Lapatinib

Uses

Lapatinib, a kinase inhibitor, is used for 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 used.

Lapatinib in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

Lapatinib is also used to associated treatment for these conditions: Metastatic Breast Cancer, Refractory, advanced Breast cancer, Refractory, metastatic Breast cancer

How Lapatinib works

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥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-florouracil (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.

Dosage

Lapatinib dosage

The recommended dosage of Lapatinib for 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 Lapatinib for hormone receptor positive, HER2 positive metastatic breast cancer is 1500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When Lapatinib is coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily.

• Lapatinib 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.
• Lapatinib should be taken once daily. Do not divide daily doses of Lapatinib.
• Modify dose for cardiac and other toxicities, severe hepatic impairment, and CYP3A4 drug interactions.

Should be taken on an empty stomach. Take at least 1 hr before or 1 hr after a meal. Do not eat/drink grapefruit products.

Side Effects

GI disturbances, dermatological reactions (e.g. palmar-plantar erythrodysesthesia, rash), fatigue, decreases in LVEF, QT interval prolongation, stomatitis, mucosal inflammation, pain in extremities, back pain, dyspnoea, insomnia, epistaxis, alopecia, nail disorders (e.g. paronychia), interstitial lung disease, pneumonitis and hypersensitivity reactions including anaphylaxis.

Toxicity

There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10.

Precaution

Patient with hypokalaemia or hypomagnesaemia, congenital QT prolongation. Severe hepatic impairment. Pregnancy and lactation.

Interaction

May increase the serum levels of CYP3A4, CYP2C8 and P-glycoprotein substrates. Increased exposure with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, atazanavir, ritonavir). CYP3A4 inducers (e.g. carbamazepine, rifampicin) may reduce exposure to lapatinib. Increased risk of QT prolongation with drugs known to prolong QT intervals (e.g. antiarrythmic agents, cumulative high-dose anthracycline therapy). May increase serum levels of digoxin.

Food Interaction

• Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of lapatinib, increasing its serum levels.
• Take separate from meals. Take lapatinib at least 1 hour before or after eating, as lapatinib bioavailability is elevated by food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lapatinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib.

According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting.

Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice.

The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal.

The lapatinib dose is administered once daily and should not be divided.

Lapatinib Hypertension interaction

[Moderate] Decreases in left ventricular ejection fraction (LVEF) have been reported with agents that block HER2 activity.

Patients who have received prior anthracyclines, those who received anthracycline after stopping therapy with agents that block HER2 activity, or patients who received prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

Therapy with these agents should be administered cautiously in patients with a previous history of heart conditions.

Evaluate cardiac function before, during, and upon completion of treatment.

Withhold or discontinue therapy with agents that block HER2 activity as appropriate, and for a confirmed clinically significant decrease in left ventricular function, or if the LVEF has not improved or has declined further.

It is recommended to monitor overall cardiac function and LVEF by echocardiogram or MUGA scan as appropriate.

Lapatinib Drug Interaction

Moderate: lithium, lithiumUnknown: arginine, arginine, levocarnitine, levocarnitine, cysteine, cysteine, valproic acid, valproic acid, cyanocobalamin, cyanocobalamin, pyridoxine, pyridoxine, cholecalciferol, cholecalciferol, phytonadione, phytonadione, menaquinone, menaquinone

Lapatinib Disease Interaction

Major: cardiomyopathy, dermatologic toxicities, pulmonary toxicity, QT prolongation, pulmonary toxicity, liver dysfunctionModerate: CHF, thrombocytopenia, renal impairment

Elimination Route

Absorption following oral administration of lapatinib is incomplete and variable.

Half Life

Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours

Elimination Route

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.

Pregnancy & Breastfeeding use

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 (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Contraindicated to hypersensitivity to any other ingredient of this product.

Special Warning

Patient on potent CYP3A4 inhibitor-

• HER2 overexpressing advanced or metastatic breast cancer: Increase gradually from 1.25 g daily up to 4.5 g daily.
• HER2 overexpressing hormone receptor positive metastatic breast cancer: Increase gradually from 1.5 g daily up to 5.5 g daily.

Hepatic Impairment (Severe)-

• HER2 overexpressing advanced or metastatic breast cancer: 750 mg once daily.
• HER2 overexpressing hormone receptor positive metastatic breast cancer: 1 g once daily.

Storage Condition

Store between 15-30° C.

Innovators Monograph

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