthly during treatment. The patient delivered a healthy male infant at 35 weeks gestation (gefitinib treatment duration was 55 days) via a planned cesarean section. At delivery (approximately 16.5 hours after the last gefitinib dose), the maternal plasma, cord blood, and amniotic fluid concentrations of gefitinib were 127.1 ng/mL, 25.7 ng/mL, and 16.9 ng/mL. Progression free survival with gefitinib was reportedly 42 weeks with an overall survival period of 22 months. Regular development was reported in the child at a 24 month follow-up exam (Gil et al, 2014).
    C) CONTRACEPTION
    1) There are no adequate or well-controlled studies of gefitinib use in pregnant women. Women of childbearing age should use effective contraception during and 2 weeks after treatment. This drug should not be used in pregnancy (Prod Info IRESSA(R) oral tablets, 2015).
    D) ANIMAL STUDIES
    1) Animal studies have shown that gefitinib crosses the placenta following a single oral dose of 5 mg/kg [about 0.2 times the recommended human dose on a mg/m(2) basis]. Animals treated with 5 mg/kg from the beginning of organogenesis to the end of weaning delivered fewer live offspring. Twenty mg/kg caused reduced fetal weight and a high rate of neonatal mortality soon after birth (Prod Info IRESSA(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether gefitinib is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Animal studies reveal that gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma (Prod Info IRESSA(R) oral tablets, 2015).
    2) Breastfeeding is not recommended (Prod Info IRESSA(R) oral tablets, 2015).
    B) ANIMAL STUDIES
    1) Based on animal studies, gefitinib is present in the milk of lactating animals at levels 11 to 19 times higher than in blood (based on a dose of 5 mg/kg) (Prod Info IRESSA(R) oral tablets, 2015).
    3.20.5) FERTILITY
    A) DECREASED FEMALE FERTILITY
    1) In animal fertility studies, doses equal to the recommended dose on a mg/m(2) basis caused an increased incidence of irregular estrous, decreased corpora lutea, and a decrease in uterine implants and live embryos per litter (Prod Info IRESSA(R) oral tablets, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of gefitinib in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of gefitinib in humans (Prod Info IRESSA(R) oral tablets, 2015).
    3.21.4) ANIMAL STUDIES
    A) HEPATOCELLULAR TUMORS
    1) At a dose approximately twice the recommended daily dose of 250 mg on a on a mg/m(2) basis, gefitinib caused hepatocellular adenomas in females (Prod Info IRESSA(R) oral tablets, 2015).
    B) HEMANGIOMAS/HEMAGIOSARCOMAS
    1) At a dose approximately 0.4 times the recommended daily dose on a mg/m(2) basis, gefitinib caused hepatocellular adenomas in female rats and hemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats (Prod Info IRESSA(R) oral tablets, 2015).

Genotoxicity

    A) An in vitro human lymphocyte assay demonstrated no evidence of clastogenic activity (Prod Info IRESSA(R) oral tablets, 2015).
    B) Bacterial mutation and mouse lymphoma assays and an in vivo rat micronucleus test demonstrated no evidence of clastogenic activity (Prod Info IRESSA(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver function as indicated in symptomatic patients.
    B) Monitor fluid and electrolyte status in patients with significant diarrhea and/or vomiting.
    C) Monitor chest radiograph, pulse oximetry and/or arterial blood gases in patients with acute respiratory signs or symptoms.

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 demonstrating severe fluid and electrolyte imbalance, interstitial lung disease (ie, pneumonitis, acute respiratory distress syndrome or pulmonary fibrosis) or hepatotoxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with an inadvertent ingestion (a single extra dose) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult an intensivist or pulmonologist in any patient that develops a new onset of respiratory (eg, interstitial lung disease) dysfunction.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor liver function as indicated in symptomatic patients.
    B) Monitor fluid and electrolyte status in patients with significant diarrhea and/or vomiting.
    C) Monitor chest radiograph, pulse oximetry and/or arterial blood gases in patients with acute respiratory signs or symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastrointestinal decontamination is unlikely to be necessary following an inadvertent minor ingestion.
    B) 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) No overdose information. Treatment is symptomatic supportive. Monitor vital signs. Monitor fluid status in patients that develop significant diarrhea; treat with IV fluids as necessary. Monitor liver enzymes as indicated. Stomatitis may occur.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor vital signs. Monitor electrolytes following a significant overdose. Patients with a new onset of dyspnea, cough and fever should be monitored closely for interstitial lung disease (ie, lung infiltration, pneumonitis, acute respiratory distress syndrome or pulmonary fibrosis). Monitor liver enzymes and bilirubin closely following a significant exposure. Severe skin disorders (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) have occurred with therapy.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    2) Monitor liver enzymes in symptomatic patients.
    3) Monitor chest radiograph, pulse oximetry and/or arterial blood gases in patients with acute respiratory signs or symptoms.

