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LAPATINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lapatinib is a dual tyrosine kinase inhibitor that targets the intracellular component of epidermal growth factor receptors HER1 and HER2, which are overexpressed in various types of tumors.

Specific Substances

    1) Lapatinib ditosylate
    2) GW-572016F
    3) CAS 231277-92-2 (lapatinib)
    4) CAS 388082-78-8 (lapatinib tosylate)
    1.2.1) MOLECULAR FORMULA
    1) Lapatinib ditosylate monohydrate - C29-H26-Cl-F-N4-O4-S (C7-H8-O3-S)2 H2-O (Prod Info TYKERB(R) oral tablets, 2007)

Available Forms Sources

    A) FORMS
    1) Lapatinib is available as 250 mg tablets for oral administration (Prod Info TYKERB(R) oral tablets, 2013).
    B) USES
    1) Lapatinib, in combination with capecitabine, is indicated for the treatment of advanced or metastatic breast cancer in patients with tumors that overexpress HER2 and who have had prior chemotherapy including an anthracycline, a taxane, and trastuzumab. Lapatinib is also indicated in combination with letrozole for the treatment of hormone receptor positive, human epidermal receptor-2 (HER2)-overexpressing, metastatic breast cancer in postmenopausal women for whom hormonal therapy is indicated (Prod Info TYKERB(R) oral tablets, 2013).

