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ERLOTINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Erlotinib, a quinazolinamine, is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR)-tyrosine kinase inhibitor that is approved for use in patients with locally advanced unresectable or metastatic non-small cell lung cancer and pancreatic cancer.

Specific Substances

    1) CP-358,774
    2) OSI-774
    3) Tarceva
    4) N-(3-ethylnylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine
    5) Molecular Formula: C22-H23-N3-O4.HCl

Available Forms Sources

    A) FORMS
    1) Erlotinib is available as 25 mg, 100 mg, and 150 mg white film-coated tablets (Prod Info TARCEVA(R) oral tablets, 2015).
    B) USES
    1) Oral erlotinib is approved as first-line therapy in patients with metastatic non-small cell lung cancer that have tumors with epidermal growth factor receptor exon 19 deletions or exon 21 substitution mutations as detected by an FDA-approved test, as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer that has not progressed following 4 cycles of platinum-based first-line chemotherapy, and for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen (Prod Info TARCEVA(R) oral tablets, 2015).
    2) Erlotinib is also approved for use in combination with gemcitabine hydrochloride for the first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer (Prod Info TARCEVA(R) oral tablets, 2015).

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: Erlotinib, a quinazolinamine, is approved for use in patients with locally advanced unresectable or metastatic non-small cell lung cancer and pancreatic cancer.
    B) PHARMACOLOGY: Erlotinib reversibly inhibits tyrosine kinase activity of the epidermal growth factor receptor (EGFR), which results in the inhibition of autophosphorylation of tyrosine residues associated with EGFR and dampened tumor cell signalling, survival, and proliferation. Binding affinity for EGFR exon 19 deletion or exon 21 substitution (L858R) mutations is higher than binding affinity for the wild type receptor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects, occurring in at least 20% of patients, are rash, nausea, vomiting, diarrhea, anorexia, dyspnea, and fatigue.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include: abdominal pain, mucositis, conjunctivitis, keratitis, trichomegaly, headaches, elevated liver enzymes, anemia, and neutropenia.
    3) RARE: Hepatic failure and hepatorenal syndrome have been rarely reported, some resulting fatalities. Other rare adverse effects that have occurred during erlotinib therapy include gastrointestinal bleeding and perforation, myocardial infarction/ischemia, microangiopathic hemolytic anemia with thrombocytopenia, and interstitial lung disease with associated fatalities.
    E) WITH POISONING/EXPOSURE
    1) Data are limited. The signs and symptoms of an acute overdose are expected to be comparable to those side effects seen with high dose therapy (eg, diarrhea, rash, and liver transaminase elevation).
    0.2.20) REPRODUCTIVE
    A) Erlotinib has been classified as FDA pregnancy category D. A case report showed no teratogenicity with prenatal erlotinib exposure from first trimester to term, but animal studies have shown an increased risk of maternal toxicity, embryo/fetal lethality, and spontaneous abortion when erlotinib was administered in high doses, or in the weeks immediately pre-and post-mating.

