= Additional active ingredients
Lapatinib ditosylate monohydrate 405 mg (equivalent to 250 mg lapatinib free base).
PRESENTATION AND DOSSAGE
TABS: 70 X 250 mg
In combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress ErbB2 (HER2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.In combination with 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. Tykerb, in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.
There are no known contraindications associated with lapatinib. Please refer to the capecitabine prescribing information for relevant contraindications and safety information when administering lapatinib in combination with capecitabine.
Data have shown that Lapatinib combined with chemotherapy is less effective than trastuzumab when combined with chemotherapy. Lapatinib is not indicated in the adjuvant setting.
Cardiac toxicity: Lapatinib has been associated with reports of decreases in LVEF. Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if Lapatinib is to be administered to patients with conditions that could impair left ventricular function (including co-administration with potentially cardiotoxic medicinal products). Evaluation of cardiac function, including LVEF determination, should be conducted for all patients prior to initiation of treatment with Lapatinib to ensure that the patient has a baseline LVEF that is within the institutions normal limits. LVEF should continue to be evaluated during treatment with Lapatinib to ensure that LVEF does not decline to an unacceptable level. In some cases, LVEF decrease may be severe and lead to cardiac failure. Fatal cases have been reported, causality of the deaths is uncertain. In studies across the clinical development programme for lapatinib, cardiac events including LVEF decreases were reported in approximately 1% of patients. Symptomatic LVEF decreases were observed in approximately 0.3% of patients who received lapatinib. However, when lapatinib was administered in combination with trastuzumab in the metastatic setting, the incidence of cardiac events including LVEF decreases was higher (7%) versus the lapatinib alone arm (2%) in the pivotal trial. The cardiac events observed in this study were comparable in nature and severity to those previously seen with lapatinib. There has been no dedicated study to assess the potential for lapatinib to prolong the QT interval. A small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label dose-escalation study of lapatinib in advanced cancer patients, such that an effect on QT interval cannot be ruled out. Caution should be taken if Lapatinib is administered to patients with conditions that could result in prolongation of QTc (including hypokalemia, hypomagnesemia, congenital long QT syndrome, or co-administration of other medicinal product known to cause QT prolongation). Hypokalemia or hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QT measurement should be considered prior to administration of Lapatinib and throughout treatment.
Interstitial lung disease and pneumonitis: Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis. Patients should be monitored for symptoms of pulmonary toxicity (dyspnoea, cough, fever) and treatment discontinued in patients who experience symptoms which are NCI CTCAE grade 3 or greater. Pulmonary toxicity may be severe and lead to respiratory failure. Fatal cases have been reported, causality of the deaths is uncertain.
Hepatotoxicity: Hepatotoxicity has occurred with Lapatinib use and may in rare cases be fatal. The hepatotoxicity may occur days to several months after initiation of treatment. At the initiation of treatment, patients should be advised of the potential for hepatotoxicity. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before the initiation of treatment and monthly thereafter, or as clinically indicated. Lapatinib dosing should be discontinued if changes in liver function are severe and patients should not be retreated. Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of Lapatinib-associated hepatotoxicity. Caution is warranted if Lapatinib is prescribed to patients with moderate or severe hepatic impairment. Caution is advised if Lapatinib is prescribed to patients with severe renal impairment.
Diarrhoea: Diarrhoea, including severe diarrhoea, has been reported with Lapatinib treatment. Diarrhoea can be potentially life-threatening if accompanied by dehydration, renal insufficiency, neutropenia and/or electrolyte imbalances and fatal cases have been reported. Diarrhoea generally occurs early during Lapatinib treatment, with almost half of those patients with diarrhoea first experiencing it within 6 days. This usually lasts 4-5 days. Lapatinib-induced diarrhoea is usually low-grade, with severe diarrhoea of NCI CTCAE grades 3 and 4 occurring in < 10% and <1% of patients, respectively. At the start of therapy, the patients bowel pattern and any other symptoms (e.g. fever, cramping pain, nausea, vomiting, dizziness and thirst) should be determined, to allow identification of changes during treatment and to help identify patients at greater risk of diarrhoea. Patients should be instructed to promptly report any change in bowel patterns. In potentially severe cases of diarrhoea the measuring of neutrophil counts and body temperature should be considered. Proactive management of diarrhoea with anti-diarrhoeal medicinal product is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhoea is persistent beyond 24 hours, there is fever, or grade 3 or 4 neutropenia) and interruption or discontinuation of Lapatinib therapy.
Concomitant treatment with inhibitors or inducers of CYP3A4: Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure to lapatinib. Concomitant treatment with strong inhibitors of CYP3A4 should be avoided due to risk of increased exposure to lapatinib. Grapefruit juice should be avoided during treatment with Lapatinib. Co-administration of Lapatinib with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 and /or CYP2C8 should be avoided. Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease.
Anorexia, Insomnia, Headache,Decreased left ventricular ejection fraction, Hot flush, Epistaxis, cough, dyspnea, Diarrhoea, nausea, vomiting, dyspepsia, stomatitis, constipation, abdominal pain, Hyperbilirubinaemia, hepatotoxicity, Rash (including dermatitis acneiform), dry skin, palmar-plantar erythrodysaesthesia, alopecia, pruritus, Nail disorders including paronychia, Pain in extremity, back pain, arthralgia, Fatigue, mucosal inflammation, asthenia.
Effects of other medicinal products on lapatinib: Lapatinib is predominantly metabolised by CYP3A. Co-administration of Lapatinib with known inducers of CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum [St John’s Wort]) should be avoided. Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin, St John’s Wort) of these proteins may alter the exposure and/or distribution of lapatinib. The solubility of lapatinib is pH-dependent. Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 27% (range: 6% to 49%). This effect decreases with increasing age from approximately 40 to 60 years.