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: Lapatinib, in combination with capecitabine or letrozole, is indicated for the treatment of advanced or metastatic breast cancer.
    B) PHARMACOLOGY: Lapatinib is a dual tyrosine kinase inhibitor against epidermal growth factor receptors (EGFR) HER1 and HER2. HER1 and HER2 are overexpressed in over 20% of breast tumors, and is a key component in regulating tumor cell growth, proliferation, metastasis, and transformation. Lapatinib reversibly binds to the intracellular cytoplasmic site of tyrosine kinase at the ATP-binding site, inhibits receptor phosphorylation and activation of HER1 and HER2 homodimers and heterodimers, thereby blocking the downstream signaling pathway involved in cell proliferation, survival and invasion.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following administration of lapatinib, in combination with capecitabine or letrozole, are diarrhea, nausea, vomiting, rash, fatigue, and plantar erythrodysesthesia. OTHER EFFECTS: Stomatitis, dyspepsia, dry skin, pain in extremity, back pain, dyspnea, insomnia, nail disorder, epistaxis, hepatotoxicity, hyperbilirubinemia, and hypersensitivity reaction, interstitial lung disease, and pneumonitis have also been reported. QT prolongation has been noted in patients receiving lapatinib. Predisposing factors include hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant anti-arrhythmic agents or other agents known to prolong the QT interval, and cumulative high-dose anthracycline therapy. QTc prolongation appeared to be related to lapatinib concentration.
    E) WITH POISONING/EXPOSURE
    1) Lapatinib overdose information is limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects. Grade 3 diarrhea and vomiting occurred in one patient who received 3000 mg of lapatinib for 10 days. Cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation.
    0.2.20) REPRODUCTIVE
    A) Lapatinib is classified as FDA pregnancy category D. In rat studies, there were minor anomalies (left-side umbilical artery, cervical rib, and precocious ossification) reported following maternal exposure.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and hepatic enzymes after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count after significant overdose.
    E) Monitor ECG for evidence of QT interval prolongation; institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Early management of diarrhea with antidiarrheal agents (ie, loperamide) should be considered. Correct serum electrolyte abnormalities and replace fluids as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant serum electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat diarrhea with antidiarrheal agents; severe cases may require intravenous fluid replacement and the use of antibiotics (ie, fluoroquinolones) especially if symptoms persist or fever is present. Severe nausea and vomiting may respond to a combination of agents from different drug classes. QT prolongation has been noted in patients receiving lapatinib for advanced cancer. Concomitant use of lapatinib and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer 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 life-threatening cardiac dysrhythmias, severe respiratory distress, or severe allergic reaction.
    E) ANTIDOTE
    1) None.
    F) ERUPTION
    1) Rash may resolve with continued therapy. Medications that may be effective include topical clindamycin 1% as monotherapy or with benzoyl peroxide 5% gel, oral tetracycline, or oral minocycline.
    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).
    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. In patients with a lapatinib overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    I) ENHANCED ELIMINATION
    1) Due to the high protein binding (greater than 99%) of lapatinib, hemodialysis is not expected to be an effective method of enhanced elimination.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of 1 or 2 extra dose(s) can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions, or inadvertent ingestion of more than 1 or 2 extra dose(s) 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 electrolyte imbalance, cardiac dysrhythmias, or respiratory distress should be admitted.
    4) CONSULT CRITERIA: Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    K) PITFALLS
    1) When managing a suspected lapatinib overdose, the possibility of multidrug involvement should be considered.
    L) PHARMACOKINETICS
    1) Tmax: about 4 hours. Absorption: incomplete and variable after oral use. Protein binding: greater than 99%. Metabolism: extensive metabolism occurs predominantly via CYP3A4 and CYP3A5. Minor metabolism via CYP2C19 and CYP2C8. Renal excretion: less than 2%. Fecal excretion: a median of 27% (range, 3% to 67%) of an oral dose. Elimination half-life: 24 hours after repeated dosing and 14.2 hours after a single dose.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause prolonged QT interval.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Grade 3 diarrhea and vomiting were reported in an adult on day 10 after taking 3000 mg of lapatinib daily for 10 days. Other cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have also been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation.
    B) THERAPEUTIC DOSE: ADULT: Lapatinib with capecitabine: Lapatinib 1250 mg orally once daily continuously (days 1 through 21) in combination with capecitabine 2000 mg/m(2)/day orally (divided into 2 doses every 12 hours) on days 1 through 14 in a repeating 21-day cycle until treatment progression or unacceptable toxicity. Lapatinib with letrozole: Lapatinib 1500 mg orally once daily continuously in combination with letrozole 2.5 mg orally once daily. PEDIATRIC: The safety and effectiveness of lapatinib have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Lapatinib, in combination with capecitabine or letrozole, is indicated for the treatment of advanced or metastatic breast cancer.
    B) PHARMACOLOGY: Lapatinib is a dual tyrosine kinase inhibitor against epidermal growth factor receptors (EGFR) HER1 and HER2. HER1 and HER2 are overexpressed in over 20% of breast tumors, and is a key component in regulating tumor cell growth, proliferation, metastasis, and transformation. Lapatinib reversibly binds to the intracellular cytoplasmic site of tyrosine kinase at the ATP-binding site, inhibits receptor phosphorylation and activation of HER1 and HER2 homodimers and heterodimers, thereby blocking the downstream signaling pathway involved in cell proliferation, survival and invasion.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following administration of lapatinib, in combination with capecitabine or letrozole, are diarrhea, nausea, vomiting, rash, fatigue, and plantar erythrodysesthesia. OTHER EFFECTS: Stomatitis, dyspepsia, dry skin, pain in extremity, back pain, dyspnea, insomnia, nail disorder, epistaxis, hepatotoxicity, hyperbilirubinemia, and hypersensitivity reaction, interstitial lung disease, and pneumonitis have also been reported. QT prolongation has been noted in patients receiving lapatinib. Predisposing factors include hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant anti-arrhythmic agents or other agents known to prolong the QT interval, and cumulative high-dose anthracycline therapy. QTc prolongation appeared to be related to lapatinib concentration.
    E) WITH POISONING/EXPOSURE
    1) Lapatinib overdose information is limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects. Grade 3 diarrhea and vomiting occurred in one patient who received 3000 mg of lapatinib for 10 days. Cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation.

