4.1. Therapeutic indications

Tyverb is indicated for the treatment of adult patients with breast cancer, whose tumours overexpress HER2 (ErbB2);

• in combination with capecitabine for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting (see section 5.1).

• in combination with trastuzumab for patients with hormone receptor-negative metastatic disease that has progressed on prior trastuzumab therapy(ies) in combination with chemotherapy (see section 5.1).

• in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor (see sections 4.4. and 5.1). No data are available on the efficacy of this combination relative to trastuzumab in combination with an aromatase inhibitor in this patient population.

4.2. Posology and method of administration

Tyverb treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products.

HER2 (ErbB2) overexpressing tumours are defined by IHC3+, or IHC2+ with gene amplification or gene amplification alone. HER2 status should be determined using accurate and validated methods.

Posology

Tyverb / capecitabine combination posology

The recommended dose of Tyverb 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.

Tyverb / trastuzumab combination posology

The recommended dose of Tyverb is 1000 mg (i.e. four tablets) once daily continuously.

The recommended dose of trastuzumab is 4 mg/kg administered as an intravenous loading dose, followed by 2 mg/kg intravenous weekly (see section 5.1). Please refer to the full prescribing information of trastuzumab.

Tyverb / aromatase inhibitor combination posology

The recommended dose of Tyverb is 1500 mg (i.e. six tablets) once daily continuously.

Please refer to the full prescribing information of the co-administered aromatase inhibitor for dosing details.

Dose delay and dose reduction

Cardiac events

Tyverb 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 (see section 4.4). Tyverb may be restarted at a reduced dose (750 mg/day when administered with trastuzumab, 1000 mg/day when administered with capecitabine or 1250 mg/day when administered with an aromatase inhibitor) after a minimum of 2 weeks and if the LVEF recovers to normal and the patient is asymptomatic.

Interstitial lung disease / pneumonitis

Tyverb should be discontinued in patients who experience pulmonary symptoms which are NCI CTCAE grade 3 or greater (see section 4.4).

Diarrhoea

Tyverb 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) (see sections 4.4 and 4.8). Tyverb 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. Tyverb dosing should be permanently discontinued in patients with diarrhoea which is NCI CTCAE grade 4.

Other toxicities

Discontinuation or interruption of dosing with Tyverb 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 1000 mg/day when administered with trastuzumab, 1250 mg/day when administered with capecitabine or 1500 mg/day when administered with an aromatase inhibitor. If the toxicity recurs, then Tyverb should be restarted at a lower dose (750 mg/day when administered with trastuzumab, 1000 mg/day when administered with capecitabine or 1250 mg/day when administered with an aromatase inhibitor).

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 Tyverb in this population (see section 5.2).

Hepatic impairment

Tyverb should be discontinued if changes in liver function are severe and patients should not be retreated (see section 4.4).

Administration of Tyverb 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 (see section 5.2).

Elderly

There are limited data on the use of Tyverb / capecitabine and Tyverb / trastuzumab in patients aged ≥ 65 years.

In the phase III clinical study of Tyverb 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 Tyverb and letrozole were observed between these patients and patients < 65 years of age.

Paediatric population

The safety and efficacy of Tyverb in children below the age of 18 years have not yet been established. No data are available.

Method of administration

Tyverb is for oral use.

The daily dose of Tyverb should not be divided. Tyverb should be taken either at least one hour before, or at least one hour after food. To minimise variability in the individual patient, administration of Tyverb should be standardised in relation to food intake, for example always to be taken one hour before a meal (see sections 4.5 and 5.2 for information on absorption).

Missed doses should not be replaced and the dosing should resume with the next scheduled daily dose (see section 4.9).

The full prescribing information of the co-administered medicinal product should be consulted for relevant details of their posology including any dose reductions, contraindications and safety information.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Data have shown that Tyverb combined with chemotherapy is less effective than trastuzumab when combined with chemotherapy.

Cardiac toxicity

Lapatinib has been associated with reports of decreases in LVEF (see section 4.8). Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if Tyverb 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 Tyverb 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 Tyverb to ensure that LVEF does not decline to an unacceptable level (see section 4.2). 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.

