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Lapatinib

FDA Drug Information • Also known as: Lapatinib, Tykerb

Brand Names
Lapatinib, Tykerb
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: HEPATOTOXICITY Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain [see Warnings and Precautions ( 5.2 )] . WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. ( 5.2 )

Description

11 DESCRIPTION Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. It is present as the monohydrate of the ditosylate salt, with chemical name N -(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4- quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. It has the molecular formula C 29 H 26 ClFN 4 O 4 S (C 7 H 8 O 3 S) 2 H 2 O and a molecular weight of 943.5 g/mol. Lapatinib ditosylate monohydrate has the following chemical structure: Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 0.001 mg/mL at 25°C. Each 250 mg tablet of lapatinib contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base. The inactive ingredients of lapatinib tablets are as follows: iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol (part hydrolyzed), povidone, sodium starch glycolate Type A, talc, and titanium dioxide. chemical structure

What Is Lapatinib Used For?

1 INDICATIONS AND USAGE Lapatinib tablets are indicated in combination with: capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Limitations of Use : Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib tablets in combination with capecitabine. letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. Lapatinib tablets in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. Lapatinib tablets are a kinase inhibitor indicated in combination with: ( 1 ) capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Limitations of Use : Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib tablets in combination with capecitabine. letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. Lapatinib tablets in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended dosage of lapatinib tablets for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. ( 2.1 ) The recommended dose of lapatinib tablets for hormone receptor-positive, HER2-positive metastatic breast cancer is 1,500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When lapatinib tablets are coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. ( 2.1 ) Lapatinib tablets should be taken at least one hour before or one hour after a meal. However, capecitabine should be taken with food or within 30 minutes after food. ( 2.1 ) Lapatinib tablets should be taken once daily. Do not divide daily doses of lapatinib tablets. ( 2.1 , 12.3 ) Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. ( 2.2 ) 2.1 Recommended Dosing HER2-Positive Metastatic Breast Cancer : The recommended dose of lapatinib tablets is 1,250 mg given orally once daily on Days 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer : The recommended dose of lapatinib tablets is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with lapatinib tablets, the recommended dose of letrozole is 2.5 mg once daily. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . 2.2 Dose Modification Guidelines Cardiac Events : Lapatinib tablets should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), and in patients with an LVEF that drops below the institution’s lower limit of normal (LLN) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] . Lapatinib tablets in combination with capecitabine may be restarted at a reduced dose (1,000 mg/day)...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most common (greater than 20%) adverse reactions during treatment with lapatinib plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue. The most common (greater than or equal to 20%) adverse reactions during treatment with lapatinib plus letrozole were diarrhea, rash, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. HER2-Positive Metastatic Breast Cancer : The safety of lapatinib has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of lapatinib in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial [see Clinical Studies ( 14.1 )] . Adverse reactions, which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm, are shown in Table 1. The most common adverse reactions (greater than 20%) during therapy with lapatinib plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication. The most common Grades 3 and 4 adverse reactions (NCI CTCAE v3.0) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2. Table 1. Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients a NCI CTCAE v3.0. b Grade 3 dermatitis acneiform was reported in less than 1% of patients in the group receiving lapatinib plus capecitabine. Lapatinib 1,250 mg/day + Capecitabine 2,000 mg/m 2 /day Capecitabine 2,500 mg/m 2 /day (N = 198) (N = 191) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Reactions % % % % % % Gastrointestinal disorders Diarrhea 65 13 1 40 10 0 Nausea 44 2 0 43 2 0 Vomiting 26 2 0 21 2 0 Stomatitis 14 0 0 11 < 1 0 Dyspepsia 11 < 1 0 3 0 0 Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia 53 12 0 51 14 0 Rash b 28 2 0 14 1 0 Dry skin 10 0 0 6 0 0 General disorders and administration site conditions Mucosal inflammation 15 0 0 12 2 0 Musculoskeletal and connective tissue disorders Pain in extremity 12 1 0 7 < 1 0 Back pain 11 1 0 6 < 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 12 3 0 8 2 0 Psychiatric disorders Insomnia 10 < 1 0 6 0 0 Table 2. Selected Laboratory Abnormalities Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a NCI CTCAE v3.0. Lapatinib 1,250 mg/day + Capecitabine 2,000 mg/m 2 /day Capecitabine 2,500 mg/m 2 /day All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Parameters % % % % % % Hematologic Hemoglobin 56 < 1 0 53 1 0 Platelets 18 < 1 0 17 < 1 < 1 Neutrophils 22 3 < 1 31 2 1 Hepatic Total Bilirubin 45 4 0 30 3 0 AST 49 2 < 1 43 2 0 ALT 37 2 0 33 1 0 Hormone Receptor-Positive, Metastatic Breast Cancer : In a randomized, Phase 3 clinical trial of patients (N = 1,286) with hormone receptor-positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without lapatinib. In this trial, the safety profile of lapatinib was consistent with previously reported results from trials of lapatinib in the advanced or metastatic breast cancer population. Adverse reactions, which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 3. Selected laboratory abnormalities are shown in Table 4. Table 3. Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients a NCI CTCAE...

Drug Interactions

7 DRUG INTERACTIONS Lapatinib is likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). ( 7.1 ) Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of lapatinib in patients coadministered a strong CYP3A4 inhibitor. ( 2.2 , 7.2 ) Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of lapatinib in patients coadministered a strong CYP3A4 inducer. ( 2.2 , 7.2 ) 7.1 Effects of Lapatinib on Drug-Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo . Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro , however, the clinical significance is unknown. Midazolam : Following coadministration of lapatinib and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%. Paclitaxel : In cancer patients receiving lapatinib and paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations. Digoxin : Following coadministration of lapatinib and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of lapatinib and throughout coadministration. If digoxin serum concentration is greater than 1.2 ng/mL, the digoxin dose should be reduced by half. 7.2 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below) . Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration ( 2.2 )] . Ketoconazole : In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine : In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately...

Contraindications

4 CONTRAINDICATIONS Lapatinib tablets are contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, lapatinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data to inform of the drug-associated risks. In an animal reproduction study, administration of lapatinib to pregnant rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were ≥ 3.3 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses (see Data) . Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of lapatinib at 30, 60, and 120 mg/kg/day during the period of organogenesis. Minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC following 1,250 mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations. In a pre- and post-natal...

Overdosage

10 OVERDOSAGE There is no known antidote for overdoses of lapatinib. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of lapatinib could result in serum concentrations exceeding those observed in clinical trials and could result in increased toxicity. Therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose. Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events [see Adverse Reactions (6.1)] and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation. Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib. Treatment of overdose with lapatinib should consist of general supportive measures.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Lapatinib tablets are available as follows: 250 mg - Each yellow, oval, film-coated tablet, debossed with “L250” on one side and “TV” on the other side contains 398 mg lapatinib ditosylate equivalent to 250 mg of lapatinib. Tablets are available in bottles of 150 (NDC 42291-035-15). Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep this and all medications out of the reach of children.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.