Laboratory Monitoring

    A) Plasma erlotinib concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor liver enzymes in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Hematologic effects, such as neutropenia and anemia may occur during erlotinib therapy. Monitor CBC periodically following an overdose.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Chest radiography and pulse oximetry determination are indicated in all patients with acute respiratory signs or symptoms. Arterial blood gas determination and computed tomography of the chest may be useful in select cases where clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    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) Ensure adequate ventilation and perform endotracheal intubation early in patients with pulmonary toxicity.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    H) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection.
    I) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: An adult with an inadvertent, small exposure, that remains asymptomatic can be managed at home. Inadvertent pediatric ingestion should be referred to a healthcare facility.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with myelosuppression should be closely monitored in an inpatient setting, with daily monitoring of CBC with differential until bone marrow suppression is resolved.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    5) TRANSFER CRITERIA: Patients with severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    K) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of erlotinib. Early symptoms of overdose may be delayed or not evident (ie, myelosuppression), so reliable follow-up is imperative. Patients taking erlotinib may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    L) PHARMACOKINETICS
    1) Bioavailability of oral tablets is 60%. Protein binding is 93% and volume of distribution is 232 L. It is extensively metabolized in the liver primarily via cytochrome P450 3A4 enzymes. Half-life is 36 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Clinical events (eg, myelosuppression) may be related to other chemotherapeutic agents that may be used in combination with erlotinib therapy.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. Single oral doses of 1,000 mg in healthy adults and weekly oral doses up to 1,600 mg in cancer patients have been well-tolerated. Repeat twice-daily doses of erlotinib 200 mg for only a few days, however, was not tolerated due to severe diarrhea, rash and liver transaminase elevation.
    B) THERAPEUTIC DOSE: Adult: 150 mg once daily for non-small cell lung cancer; 100 mg once daily in combination with gemcitabine for pancreatic cancer. Pediatric: Safety and efficacy not established.