A concentration-dependent increase of the QTc interval was demonstrated in a dedicated placebo-controlled crossover study in subjects with advanced solid tumours.

Caution should be taken if Tyverb is administered to patients with conditions that could result in prolongation of QTc (including hypokalemia, hypomagnesemia, and congenital long QT syndrome), co-administration of other medicinal product known to cause QT prolongation, or conditions that increase the exposure of lapatinib, such as co-administration of strong CYP3A4 inhibitors. Hypokalemia or hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QT measurement should be performed prior to and one to two weeks after the start of Tyverb therapy. When clinically indicated, e.g. after initiation of a concomitant treatment that might affect QT or that may interact with lapatinib, ECG measurement should also be considered.

Interstitial lung disease and pneumonitis

Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis (see section 4.8). 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 Tyverb 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. Tyverb 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 Tyverb-associated hepatotoxicity. In a large, randomised clinical trial of Tyverb monotherapy (n=1,194), the cumulative frequency of severe liver injury (ALT >5 times the upper limit of normal, NCI CTCAE grade 3) at 1 year of treatment was 2.8% overall. The cumulative frequency in DQA1*02:01 and DRB1*07:01 allele carriers was 10.3% and in non-carriers was 0.5%. Carriage of the HLA risk alleles is common (15 to 25%) in Caucasian, Asian, African and Hispanic populations but lower (1%) in Japanese populations.

Caution is warranted if Tyverb is prescribed to patients with moderate or severe hepatic impairment and to patients with severe renal impairment (see sections 4.2 and 5.2).

Diarrhoea

Diarrhoea, including severe diarrhoea, has been reported with Tyverb treatment (see section 4.8). 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 Tyverb treatment, with almost half of those patients with diarrhoea first experiencing it within 6 days. This usually lasts 4-5 days. Tyverb-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 Tyverb therapy (see section 4.2 – dose delay and dose reduction –diarrhoea).

Serious cutaneous reactions

Serious cutaneous reactions have been reported with Tyverb. If erythema multiforme or life-threatening reactions such as Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with Tyverb.

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 (see section 4.5).

Concomitant treatment with strong inhibitors of CYP3A4 should be avoided due to risk of increased exposure to lapatinib (see section 4.5).

Grapefruit juice should be avoided during treatment with Tyverb (see section 4.5).

Co-administration of Tyverb with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 and /or CYP2C8 should be avoided (see section 4.5).

Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease (see section 4.5).

Tyverb contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on lapatinib

Lapatinib is predominantly metabolised by CYP3A (see section 5.2).

In healthy volunteers receiving ketoconazole, a strong CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure to lapatinib (100 mg daily) was increased approximately 3.6–fold, and half-life increased 1.7–fold. Co-administration of Tyverb with strong inhibitors of CYP3A4 (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Co-administration of Tyverb with moderate inhibitors of CYP3A4 should proceed with caution and clinical adverse reactions should be carefully monitored.

In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased approximately 72%. Co-administration of Tyverb 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, and erythromycin) and inducers (rifampicin and St John's Wort) of these proteins may alter the exposure and/or distribution of lapatinib (see section 5.2).

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 Tyverb 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 Tyverb with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should be avoided (see sections 4.4 and 5.2).

Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of Tyverb with medicinal products with narrow therapeutic windows that are substrates of CYP2C8 (e.g. repaglinide) should be avoided (see sections 4.4 and 5.2).

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 Tyverb 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 Tyverb 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) (see section 5.2).

Concomitant administration of Tyverb with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these medicinal products (or the metabolites of capecitabine) or lapatinib.

Interactions with food and drink

The bioavailability of lapatinib is increased up to about 4 times by food, depending on e.g. the fat content in the meal. Furthermore, depending on type of food the bioavailability is approximately 2-3 times higher when lapatinib is taken 1 hour after food compared with 1 hour before the first meal of the day (see sections 4.2 and 5.2).

Grapefruit juice may inhibit CYP3A4 in the gut wall and increase the bioavailability of lapatinib and should therefore be avoided during treatment with Tyverb.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with Tyverb and for at least 5 days after the last dose.