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) SORE SCALP: Cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation (Prod Info TYKERB(R) oral tablets, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) DEPRESSION OF LEFT VENTRICULAR SYSTOLIC FUNCTION
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with 3 cases of grade 2 decline in left ventricular ejection fraction (LVEF) and 1 case of grade 3 decline in LVEF. Most cases (greater than 57%) of LVEF decline have occurred within the first 12 weeks of treatment (Prod Info TYKERB(R) oral tablets, 2013).
    b) Among 654 patients who received lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily in a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer who had not received prior therapy, 26 patients experienced grade 1 or grade 2 left ventricular ejection fraction (LVEF) adverse reactions. Grade 3 or 4 LVEF adverse events were reported in 6 patients (Prod Info TYKERB(R) oral tablets, 2013).
    c) In a cardiac safety evaluation (n=3127), 1.3% of patients receiving lapatinib experienced a decrease in LVEF (1.2% asymptomatic and 0.1% symptomatic). The time to onset was within 9 weeks from treatment initiation in 66% of patients, 10 to 16 weeks in 15% of patients, and 17 to 24 weeks in 12% of patients. The lower than expected cardiac event rate could be attributed to no prior exposure to anthracycline or trastuzumab therapy (Moy & Goss, 2006).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QT prolongation has been noted in patients receiving lapatinib for advanced cancer in an uncontrolled, open-label dose escalation study. Eighty-one patients received doses between 175 mg to 1800 mg daily and were monitored with continual ECGs between days 1 through 14. Collected data suggests a consistent concentration-dependent increase in QTc interval. Predisposing factors include hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant anti-arrhythmic agents or other agents known to prolong the QT interval, and cumulative high-dose anthracycline therapy (Prod Info TYKERB(R) oral tablets, 2013).
    C) PRINZMETAL ANGINA
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=324), the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days was associated with one case of Prinzmetal's angina that resolved upon treatment discontinuation (Geyer et al, 2006).
    D) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic dose. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation (Prod Info TYKERB(R) oral tablets, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 milligrams (mg) once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days was associated with a slightly higher incidence of dyspnea compared with capecitabine monotherapy given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (12% vs 8%). The vast majority of the reported cases in the combination group were mild to moderate in severity, (grade 1 or 2) with grade 3 events accounting for 3% (Prod Info TYKERB(R) oral tablets, 2013).
    B) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung disease and pneumonitis have been reported in patients receiving lapatinib as monotherapy or in combination with other chemotherapeutic agents (Prod Info TYKERB(R) oral tablets, 2013).
    C) EPISTAXIS
    1) WITH THERAPEUTIC USE
    a) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=1278) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of epistaxis compared with letrozole monotherapy given at 2.5 mg per day (11% vs 2%, respectively). Less than 1% of cases were grade 3 in either treatment arm (Prod Info TYKERB(R) oral tablets, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a 10% incidence of insomnia compared with a 6% incidence with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle. Less than 1% of cases in the combination group were grade 3 (Prod Info TYKERB(R) oral tablets, 2013).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=1278) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of fatigue compared with letrozole monotherapy given at 2.5 mg per day (20% vs 17%, respectively). The vast majority of the reported cases were mild to moderate in severity, with grade 3 events accounting for 2% (Prod Info TYKERB(R) oral tablets, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea, which may be severe and fatal, has been reported with lapatinib therapy. Diarrhea typically occurs within the first 6 days of treatment and lasts for 4 to 5 days. Most cases are low grade in severity, with grade 3 reported in less than 10% of patients and grade 4 reported in less than 1%. Severe cases may require administration of oral or IV electrolytes and fluids, the use of antibiotics for diarrhea lasting longer than 24 hours or if the patient is febrile or has grade 3 or 4 neutropenia, and interruption or discontinuation of therapy (Prod Info TYKERB(R) oral tablets, 2013a).
    b) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=1278) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of diarrhea compared with letrozole monotherapy given at 2.5 mg per day (64% vs 20%). Grade 3 and grade 4 diarrhea was reported in 9% and less than 1%, respectively, of cases in the combination treatment arm (Prod Info TYKERB(R) oral tablets, 2013a).
    c) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2)/day on days 1 to 14 every 21 days (n=198) was associated with higher incidence of diarrhea compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2)/day on days 1 to 14 during each 21-day cycle (65% vs 40%). Of these, 14% were grade 3 or 4. Diarrhea was the most common adverse effect that led to discontinuation of therapy (Prod Info TYKERB(R) oral tablets, 2013a).
    2) WITH POISONING/EXPOSURE
    a) Grade 3 diarrhea and vomiting occurred on Day 10 in a patient who received 3000 mg of lapatinib for 10 days. The patient recovered following supportive care (Prod Info TYKERB(R) oral tablets, 2007).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a similar incidence of nausea compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (44% vs 43%, respectively). Less than 2% of cases in either arm were grade 3 (Prod Info TYKERB(R) oral tablets, 2013).