Clinical Effects

Summary Of Exposure

    A) USES: Erlotinib, a quinazolinamine, is approved for use in patients with locally advanced unresectable or metastatic non-small cell lung cancer and pancreatic cancer.
    B) PHARMACOLOGY: Erlotinib reversibly inhibits tyrosine kinase activity of the epidermal growth factor receptor (EGFR), which results in the inhibition of autophosphorylation of tyrosine residues associated with EGFR and dampened tumor cell signalling, survival, and proliferation. Binding affinity for EGFR exon 19 deletion or exon 21 substitution (L858R) mutations is higher than binding affinity for the wild type receptor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects, occurring in at least 20% of patients, are rash, nausea, vomiting, diarrhea, anorexia, dyspnea, and fatigue.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include: abdominal pain, mucositis, conjunctivitis, keratitis, trichomegaly, headaches, elevated liver enzymes, anemia, and neutropenia.
    3) RARE: Hepatic failure and hepatorenal syndrome have been rarely reported, some resulting fatalities. Other rare adverse effects that have occurred during erlotinib therapy include gastrointestinal bleeding and perforation, myocardial infarction/ischemia, microangiopathic hemolytic anemia with thrombocytopenia, and interstitial lung disease with associated fatalities.
    E) WITH POISONING/EXPOSURE
    1) Data are limited. The signs and symptoms of an acute overdose are expected to be comparable to those side effects seen with high dose therapy (eg, diarrhea, rash, and liver transaminase elevation).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) According to pooled data from 3 monotherapy lung cancer studies, the incidence of ocular disorders, including decreased tear production, keratoconjunctivitis sicca, keratitis, and abnormal eyelash growth, was 17.8% in the erlotinib arms and 4% in the control arms (Prod Info TARCEVA(R) oral tablets, 2015).
    2) Trichomegaly has been reported in several patients, who developed long, coarsened, tangled eyelashes and eyebrows in the course of therapy (Lane & Goldstein, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction/ischemia was reported in 6 (2.1%) patients, including 1 myocardial infarction fatality, receiving erlotinib plus gemcitabine compared to 3 (1.1%) patients, including 1 myocardial infarction fatality, receiving placebo plus gemcitabine during a pancreatic cancer clinical trial (Prod Info TARCEVA(R) oral tablets, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was reported in 41% of subjects (n=485) treated with erlotinib in clinical trials (Prod Info TARCEVA(R) oral tablets, 2015).
    B) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) There have been infrequent reports of pulmonary toxicity in patients treated with erlotinib. The incidence of interstitial lung disease (ILD) was 0.6% to 0.8% in erlotinib pivotal trials (n=488), and ILD-associated fatalities have been reported (Liu et al, 2007).
    b) The incidence of interstitial lung disease in approximately 32,000 erlotinib-treated patients, involved in uncontrolled studies as well as trials with concurrent chemotherapy, was approximately 1.1%, with symptom-onset occurring at a median of 39 days (range from 5 days to greater than 9 months) after initiating erlotinib therapy (Prod Info TARCEVA(R) oral tablets, 2015).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported in 16% of patients receiving erlotinib plus gemcitabine (n=259) compared to 11% of patients receiving placebo plus gemcitabine (n=256) during a pancreatic cancer clinical trial (Prod Info TARCEVA(R) oral tablets, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occur in some patients, and generally responds to non-opioid analgesics (Prod Info TARCEVA(R) oral tablets, 2015; Hidalgo et al, 2001; Hammond et al, 2000).
    B) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) Cerebrovascular accidents were reported in 7 (2.5%) patients, including one fatal hemorrhagic event, who received erlotinib plus gemcitabine as compared to no cerebrovascular accidents reported in the placebo plus gemcitabine control arm during a pancreatic carcinoma clinical trial (Prod Info TARCEVA(R) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is a common side-effect of therapy and occurred in 54% (n=485) of patients receiving the drug in clinical trials. The median time to onset of diarrhea was 12 days (Prod Info TARCEVA(R) oral tablets, 2015).
    b) The incidence and severity of diarrhea appears to be dose-related. With standard doses of 150 mg daily, it occurred in 30% to 40% of patients. Although diarrhea is usually mild or moderate in severity, severe life-threatening diarrhea has been reported in up to 6% of patients (Siu et al, 2000; Ciardiello & Tortora, 2001; Hidalgo et al, 2001; Evans & Lynch, 2001).
    c) Diarrhea was generally seen within 3 weeks of the onset of daily administration in a phase I study; it was often self-limiting or responded well to loperamide, and did not worsen in most patients with cumulative therapy (Hidalgo et al, 2001).
    B) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal bleeding, including fatalities, has rarely been reported, and, in some cases, was associated with warfarin or NSAID co-administration (Prod Info TARCEVA(R) oral tablets, 2015).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia occurred in 52% (n=485) of subjects treated with erlotinib (Prod Info TARCEVA(R) oral tablets, 2015).
    D) VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported in 33% and 23%, respectively, of erlotinib-treated subjects (n=485) in clinical trials (Prod Info TARCEVA(R) oral tablets, 2015; Prod Info TARCEVA(R) oral tablet, 2007).
    E) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Mucositis (usually grade 1 or 2) has been relatively infrequent during erlotinib therapy and does not appear to be dose-related (Hammond et al, 2000; Hidalgo et al, 2001). It has often resolved spontaneously without treatment; however, temporary discontinuation of therapy has occasionally been required (Hidalgo et al, 2001).
