Lapatinib - Use | Dose | Side Effects

The medicine lapatinib (Tyverb) in combination with capecitabine, is indicated for the treatment of patients with advanced or metastatic breast cancer whose tumors showed excessive ErbB2 (HER2) expression. The medicine is intended for administration to patients with progressive disease, and its implementation should be preceded by treatment with anthracyclines and taxanes, as well as the treatment of metastatic disease with trastazumab.

Mechanism of action

Lapatinib is the intracellular tyrosine kinase inhibitor of the action of both, EGFR (ErbB1) and ErbB2 (HER2) receptor (the estimated value of 3nM Kiapp and 13nm, respectively), with a slow release of these receptors (for a longer half-life or equal to 300 minutes). Lapatinib inhibits the ErbB-mediated growth of tumor cells, in vitro and in various animal models. The inhibitory effect on cell growth of lapatinib were evaluated in cell lines treated with trastuzumab. Lapatinib is retained a significant degree of activity against breast cancer cell cultures, isolated for the purpose of long-term culturing in medium containing trastuzumab, under in vitro conditions. Using lapatinib with trastuzumab

The dosage and administration

Treatment with lapatinib should introduce your doctor with experience in the application of anti-cancer medicines. Tumors with over- expression of ErbB2 defined by IHC3 + or + IHC2 and gene amplification  or exclusively through gene amplification. Gene amplification must be performed using accurate and validated tests. Lapatinib is administered in combination with capecitabine. The recommended dose of lapatinib is 1250 mg (or 5 tablets), administered once daily continuously. The daily dose should not be divided. Lapatinib should be administered at least one hour before or at least one hour after eating the food. To the variation in the individual response of each patient decreased to a minimum, the use of lapatinib should be standardized according to the use of food, for example, that a medicine is used always before a meal. The recommended dose of capecitabine is 2000mg/m2/daily applied in 2 doses, every 12 hours, from 1 to 14 days during the treatment cycle that lasts 21 days. Capecitabine is administered with a meal or during the 30 minutes after a meal.

Disposal of application dose or dose reduction

Cardiac conditions: It is necessary to quit the application of lapatinib in patients with symptoms associated with a lowering of the left ventircular ejection fraction (LVEF) grade 3 or higher, according to the common terminology criteria for adverse effects of the National Cancer Institute (National Cancer Institute Common Terminology Criteria for Adverse Events, NCI CTCAE ) or if their LVEF drops below the established lower limit of the normal range. After at least two weeks may again begin with the application of a reduced dose of lapatinib (1000mg/daily) if the return value of LVEF in frames of reference values, the asymptomatic patient's condition. Interstitial lung disease / pneumonitis: It is necessary to suspend the lapatinib in patients with pulmonary symptoms are grade 3 or higher according to the NCI CTCAE. Other toxicities: It is necessary to consider the suspension or discontinuation of dosing of lapatinib in the event that the patient develops toxicity is higher or equal to grades 2 Habitual terminology criteria for adverse effects  National Cancer Institute (NCI CTCAE). It can be re-commence application of 1250mg/daily, when reducing the toxicity of grade 1 or less. If the toxicity recurs, it is necessary to re-start the application in a lower dose of lapatinib (1000mg/daily). Information relating to the prescription of capecitabine should be in accordance with the recommendations for dose delay and dose reduction of capecitabine. Kidney diseases: No dose adjustment is required for patients with mild to moderate renal impairment. Caution is advised in patients with severe renal impairment, as there is no experience with the implementation of lapatinib in this population. Liver diseases: If there are severe changes in liver function is necessary to suspend the implementation of lapatinib and medicine should not be re-introduced into therapy. Application of lapatinib in patients with moderate to severe hepatic impairment should be performed with caution, since prolonged exposure to the effects of the medicine. The available data are insufficient to make recommendations on adjusting dosage in patients with liver diseases. Children: Not recommended for use of lapatinib in children, as there is insufficient data on safety and efficacy of the medicine in this population group. Elderly: There are limited reports of the use of lapatinib in patients aged 65 years and older.

Special warnings and precautions

It was stated that the use of lapatinib was associated with a decrease in left ventricular ejection fraction (LVEF). Caution is advised when applying lapatinib in patients with conditions that may cause damage to the left ventricular function. Before starting treatment lapatinib, it is necessary to examine the LVEF in all patients, to determine whether the underlying value of LVEF in patients located within the established range of normal values. During treatment lapatinib is necessary to continue to monitor the values of LVEF, to ensure that the value of LVEF drops below unacceptable levels. Application of lapatinib was associated with toxicity and pulmonary applications pneumonitis. Patients should be monitored for the possible occurrence of symptoms of pulmonary toxicity. In applying lapatinib occurred to hepatotoxicity, which in rare cases can be fatal. It is necessary to monitor the function of the liver (transaminase, bilirubin, and alkaline phosphatase) prior to the commencement of treatment, then on a monthly basis, or, depending on the clinical indication. It is necessary to suspend the lapatinib if there are severe changes in liver function and treating patients with this medicine should not re-start. Caution is warranted when prescribing lapatinib in patients with moderate to severe hepatic impairment. Caution is advised when prescribing lapatinib in patients with severe renal impairment. During treatment with lapatinib reported the occurrence of diarrhea, including severe diarrhea. Severe cases of diarrhea may require application of electrolytes and fluids orally or intravenously, and the interruption or cessation of therapy lapatinib. Necessary to avoid concurrent therapy inducers of CYP3A4 due to the potential risk of reduced exposure to lapatinib. During treatment lapatinib should avoid drinking grapefruit juice