    b) Nausea occurred in 13% of patients treated with lapatinib as a single agent from 500-mg to 1600-mg dose levels in a multicenter, randomized, parallel-group, repeated dose-ranging study (n=67) for various metastatic solid tumors over-expressing ErbB-1 and/or ErbB-2, all of which were mild to moderate in severity (grade 1/2) (Burris et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) Grade 3 diarrhea and vomiting occurred on Day 10 in a patient who received 3000 mg of lapatinib for 10 days. The patient recovered following supportive care (Prod Info TYKERB(R) oral tablets, 2013).
    C) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=324) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days was associated with a significantly higher incidence of dyspepsia compared with capecitabine monotherapy given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (11% vs 3%, respectively; p=0.014). The reported cases were mild to moderate in severity (grade 1 or 2), with the incidence of grade 3 or 4 events as less than 1% (Prod Info TYKERB(R) oral tablets, 2013; Geyer et al, 2006).
    D) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a similar incidence of stomatitis compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (14% vs 11%, respectively) (Prod Info TYKERB(R) oral tablets, 2013).
    E) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a similar incidence of mucosal inflammation compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (15% vs 12%, respectively) The reported cases in the combination group were mild to moderate in severity (grade 1 or 2) (Prod Info TYKERB(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation (Prod Info TYKERB(R) oral tablets, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of hyperbilirubinemia compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (45% vs 30%, respectively). The vast majority of the reported cases in the combination group were mild to moderate in severity, (grade 1 or 2) with grade 3 events accounting for 4% (Prod Info TYKERB(R) oral tablets, 2013).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of elevated AST levels compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (49% vs 43%, respectively). The vast majority of the reported cases in the combination group were mild to moderate in severity (grade 1 or 2) with grade 3 events accounting for 2% and grade 4 events accounting for less than 1% (Prod Info TYKERB(R) oral tablets, 2013).
    C) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Severe and potentially fatal hepatotoxicity (AST or ALT greater than 3 times the upper limit of the normal (ULN) and total bilirubin greater than 2 times the ULN) has been reported in less than 1% of patients receiving lapatinib during clinical trials and postmarketing evaluation. Causality of the deaths is not clear. Hepatotoxicity may develop in days to several months after initiation of therapy (Prod Info TYKERB(R) oral tablets, 2010).
    b) Human leukocyte antigen (HLA) alleles DQA1x02:01 and DRB1x07:01 were associated with hepatotoxicity reactions during a genetic, monotherapy substudy of lapatinib (n=1194). Severe liver injury (ALT greater than 5 times the ULN) was reported in 2% of patients overall; the risk increased to 8% in HLA carrier patients compared with 0.5% of non-carrier patients (Prod Info TYKERB(R) oral tablets, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a similar incidence of all-grade anemia compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (56% vs 53%, respectively). The vast majority of the reported cases in the combination group were mild to moderate in severity (grade 1 or 2) with grade 3 events accounting for less than 1% (Prod Info TYKERB(R) oral tablets, 2013).
    b) Three cases of grade 1 anemia were reported at lapatinib 500-, 900-, and 1600-mg dose levels in a multicenter, randomized, parallel-group, repeated dose-ranging study (n=67) among adult patients with various metastatic solid tumors over-expressing HER1 and/or HER2 (Burris et al, 2005).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a similar incidence of all-grade thrombocytopenia compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (18% vs 17%, respectively). The vast majority of the reported cases in the combination group were mild to moderate in severity (grade 1 or 2) with grade 3 events accounting for less than 1% (Prod Info TYKERB(R) oral tablets, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=654) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of rash compared with letrozole monotherapy given at 2.5 mg per day (44% vs 13%, respectively). The majority of the reported cases were mild to moderate in severity, with grade 3 events accounting for 1% (Prod Info TYKERB(R) oral tablets, 2013).
    b) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of rash compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (28% vs 14%, respectively). The vast majority of the reported cases were mild to moderate in severity (grade 1 or 2), with grade 3 events accounting for 2% (Prod Info TYKERB(R) oral tablets, 2013).
    c) Rash occurred in 31% of patients treated with lapatinib as a single agent from 500-mg to 1600-mg dose levels in a multicenter, randomized, parallel-group, repeated dose-ranging study (n=67) for various metastatic solid tumors over-expressing HER1 and/or HER2. Manifestations included rash, acne, and dermatitis acneiform. The vast majority of rashes were mild to moderate in severity (grade 1/2). The onset ranged from 2 to 66 days after initiation of therapy, and generally resolved without treatment interruption (Burris et al, 2005).