    b) Stomatitis has been reported in 17% of erlotinib-treated subjects (n=485) in clinical trials (Prod Info TARCEVA(R) oral tablets, 2015).
    F) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in 11% of erlotinib-treated subjects (n=485) in clinical trials (Prod Info TARCEVA(R) oral tablet, 2007).
    G) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal perforation has been rarely reported with erlotinib therapy. According to pooled data from 3 monotherapy lung cancer studies, gastrointestinal perforation was reported in 0.2% of erlotinib-treated patients compared to 0.1% of patients in the control arms. During a pancreatic cancer clinical trial, gastrointestinal perforation was reported in 0.4% of patients receiving erlotinib plus gemcitabine (n=259) compared to 0% of patients receiving placebo plus gemcitabine (n=256) (Prod Info TARCEVA(R) oral tablets, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER FINDING
    1) WITH THERAPEUTIC USE
    a) An increase in liver enzymes (transaminases, bilirubin) have been observed in patients receiving erlotinib. Grade 2 elevations of alanine aminotransferase (greater than 2.5 to 5 times the upper limit of normal) occurred in 4% and less than 1% of erlotinib- and placebo-treated subjects (n=485 erlotinib; n=242 placebo), respectively (Prod Info TARCEVA(R) oral tablets, 2015).
    b) Isolated hyperbilirubinemia was reported in 8 of 39 cancer patients treated with erlotinib 25 to 200 mg daily in one phase I study, with no apparent dose relationship (Hidalgo et al, 2001). It was not accompanied by transaminase elevations, and either resolved or remained unchanged with continued treatment.
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 monotherapy lung cancer studies where patients with moderate to severe hepatic toxicity were excluded, the incidence of hepatic failure was 0.4% in the erlotinib arms and 0% in the control arms (Prod Info TARCEVA(R) oral tablets, 2015).
    b) In a pharmacokinetic study of 15 patients with significant liver tumor burden and moderate (Child-Pugh B) hepatic impairment, 1 patient died from rapidly progressing hepatic failure within 30 days of the last erlotinib dose (Prod Info TARCEVA(R) oral tablets, 2015).
    C) HEPATORENAL SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a pharmacokinetic study of 15 patients with significant liver tumor burden and moderate hepatic impairment (Child-Pugh B) , 1 patient died from hepatorenal syndrome within 30 days of receiving the last dose of erlotinib(Prod Info TARCEVA(R) oral tablets, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HEPATORENAL SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a pharmacokinetic study of 15 patients with significant liver tumor burden and moderate hepatic impairment (Child-Pugh B) , 1 patient died from hepatorenal syndrome within 30 days of receiving the last dose of erlotinib(Prod Info TARCEVA(R) oral tablets, 2015).
    B) RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Renal impairment was reported in 1.4% of patients receiving erlotinib plus gemcitabine compared to 0.4% receiving the control arm of placebo plus gemcitabine during a pancreatic cancer clinical trial (Prod Info TARCEVA(R) oral tablets, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Neutropenia and anemia (grade 1 or 2) have been observed occasionally during therapy (Hammond et al, 2000).
    b) Microangiopathic hemolytic anemia with thrombocytopenia has been rarely reported with erlotinib therapy with an incidence of 1.4% of patients receiving erlotinib plus gemcitabine compared to 0% of patients receiving a placebo plus gemcitabine during a pancreatic cancer clinical trial (Prod Info TARCEVA(R) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Overall, rash (including palmar-plantar erythrodyaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation) has occurred in 75% (n=485) of patients receiving erlotinib in therapeutic doses during a phase III randomized trial versus placebo. The median time to onset of rash is 8 days. Grades 3/4 rash occurred in 9% of patients in clinical trials, with dose reductions needed in 6%. Rash was the definitive cause of treatment discontinuation in 1% of patients (Prod Info TARCEVA(R) oral tablets, 2015).
    b) The rash is characterized as a reversible maculopapular rash with clusters of monomorphic pustular lesions typically involving the face and upper trunk. Although it is typically described as acneiform, it is predominantly pustular not associated with comedones, and the sebaceous glands are not affected (Gridelli et al, 2008). A similar rash (and incidence) has been reported during gefitinib (Iressa(R)) therapy. Histopathological examination reveals primarily inflammatory dermal changes, but bacterial super-infection may occur.
    c) In a phase I study, rashes developed in 59% of cancer patients (n=40) receiving doses up to 200 mg daily (Hidalgo et al, 2001). Rash onset was usually within 1.5 weeks of starting therapy, with maximal intensity during the second week; it usually subsided despite continued therapy (by week 4 in some patients). Treatment of the rash with retinoids, vitamin A or D, or steroids did not shorten the course. However, treatment with minocycline or topical silver sulfadiazine was reported to be beneficial in one clinical study (Adjei, 2001).
    d) A significant positive correlation has been noted between median time of survival and severity of rash in multiple trials (Gridelli et al, 2008). Variability in the occurrence and severity of rash may be a marker of pharmacogenetic variability in the ability of erlotinib to block the EGFR, a surrogate of immunocompetence (and ability to mount an inflammatory response), or have some other significance entirely.