Interactions with other medicines and other forms of interaction

Lapatinib is predominantly metabolized via the enzyme CYP3A4. In healthy volunteers who used the ketoconazole which is a potent inhibitor of CYP3A4 in a dose of 200 mg twice daily for 7 days, the systemic exposure to lapatinib ( 100 mg per day ) increased by approximately 3.6 times , and the half-life was prolonged about 1.7 times . It is not advisable concomitant use of lapatinib with strong CYP3A4 inhibitors (eg ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, pasakonazolom, nefazodone). Caution is advised with concomitant use of lapatinib with moderate inhibitors of CYP3A4, with careful monitoring of clinical adverse events. Systemic exposure to lapatinib was reduced approximately 72 % in healthy volunteers who had used carbamazepine, CYP3A4 inducer, at a dose of 100 mg twice a day for 3 days and 200 mg twice daily for 17 days . It is necessary to avoid the simultaneous use of lapatinib with known inducers of CYP3A4 (eg rifampicin, rifabutin, carbamazepine, phenytoin). Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin) above proteins may alter the exposure and / or distribution of lapatinib. The solubility of lapatinib is pH-dependent . It is necessary to avoid the simultaneous application of substances which increase the pH of the stomach , due to a possible decrease in the solubility and absorption of lapatinib.

Effects of lapatinib on other medical products

At clinically relevant concentrations, lapatinib inhibits CYP3A4 and CYP2C8 in vitro . It is necessary to avoid simultaneous application lapatinib with medicaments which have a small therapeutic breadth and the substrate for CYP3A4 (for example, cisapride , quinidine and pimozide) , and CYP2C8 (e.g. repaglinide). If lapatinib is used in combination therapy with paclitaxel (175mg/m2 every three weeks), you may experience severe neutropenia associated with diarrhea. The above phenomenon requires monitoring and early treatment of diarrhea. Lapatinib inhibits transport proteins Pgp and BCRP in vitro. Has not yet determined the clinical significance of the above effects. One can not exclude the possibility that the application will affect the pharmacokinetics of lapatinib Pgp substrate (e.g. digoxin), BCRP (e.g. topotecan) and OATP1B1 (for example, Rosuvastatin (Crestor)). Co-administration of lapatinib with capecitabine or trastuzumab does not change significantly the pharmacokinetics of the above medicines (or metabolites of capecitabine) or lapatinib.

Interaction with food

With the use of the food increases the bioavailability of lapatinib to about 4 times, depending on, for example, the content of fats in the diet. Grapefruit juice can inhibit CYP3A4 in the intestinal wall and increase the bioavailability of lapatinib, so it is necessary to avoid the use of grapefruit juice during treatment with lapatinib.

Using this medicine during the pregnancy and lactation

There are no adequate data from the use of lapatinib in pregnant women. Animal studies have indicated the existence of reproductive toxicity. The potential risk for humans is unknown. We do not advise the use of lapatinib during pregnancy, unless it is necessary. Women of childbearing potential should be advised to use adequate contraception and avoid pregnancy during treatment with lapatinib. Not tested security application lapatinib during lactation. It is not known whether lapatinib is excreted in human milk. There was growth retardation offspring of rats that were exposed to lapatinib via breast milk. It is essential that women who are treated with lapatinib stop breastfeeding.

Side effects

The safety of lapatinib was determined in application of the medicine as monotherapy, or in combination with chemotherapy in the treatment of various forms of cancer, including patients who have used lapatinib in combination with capecitabine therapy. The most common adverse reactions (25 %) in the application of lapatinib in combination therapy with capecitabine were gastrointestinal (diarrhea, nausea and vomiting) or dermatologic nature (Palmar-Plantar Erythrodysesthesia (PPE) and rash). In both treatment groups the incidence of rash was similar: the group in which the combination therapy is administered lapatinib and capecitabine, in the group wherein capecitabine is administered as a monotherapy. The most common adverse reactions resulting in discontinuation of treatment were diarrhea, with a similar incidence in both treatment groups (lapatinib plus capecitabine, 5 %, capecitabine : 3%). For the purpose of classification the frequency of adverse reactions listed below was used convention: very common (>= 1/10), common (>=1/100 to 1/10), uncommon (>= 1/1.000 ,1/100), rare (>= 1/10.000 1/1.000), very rare (1/10.000), unknown (based on the available data it is not possible to determine the frequency of occurrence).

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