It is a kinase inhibitor, is indicated in combination with: ? capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. ? 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. itin combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cance
Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of greater than or equal to 300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when Lapatinib and 5-FU (the active metabolite of Capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of Lapatinib were evaluated in Trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in Trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.
Absorption: Absorption following oral administration of Lapatinib is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of Lapatinib are achieved approximately 4 hours after administration. Daily dosing of Lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours. At the dose of 1,250 mg daily, steady-state geometric mean [95% confidence interval (CI)] values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL). Divided daily doses of Lapatinib resulted in approximately 2-fold higher exposure at steady state (steady-state AUC) compared to the same total dose administered once daily. Systemic exposure to Lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a lowfat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.
Distribution: Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that Lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.
Metabolism: Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of Lapatinib concentration in plasma.
Elimination: At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours. Elimination of Lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (less than 2%) renal excretion. Recovery of parent Lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.
The recommended dosage of itfor advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. The recommended dose of itfor hormone receptor positive, HER2 positive metastatic breast cancer is 1500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When itis coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. ? It 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. ? It should be taken once daily. Do not divide daily doses of it. ? Modify dose for cardiac and other toxicities, severe hepatic impairment, and CYP3A4 drug interactions
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. 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. Dose adjustment of Lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes.
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 72%.
Drugs That Inhibit Drug Transport Systems: Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Lapatinib is administered with drugs that inhibit P-gp, increased concentrations of Lapatinib are likely, and caution should be exercised.
Acid-Reducing Agents: The aqueous solubility of Lapatinib is pH dependent, with higher pH resulting in lower solubility. However, Esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in Lapatinib steady-state exposure.
Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its component
Diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue.
Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from this, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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 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.
Store below 30°C in a dry place. Keep out of the reach of children.
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