Reproductive

    3.20.1) SUMMARY
    A) Erlotinib has been classified as FDA pregnancy category D. A case report showed no teratogenicity with prenatal erlotinib exposure from first trimester to term, but animal studies have shown an increased risk of maternal toxicity, embryo/fetal lethality, and spontaneous abortion when erlotinib was administered in high doses, or in the weeks immediately pre-and post-mating.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS, RATS: There was no evidence of teratogenicity in rabbits given erlotinib, during organogenesis, at doses up to 600 mg/m(2)/day (resulting in plasma drug levels of approximately 3 times those in humans based on the AUCs at 150-mg daily dose), or in rats who received erlotinib, during organogenesis, at doses up to 60 mg/m(2)/day (0.7 times the recommended human dose of 150 mg/day on a mg/m(2) basis) (Prod Info TARCEVA(R) oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified erlotinib as FDA pregnancy category D (Prod Info TARCEVA(R) oral tablets, 2013).
    B) CASE REPORT
    1) A woman in her forties, who was 10 weeks pregnant with twins, was diagnosed with stage IV exon 19 deletion adenocarcinoma with a primary tumor in the right lung and metastases to another lobe and the brain. At the start of her second trimester, she was started on erlotinib 150 mg daily. By 33 weeks of gestation, intrauterine growth restriction was diagnosed in 1 of the twins, so both were delivered by cesarean section at 37 weeks of gestation. Both neonates were small for their gestational age (87% of expected) but comparable in size to other neonates exposed to chemotherapy in utero. No metastases were seen in the placenta. Analysis of the cord blood revealed that erlotinib and its active metabolite OSI-420 were present at approximately 25% and 10% of the maternal plasma concentration, respectively. Both twins were thriving at the 12-month point. This case demonstrated the low-efficiency transplacental transfer of erlotinib, which decreased fetal exposure and potential toxic effects but showed that intrauterine growth restriction and liver toxic effects may still be concerning (Ji et al, 2015).
    C) CASE REPORT
    1) A live female infant exposed to erlotinib from the first trimester of gestation to term was delivered at 33 weeks weighing 1600 g and with no congenital malformations via cesarean section, due to oligohydramnios and intrauterine growth restriction. The 40-year-old mother had continued erlotinib therapy for metastatic stage 4 lung cancer after the pregnancy was discovered. Neonatal thyroid, hepatic, renal, hematological, auditory, and visual assessments were normal. No metastases were detected in the placenta (Rivas et al, 2012).
    D) LACK OF EFFECT
    1) A live female infant exposed to erlotinib from the first trimester of gestation to term was delivered at 33 weeks weighing 1600 g and with no congenital malformations via cesarean section, due to oligohydramnios and intrauterine growth restriction. The 40-year-old mother had continued erlotinib therapy for metastatic stage 4 lung cancer after the pregnancy was discovered. Neonatal thyroid, hepatic, renal, hematological, auditory, and visual assessments were normal. No metastases were detected in the placenta (Rivas et al, 2012).
    E) ANIMAL STUDIES
    1) RABBITS: Maternal toxicity with associated embryo/fetal lethality and abortion have been reported when rabbits were given doses up to 600 mg/m(2)/day (resulting in plasma drug levels of approximately 3 times those in humans based on the AUCs at 150-mg daily dose). No increased incidence of embryo/fetal lethality or abortion was observed when doses were given during the period of organogenesis to achieve plasma drug levels approximately equal to those in humans, based on AUC (Prod Info TARCEVA(R) oral tablets, 2013).
    2) RATS: Female rats treated with doses of 30 mg/m(2)/day or 60 mg/m(2)/day (0.3 or 0.7 times the human dose, based on body surface area) prior to mating and continuing through the first week of gestation had more early resorptions and a decreased number of live fetuses. However, no increased incidence of embryo/fetal lethality or abortion was observed when doses were given during the period of organogenesis to achieve plasma drug levels approximately equal to those in humans, based on AUC (Prod Info TARCEVA(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info TARCEVA(R) oral tablets, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Erlotinib did not impair fertility in either male or female rats (Prod Info TARCEVA(R) oral tablets, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma erlotinib concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor liver enzymes in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Hematologic effects, such as neutropenia and anemia may occur during erlotinib therapy. Monitor CBC periodically following an overdose.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Chest radiography and pulse oximetry determination are indicated in all patients with acute respiratory signs or symptoms. Arterial blood gas determination and computed tomography of the chest may be useful in select cases where clinically indicated.