    B) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of dry skin compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (10% vs 6%, respectively). The reported cases were mild in severity (grade 1 or 2) (Prod Info TYKERB(R) oral tablets, 2013).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=1278) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of pruritus compared with letrozole monotherapy given at 2.5 mg per day (12% vs 9%, respectively). Less than 1% of cases in the combination treatment arm were considered grade 3 (Prod Info TYKERB(R) oral tablets, 2013).
    D) ABNORMALITY OF NAIL TISSUE
    1) WITH THERAPEUTIC USE
    a) Nail disorders, including paronychia have been reported with lapatinib use during postmarketing surveillance (Prod Info TYKERB(R) oral tablets, 2013).
    b) In a double-blind, placebo-controlled, multicenter trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=1278) who had not received prior therapy, the use of lapatinib 1500 mg once daily continuously in combination with letrozole 2.5 mg once daily was associated with a higher incidence of nail disorder compared with letrozole monotherapy given at 2.5 mg per day (11% vs less than 1%, respectively). The vast majority of the reported cases were mild to moderate in severity, with grade 3 events accounting for less than 1% (Prod Info TYKERB(R) oral tablets, 2013).
    E) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days was associated with a 53% incidence of hand-foot syndrome, similar to the reported rate of capecitabine monotherapy (51%) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle. The vast majority of the reported cases were mild to moderate in severity (grade 1 or 2) , with grade 3 events accounting for 12% (Prod Info TYKERB(R) oral tablets, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of back pain compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (11% vs 6%, respectively). The vast majority of the reported cases were mild to moderate in severity (grade 1 or 2), with grade 3 events accounting for 1% (Prod Info TYKERB(R) oral tablets, 2013).
    B) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) In a phase III, open-label, randomized trial among patients with human epidermal receptor-2 (HER2)-positive, advanced or metastatic breast cancer (n=389) who had progressed after prior therapies, the use of lapatinib 1250 mg once daily continuously in combination with capecitabine 2000 mg/m(2) per day on days 1 to 14 every 21 days (n=198) was associated with a higher incidence of pain in extremity compared with capecitabine monotherapy (n=191) given at 2500 mg/m(2) per day on days 1 to 14 during each 21-day cycle (12% vs 7%, respectively). The vast majority of the reported cases were mild to moderate in severity (grade 1 or 2), with grade 3 events accounting for 1% (Prod Info TYKERB(R) oral tablets, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reaction, including anaphylaxis has been reported with lapatinib use during postmarketing surveillance (Prod Info TYKERB(R) oral tablets, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Lapatinib is classified as FDA pregnancy category D. In rat studies, there were minor anomalies (left-side umbilical artery, cervical rib, and precocious ossification) reported following maternal exposure.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Minor anomalies, including left-side umbilical artery, cervical rib, and precocious ossification, were reported in rats following maternal exposure to lapatinib at 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). Decreased fetal body weights and minor skeletal variations were reported in rabbits following maternal exposure to lapatinib at doses of 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively) (Prod Info TYKERB(R) oral tablets, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified lapatinib as FDA pregnancy category D (Prod Info TYKERB(R) oral tablets, 2007).
    B) LACK OF EFFECT
    1) CASE REPORT - A 44-year-old pregnant woman who received lapatinib for 11 weeks in the first and second trimesters, had an uneventful pregnancy, and following induction at week 36, gave birth to a healthy baby who had met all developmental milestones on schedule 18 months later. The woman had stage IV, HER2/neu-overexpressing, infiltrating ductal carcinoma of the left breast and was part of a phase 1b clinical trial of lapatinib for patients with advanced solid tumors. Lapatinib therapy was initiated at a dose of 1500 mg/day, which was subsequently reduced by 50% due to the development diarrhea and rash. At approximately 14 weeks' gestation the pregnancy was discovered and lapatinib was discontinued. The estimated date of conception was during the third to fourth week of lapatinib therapy. Although the pregnancy was uneventful, due to disease progression, the patient was induced at week 36 and gave birth to a female child weighing 2.6 kilograms, with normal Apgar scores of 8 and 9 at 1 minute and 5 minutes, respectively (Kelly et al, 2006).
    C) ANIMAL STUDIES
    1) A lapatinib dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure), administered to rats during organogenesis and through lactation, resulted in a pup mortality rate of 91% by the fourth day after birth (Prod Info TYKERB(R) oral tablets, 2007).
    2) Abortions were reported in rabbits following maternal exposure to lapatinib at a dose of 120 mg/kg/day (Prod Info TYKERB(R) oral tablets, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if lapatinib is excreted into human milk, and there is insufficient clinical experience with lapatinib to confirm its safety in breast-feeding (Prod Info TYKERB(R) oral tablets, 2007a).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS231277-92-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) In animal studies, oral lapatinib was not carcinogenic in mice following the administration of doses about 0.7 to 2 times the expected human clinical exposure (based on AUC for a clinical dose of 1250 mg/day) for up to 104 weeks. However, there was an increased incidence of whole body hemangiomas and hemangiosarcomas in male rats administered lapatinib doses about 0.6 to 2.3 times the expected human clinical exposure (based on AUC) (Prod Info TYKERB(R) oral tablets, 2015).