Effects of lapatinib on other medicinal products: Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Co-administration of Lapatinib with orally administered midazolam resulted in an approximate 45% increase in the AUC of midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed intravenously. Co-administration of Lapatinib with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should be avoided. Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of Lapatinib with medicinal products with narrow therapeutic windows that are substrates of CYP2C8 (e.g. repaglinide) should be avoided. Co-administration of lapatinib with intravenous paclitaxel increased the exposure of paclitaxel by 23%, due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity of diarrhoea and neutropenia has been observed with this combination in clinical studies. Caution is advised if lapatinib is co-administered with paclitaxel. Co-administration of lapatinib with intravenously administered docetaxel did not significantly affect the AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced neutropenia was increased. Co-administration of Lapatinib with irinotecan (when administered as part of the FOLFIRI regimen) resulted in an approximate 40% increase in the AUC of SN-38, the active metabolite of irinotecan. The precise mechanism of this interaction is unknown, but it is assumed to be due to inhibition of one or more transport proteins by lapatinib. Adverse reactions should be carefully monitored if Lapatinib is co-administered with irinotecan, and a reduction in the dose of irinotecan should be considered. Lapatinib inhibits the transport protein Pgp in vitro at clinically relevant concentrations. Co-administration of lapatinib with orally administered digoxin resulted in an approximate 80% increase in the AUC of digoxin. Caution should be exercised when dosing lapatinib concurrently with medicinal products with narrow therapeutic windows that are substrates of Pgp, and a reduction in the dose of the Pgp substrate should be considered. Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of this effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin). Concomitant administration of Lapatinib with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these medicinal products (or the metabolites of capecitabine) or lapatinib..
The recommended dose of Tykerb is 1250 mg (i.e. five tablets) once daily continuously.
The recommended dose of capecitabine is 2000 mg/m2/day taken in 2 doses 12 hours apart on days 1-14 in a 21 day cycle (see section 5.1). Capecitabine should be taken with food or within 30 minutes after food. Please refer to the full prescribing information of capecitabine.
Tykerb / letrozole combination posology
The recommended dose of Tykerb is 1500 mg (i.e. six tablets) once daily continuously.
Please refer to the full prescribing information of the co-administered letrozole for dosing details.
Dose delay and dose reduction
Cardiac events: Tykerb should be discontinued in patients with symptoms associated with decreased left ventricular ejection fraction (LVEF) that are National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 3 or greater or if their LVEF drops below the institutions lower limit of normal. Tykerb may be restarted at a reduced dose (1000 mg/day when administered with capecitabine or 1250 mg/day when administered with letrozole) after a minimum of 2 weeks and if the LVEF recovers to normal and the patient is asymptomatic.
Interstitial lung disease / pneumonitis
Tykerb should be discontinued in patients who experience pulmonary symptoms which are NCI CTCAE grade 3 or greater.
Diarrhoea: Tykerb dosing should be interrupted in patients with diarrhoea which is NCI CTCAE grade 3 or grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration). Tykerb may be reintroduced at a lower dose (reduced from 1000 mg/day to 750 mg/day, from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day) when diarrhoea resolves to grade 1 or less. Tykerb dosing should be permanently discontinued in patients with diarrhoea which is NCI CTCAE grade 4.
Other toxicities: Discontinuation or interruption of dosing with Tykerb may be considered when a patient develops toxicity greater than or equal to grade 2 on the NCI CTCAE. Dosing can be restarted, when the toxicity improves to grade 1 or less, at either 1250 mg/day when administered with capecitabine or 1500 mg/day when administered with letrozole. If the toxicity recurs, then Tykerb should be restarted at a lower dose (1000 mg/day when administered with capecitabine or 1250 mg/day when administered with letrozole.
Renal impairment :No dose adjustment is necessary in patients with mild to moderate renal impairment. Caution is advised in patients with severe renal impairment as there is no experience of Tykerb in this population.
Hepatic impairment: Tykerb should be discontinued if changes in liver function are severe and patients should not be retreated. Administration of Tykerb to patients with moderate to severe hepatic impairment should be undertaken with caution due to increased exposure to the medicinal product. Insufficient data are available in patients with hepatic impairment to provide a dose adjustment recommendation.
Elderly: There are limited data of the use of Tykerb and capecitabine in patients aged ≥ 65 years. In the phase III clinical study of Tykerb in combination with letrozole, of the total number of hormone receptor positive metastatic breast cancer patients (Intent to treat population N= 642), 44 % were ≥ 65 years of age. No overall differences in efficacy and safety of the combination of Tykerb and letrozole were observed between these patients and patients < 65 years of age.
Paediatric population :The safety and efficacy of Tykerb in children below the age of 18 years have not yet been established.
There is no specific antidote for the inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine phosphorylation. The maximum oral dose of lapatinib that has been administered in clinical studies is 1800 mg once daily. Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with Tykerb. In patients who took up to 5000 mg of lapatinib, symptoms observed include known lapatinib associated events and in some cases sore scalp and/or mucosal inflammation. In a single case of a patient who took 9000 mg of Tykerb, sinus tachycardia (with otherwise normal ECG) was also observed. Lapatinib is not significantly renally excreted and is highly bound to plasma proteins, therefore haemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
PREGNANCY & LACTATION
Women of childbearing potential: Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with Tykerb.
Pregnancy: There are no adequate data from the use of Tykerb in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is not known. Tykerb should not be used during pregnancy unless clearly necessary.
Storage: Do not store above 30ºc.
Shelf life: The expiry date of the product is indicated on the label and packaging. Use within 30 days after opening.
MANUFACTURER & DISTRIBUTER:
License Holder: GlaxoSmithKline Israel Ltd.