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 should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with myelosuppression should be closely monitored in an inpatient setting, with daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An adult with an inadvertent, small exposure, that remains asymptomatic can be managed at home. Inadvertent pediatric ingestion should be referred to a healthcare facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients with severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma erlotinib concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor liver enzymes in symptomatic patients.
    C) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    D) Hematologic effects, such as neutropenia and anemia may occur during erlotinib therapy. Monitor CBC periodically following an overdose.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Chest radiography and pulse oximetry determination are indicated in all patients with acute respiratory signs or symptoms. Arterial blood gas determination and computed tomography of the chest may be useful in select cases where clinically indicated.

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. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    B) MONITORING OF PATIENT
    1) Plasma erlotinib concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor liver enzymes in symptomatic patients.
    3) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    4) Hematologic effects, such as neutropenia and anemia may occur during erlotinib therapy. Monitor CBC periodically following an overdose.
    5) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    6) Chest radiography and pulse oximetry determination are indicated in all patients with acute respiratory signs or symptoms. Arterial blood gas determination and computed tomography of the chest may be useful in select cases where clinically indicated.
    C) MYELOSUPPRESSION
    1) Severe myelosuppression should be expected after overdose.
    2) Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    3) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). They should be administered to any patient who receives an erlotinib overdose.
    4) Patients with severe neutropenia should be in protective isolation. Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    D) NEUTROPENIA
    1) COLONY STIMULATING FACTORS
    a) DOSING
    1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or continuous IV infusion (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013). Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013; Smith et al, 2006).
    2) HIGH-DOSE THERAPY
    a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
    b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion no longer than 24 hours. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015):
    1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
    2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
    3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.
    c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion over a 2-hour period. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013).
    3) SPECIAL CONSIDERATIONS
    a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
    4) ANTIBIOTIC PROPHYLAXIS
    a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).
    E) VOMITING
    1) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING
    a) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
    b) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
    c) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
    d) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
    e) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
    f) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
    g) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
    F) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Patients who are receiving myelosuppressive therapy may receive prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection (Bensinger et al, 2008).
    2) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to erlotinib's high degree of protein binding (93%) and large volume of distribution (232 L) (Prod Info TARCEVA(R) oral tablets, 2015), hemodialysis is UNLIKELY to be of value following overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. Single oral doses of 1,000 mg in healthy adults and weekly oral doses up to 1,600 mg in cancer patients have been well-tolerated. Repeat twice-daily doses of erlotinib 200 mg for only a few days, however, was not tolerated due to severe diarrhea, rash and liver transaminase elevation.
    B) THERAPEUTIC DOSE: Adult: 150 mg once daily for non-small cell lung cancer; 100 mg once daily in combination with gemcitabine for pancreatic cancer. Pediatric: Safety and efficacy not established.

Therapeutic Dose

    7.2.1) ADULT
    A) METASTATIC NON-SMALL CELL LUNG CANCER: 150 mg orally once daily, taken 1 hour before or 2 hours after the ingestion of food. In cases where dose reductions are needed, decreasing the dose by decrements of 50 mg is recommended (Prod Info TARCEVA(R) oral tablets, 2013).
    B) PANCREATIC CANCER: In combination with gemcitabine, the usual dose is 100 mg orally once daily, taken at least 1 hour before or 2 hours after the ingestion of food (Prod Info TARCEVA(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of erlotinib have not been established in pediatric patients (Prod Info TARCEVA(R) oral tablets, 2013).