Genotoxicity

    A) At single doses up to 2000 mg/kg, lapatinib was not mutagenic or clastogenic according to the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay, or the in vivo rat bone marrow chromosome aberration assay (Prod Info TYKERB(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and hepatic enzymes after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count after significant overdose.
    E) Monitor ECG for evidence of QT interval prolongation; institute continuous cardiac monitoring.

Radiographic Studies

    A) An echocardiogram may be helpful in monitoring left ventricular function in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) Bai et al (2006) described a high-performance liquid chromatographic method with tandem mass spectrometry for determination of lapatinib in human plasma (Bai et al, 2006).

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 electrolyte imbalance, cardiac dysrhythmias, or respiratory distress should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions of 1 or 2 extra dose(s) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions, or inadvertent ingestion of more than 1 or 2 extra dose(s) 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) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and hepatic enzymes after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count after significant overdose.
    E) Monitor ECG for evidence of QT interval prolongation; institute continuous cardiac monitoring.

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. Early management of diarrhea with antidiarrheal agents (ie, loperamide) should be considered. Correct serum electrolyte abnormalities and replace fluids as needed.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant serum electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat diarrhea with antidiarrheal agents; severe cases may require intravenous fluid replacement and the use of antibiotics (ie, fluoroquinolones) especially if symptoms persist or fever is present. Severe nausea and vomiting may respond to a combination of agents from different drug classes. QT prolongation has been noted in patients receiving lapatinib for advanced cancer. Concomitant use of lapatinib and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and hepatic enzymes after significant overdose.
    3) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    4) Monitor CBC with differential and platelet count after significant overdose.
    5) Monitor ECG for evidence of QT interval prolongation; institute continuous cardiac monitoring.
    C) ERUPTION
    1) A facial erythematous rash may commonly occur with lapatinib therapy. Although, in the majority of patients, the rash may resolve with either continued therapy or following treatment cessation, medication may also be effective as treatment, including topical clindamycin 1% gel as monotherapy or in combination with benzoyl peroxide 5% gel, tetracycline (250 mg orally four times daily) or minocycline (100 mg orally two times daily) (Moy & Goss, 2007).
    2) Topical administration of colloidal oatmeal lotion was helpful in controlling a rash in 10 patients with acneform eruptions induced by tyrosine-kinase inhibitors, including erlotinib and sorafenib (Alexandrescu et al, 2007).
    D) DIARRHEA
    1) Diarrhea, which may be severe and fatal, has been reported with lapatinib therapy. Diarrhea typically occurs within the first 6 days of treatment and lasts for 4 to 5 days. Most cases are low grade in severity, with grade 3 reported in less than 10% of patients and grade 4 reported in less than 1%. Early treatment with antidiarrheal agents (ie, loperamide) is recommended. Severe cases may require administration of oral or IV electrolytes and fluids, the use of antibiotics for diarrhea lasting longer than 24 hours or if the patient is febrile or has grade 3 or 4 neutropenia, and interruption or discontinuation of therapy (Prod Info TYKERB(R) oral tablets, 2013a).
    E) VOMITING
    1) SUMMARY
    a) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING
    1) 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); 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.
    2) 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).
    3) 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).
    4) 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).
    5) 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).