Enhanced Elimination

    A) SUMMARY
    1) Due to extensive distribution of gefitinib and a high degree of protein binding (90%) (Prod Info IRESSA(R) oral tablets, 2015), hemodialysis is unlikely to be effective.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. In a clinical trial, 23 patients were treated weekly with doses from 1500 to 3500 mg and exposure did not appear to be dose-dependent. Adverse events were mild to moderate and were similar to events reported with therapeutic use. THERAPEUTIC: ADULT: ORAL: 250 mg once daily; PEDIATRIC: The safety and efficacy of gefitinib in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 250 mg orally once daily without regard to food until disease progression or unacceptable toxicity; do not administer a missed dose within 12 hours of the next dose (Prod Info IRESSA(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of gefitinib in pediatric patients have not been established (Prod Info IRESSA(R) oral tablets, 2015).

Minimum Lethal Exposure

    A) SUMMARY
    1) A minimum toxic dose has not been established.
    B) ANIMAL STUDIES
    1) In animal studies, a single dose of 12,000 mg/squared meter (about 80 times the recommended clinical dose on a mg/squared meter basis) was lethal to rats(Prod Info Iressa(TM), 2003) .

Maximum Tolerated Exposure

    A) SUMMARY
    1) In a clinical trial, 23 patients were treated weekly with doses from 1500 to 3500 mg and exposure did not appear to be dose-dependent. Adverse events were mild to moderate and were similar to events reported with therapeutic use (Prod Info IRESSA(R) oral tablets, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Gefitinib is an orally-active, low-molecular-weight anilinoquinazoline derivative; it is a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor which blocks signal transduction pathways involved in proliferation, survival, and metastases of cancer cells, and other processes promoting tumor growth (Prod Info Iressa(TM), 2003; Baselga & Averbuch, 2000; Anon, 2002b; Norman, 2001; Moasser et al, 2001; Albanell et al, 2002; Barker et al, 2001; Arteaga & Johnson, 2001).
    B) Selectivity of gefitinib has been demonstrated in vitro; 50% inhibition of EGFR kinase activity was observed at concentrations of 0.02 to 0.08 micromol/liter (L), whereas concentrations required for similar inhibition of other tyrosine kinases (eg, erbB-2, KDR, c-flt, serine/threonine kinases) have been at least 100-fold higher(Chan et al, 2002; Albanell et al, 2001; Arteaga et al, 2001). The drug has prevented autophosphorylation of EGFR in various tumor cell lines and xenografts with different receptor levels; this can block activation of downstream signaling molecules and tumor growth (Prod Info Iressa(TM), 2003; Albanell et al, 2001; Baselga & Averbuch, 2000; Arteaga & Johnson, 2001).
    C) Specific mechanisms of antitumor activity remain unclear. One speculation is upregulation of levels of the cyclin-dependent kinase (Cdk) inhibitor p27 via EGFR kinase inhibition, leading to inhibited Cdk activity and arrest in the G1 cell-cycle phase (Arteaga & Johnson, 2001). Inhibition of both EGFR and erbB-2 may be involved in some cancers (Arteaga et al, 2001; Moasser et al, 2001; Arteaga & Johnson, 2001). Inhibition of tumor neoangiogenesis by gefitinib may also be involved in antitumor activity (Arteaga & Johnson, 2001; Ciardiello et al, 2001).

Physicochemical

Molecular Weight

    A) 446.9(Prod Info Iressa(TM), 2003)

References

General Bibliography

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