Maximum Tolerated Exposure

    A) A minimum toxic dose has not been established. In clinical trials, healthy subjects and cancer patients tolerated single oral doses of erlotinib up to 1,000 mg and weekly doses up to 1,600 mg, respectively. However, healthy subjects did not tolerate repeated twice-daily doses of erlotinib 200 mg for only a few days. An unacceptable incidence of severe adverse events (eg, diarrhea, rash, and liver transaminase elevation), may occur with doses above 150 mg daily (the recommended dose) (Prod Info TARCEVA(R) oral tablets, 2015).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Data from preclinical (animal) studies suggest that a plasma concentration of 0.5 mcg/mL provides significant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibition and antiproliferative activity (Hidalgo et al, 2001; de Bono & Rowinsky, 2002). Steady-state trough plasma concentrations in most cancer patients have exceeded 0.5 mcg/mL during oral administration of 150 mg once daily; in contrast, this concentration was only occasionally sustained with lower doses (eg; 50 or 100 mg daily) (Hidalgo et al, 2001).
    2) ONSET
    a) INITIAL RESPONSE: Non-small cell lung cancer, oral: 2 months (time to objective tumor response with continuous oral doses of 150 mg daily in a phase II study) (Bonomi et al, 2000).
    b) PEAK RESPONSE: EGFR inhibition, oral: In animal studies, maximum inhibition of EGFR autophosphorylation was evident 1 hour following a 100-mg/kg oral dose of erlotinib (Hidalgo et al, 2001). Immunohistochemical evaluation of this activity in cancer patients has not been conducted.
    3) DURATION
    a) SINGLE DOSE: EGFR inhibition, oral: In animal models, EGFR autophosphorylation was decreased by about 75% for at least 12 hours following a 100-mg/kg oral dose of erlotinib; total recovery of EGFR function was observed 24 hours after dosing (Hidalgo et al, 2001). These findings were the basis for a protracted daily oral administration schedule. However, immunohistochemical evaluation of this activity in cancer patients has not been performed.
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) No significant correlation between plasma levels and cutaneous toxicity or diarrhea was observed in a phase I study. However, AUC (0 to 24) values were significantly higher on day 1 of treatment in patients experiencing cutaneous toxicity relative to those who did not (18 versus 12 mcg x hr/mL); this was not found for diarrhea (Hidalgo et al, 2001).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Erlotinib (OSI-774) is a quinazoline derivative chemically similar to gefitinib (Iressa(R)), and with similar pharmacologic activity (de Bono & Rowinsky, 2002). It reversibly inhibits tyrosine kinase activity of the epidermal growth factor receptor (EGFR), which results in the inhibition of autophosphorylation of tyrosine residues associated with EGFR and dampened tumor cell signalling, survival, and proliferation. Binding affinity for EGFR exon 19 deletion or exon 21 substitution (L858R) mutations is higher than binding affinity for the wild type receptor (Prod Info TARCEVA(R) oral tablets, 2015).
    B) Erlotinib is a specific, reversible, and ATP-competitive inhibitor of tumor-cell EGFR (erbB-1) tyrosine kinase (50% inhibitory concentration of 2 nanomoles (nM)) and EGFR autophosphorylation (15 to 20 nM) (Allen et al, 2000; Hidalgo et al, 2001; de Bono & Rowinsky, 2002). The activity of erlotinib against EGFR tyrosine kinase is at least 1000-fold that of other human kinases (eg; c-src) (Hidalgo et al, 2001). It is about 10 times as potent as gefitinib (de Bono & Rowinsky, 2002).

Physicochemical

Physical Characteristics

    A) Very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane (Prod Info Tarceva(TM), 2004).