    6) 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).
    7) 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) Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis. (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). In patients with an lapatinib overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.
    G) TORSADES DE POINTES
    1) QT prolongation has been noted in patients receiving lapatinib for advanced cancer (Prod Info TYKERB(R) oral tablets, 2013). Concomitant use of lapatinib and other drugs that prolong the QT interval may increase the risk of torsades de pointes.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to high protein binding (greater than 99%) of lapatinib, hemodialysis is not expected to be an effective method of enhanced elimination (Prod Info TYKERB(R) oral tablets, 2013).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Grade 3 diarrhea and vomiting were reported in an adult on day 10 after taking 3000 mg of lapatinib daily for 10 days. Other cases of lapatinib overdose (doses 2500 to 9000; duration: 1 to 17 days) have also been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation.
    B) THERAPEUTIC DOSE: ADULT: Lapatinib with capecitabine: Lapatinib 1250 mg orally once daily continuously (days 1 through 21) in combination with capecitabine 2000 mg/m(2)/day orally (divided into 2 doses every 12 hours) on days 1 through 14 in a repeating 21-day cycle until treatment progression or unacceptable toxicity. Lapatinib with letrozole: Lapatinib 1500 mg orally once daily continuously in combination with letrozole 2.5 mg orally once daily. PEDIATRIC: The safety and effectiveness of lapatinib have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) LAPATINIB WITH CAPECITABINE: Lapatinib 1250 mg orally once daily continuously (days 1 through 21) in combination with capecitabine 2000 mg/m(2)/day orally (divided into 2 doses every 12 hours) on days 1 through 14 in a repeating 21-day cycle until treatment progression or unacceptable toxicity (Prod Info TYKERB(R) oral tablets, 2013a).
    B) LAPATINIB WITH LETROZOLE: Lapatinib 1500 mg orally once daily continuously in combination with letrozole 2.5 mg orally once daily (Prod Info TYKERB(R) oral tablets, 2013a).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of lapatinib have not been established in pediatric patients (Prod Info TYKERB(R) oral tablets, 2013a).

Maximum Tolerated Exposure

    A) Grade 3 diarrhea and vomiting were reported in one patient on day 10 after taking 3000 mg of lapatinib daily for 10 days (Prod Info TYKERB(R) oral tablets, 2007).
    B) Cases of lapatinib overdose (doses 2500 to 9000; variable duration of 1 to 17 days) have been reported. Patients were either asymptomatic or developed symptoms that were similar to adverse effects following therapeutic doses. Some patients also developed sore scalp, sinus tachycardia, and/or mucosal inflammation (Prod Info TYKERB(R) oral tablets, 2013).

Workplace Standards

    A) ACGIH TLV Values for CAS231277-92-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS231277-92-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS231277-92-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS231277-92-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Lapatinib is a dual tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR) HER1 and HER2. HER1 and HER2 are overexpressed in over 20% of breast tumors, and is a key component in regulating tumor cell growth, proliferation, metastasis, and transformation. Tyrosine kinase consists of an extracellular ligand-binding domain, a transmembrane and an intracellular cytoplasmic catalytic domain. Ligand binding and dimerization activate cytoplasmic autophosphorylation of tyrosine kinase at the ATP site, resulting in downstream signaling pathway involved in tumor cell proliferation. Lapatinib reversibly targets the cytoplasmic ATP-binding site of the tyrosine kinase, inhibits receptor phosphorylation, and blocks the downstream signaling of HER1 and HER2 homodimers and heterodimers, thereby promoting apoptosis (Moy & Goss, 2006; Burris, 2004).

Physicochemical

Physical Characteristics

    A) Lapatinib is a yellow solid with a solubility in water of 0.007 mg/mL and in 0.1N HCl of 0.001 mg/mL at 25 degrees C (Prod Info TYKERB(R) oral tablets, 2007).

Molecular Weight

    A) Lapatinib ditosylate monohydrate - 943.5 (Prod Info TYKERB(R) oral tablets, 2007)

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