Molecular Weight

    A) 429.90 (Prod Info Tarceva(TM), 2004)

References

General Bibliography

    1) Adjei AA: Epidermal growth factor receptor tyrosine kinase inhibitors in cancer therapy. Drug Future 2001; 26(11):1087.
    2) 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.
    3) Allen LF, Cerna C, Gomez L, et al: Investigation of the effects of CP-358,774 on various human tumor specimens taken directly from patients (abstract 384). Clin Cancer Res 2000; 6(suppl):4543s.
    4) Bensinger W, Schubert M, Ang KK, et al: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 2008; 6 Suppl 1:S1-21.
    5) Bonomi P, Perez-Soler R, Chachoua A, et al: A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), CP-358,774, following platinum based chemotherapy in patients (pts) with advanced non-small cell lung cancer NSCLC (abstract 386). Clin Cancer Res 2000; 6(suppl):4544s.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) Ciardiello F & Tortora G: A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Can Res 2001; 7:2958-2970.
    8) 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.
    9) Dupuis LL & Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 2003; 5(9):597-613.
    10) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    11) Evans TL & Lynch TJ Jr: Lung cancer. Oncologist 2001; 6:407-414.
    12) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    13) Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52(4):e56-e93.
    14) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    15) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    16) Grenader T, Gipps M, Shavit L, et al: Significant drug interaction: phenytoin toxicity due to erlotinib. Lung Cancer 2007; 57(3):404-406.
    17) Gridelli C, Maione P, Amoroso D, et al: Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: Results of an Experts Panel Meeting. Crit Rev Oncol Hematol 2008; 66(2):155-162.
    18) 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.
    19) Hammond LA, Denis LJ, Salman UA, et al: FDG-PET evaluation of patients treated with the epidermal growth factor (EGFR) tyrosine kinase inhibitor, CP-358,774 (abstract 385). Clin Cancer Res 2000; 6(Suppl):4543.
    20) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    21) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    22) Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19(13):3267-3279.
    23) Ji Y, Schwartz J, Hartford A, et al: Successful Treatment of Non-Small Cell Lung Cancer With Erlotinib Throughout Pregnancy. JAMA Oncol 2015; 1(6):838-840.
    24) Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
    25) Lane K & Goldstein SM: Erlotinib-associated trichomegaly. Ophthal Plast Reconstr Surg 2007; 23(1):65-66.
    26) Liu V, White DA, Zakowski MF, et al: Pulmonary toxicity associated with erlotinib. Chest 2007; 132(3):1042-1044.
    27) None Listed: ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999; 56(8):729-764.
    28) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    29) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    30) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    31) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    32) Product Information: LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, sargramostim subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution. sanofi-aventis U.S. LLC (per manufacturer), Bridgewater, NJ, 2013.
    33) Product Information: NEUPOGEN(R) subcutaneous injection, intravenous injection, filgrastim subcutaneous injection, intravenous injection. Amgen Inc. (per FDA), Thousand Oaks, CA, 2015.
    34) Product Information: TARCEVA(R) oral tablet, erlotinib oral tablet. OSI Pharmaceuticals, Melville, NY, 2007.
    35) Product Information: TARCEVA(R) oral tablets, erlotinib oral tablets. Genentech USA, Inc. (per FDA), South San Francisco, CA, 2015.
    36) Product Information: TARCEVA(R) oral tablets, erlotinib oral tablets. OSI Pharmaceuticals, LLC (per FDA), Farmingdale, NY, 2013.
    37) Product Information: Tarceva(TM), erlotinib tablets. Genentech Incorporated, South San Francisco, CA, 2004.
    38) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
    39) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    40) Rivas G , Llinas N , Bonilla C , et al: Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma. Lung Cancer 2012; 77(2):469-472.
    41) Siu LL, Soulieres D, Senzer N, et al: A phase II, multi-center study of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI), CP-358,774, in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN) (abstract 387). Clin Cancer Res 2000; 6:4544s.
    42) Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-3205.
    43) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    44) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    45) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    46) de Bono JS & Rowinsky EK: The ErbB receptor family: a therapeutic target for cancer. Trends Molecul Med 2002; 8(Suppl) 4:S19-S26.