Pregnancy

There are no adequate data from the use of Tyverb in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is not known.

Tyverb should not be used during pregnancy unless clearly necessary.

Breast-feeding

The safe use of Tyverb during breast-feeding has not been established. It is not known whether lapatinib is excreted in human milk. In rats, growth retardation was observed in pups which were exposed to lapatinib via breast milk. Breast-feeding must be discontinued in women who are receiving therapy with Tyverb and for at least 5 days after the last dose.

Fertility

There are no adequate data from the use of Tyverb in women of childbearing potential.

4.7. Effects on ability to drive and use machines

Tyverb has no influence on the ability to drive and use machines. A detrimental effect on such activities cannot be predicted from the pharmacology of lapatinib. The clinical status of the patient and the safety profile of lapatinib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.

4.8. Undesirable effects

Summary of the safety profile

The safety of lapatinib has been evaluated as monotherapy or in combination with other chemotherapies for various cancers in more than 20,000 patients, including 198 patients who received lapatinib in combination with capecitabine, 149 patients who received lapatinib in combination with trastuzumab and 654 patients who received lapatinib in combination with letrozole (see section 5.1).

The most common adverse reactions (>25%) during therapy with lapatinib were gastrointestinal events (such as diarrhoea, nausea, and vomiting) and rash. Palmar-plantar erythrodysesthesia (PPE) was also common (>25%) when lapatinib was administered in combination with capecitabine. The incidence of PPE was similar in the lapatinib plus capecitabine and capecitabine alone treatment arms. Diarrhoea was the most common adverse reaction resulting in discontinuation of treatment when lapatinib was administered in combination with capecitabine, or with letrozole.

No additional adverse reactions were reported to be associated with lapatinib in combination with trastuzumab. There was an increased incidence of cardiac toxicity, but these events were comparable in nature and severity to those reported from the lapatinib clinical programme (see section 4.4 – cardiac toxicity). These data are based on exposure to this combination in 149 patients in the pivotal trial.

Tabulated list of adverse reactions

The following adverse reactions have been reported to have a causal association with lapatinib alone or lapatinib in combination with capecitabine, trastuzumab or letrozole.

The following convention has been utilised for the classification of frequency: very common ((≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Rare

Hypersensitivity reactions including anaphylaxis (see section 4.3)

Metabolism and nutrition disorders

Very common

Anorexia

Psychiatric disorders

Very common

Insomnia*

Nervous system disorders

Very common

Headache†

Common

Headache*

Cardiac disorders

Common

Decreased left ventricular ejection fraction (see section 4.2 - dose reduction – cardiac events and section 4.4).

Not known

Ventricular arrhythmias/Torsades de Pointes, electrocardiogram QT prolonged**

Vascular disorders

Very common

Hot flush†

Respiratory, thoracic and mediastinal disorders

Very common

Epistaxis†, cough†, dyspnoea†.

Uncommon

Interstitial lung disease/pneumonitis.

Not known

Pulmonary arterial hypertension**.

Gastrointestinal disorders

Very common

Diarrhoea, which may lead to dehydration (see section 4.2 - dose delay and dose reduction – other toxicities and section 4.4), nausea, vomiting, dyspepsia*, stomatitis*, constipation*, abdominal pain*.

Common

Constipation†

Hepatobiliary disorders

Common

Hyperbilirubinaemia, hepatotoxicity (see section 4.4).

Skin and subcutaneous tissue disorders

Very common

Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose reduction – other toxicities), dry skin*†, palmar-plantar erythrodysaesthesia*, alopecia†, pruritus†.

Common

Nail disorders including paronychia, skin fissures.

Not known

Serious cutaneous reactions, including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)**

Musculoskeletal and connective tissue disorders

Very common

Pain in extremity*†, back pain*†, arthralgia†.

General disorders and administration site conditions

Very common

Fatigue, mucosal inflammation*, asthenia†.

* These adverse reactions were observed when lapatinib was administered in combination with capecitabine.

† These adverse reactions were observed when lapatinib was administered in combination with letrozole.

** Adverse reactions from spontaneous reports and literature

Description of selected adverse reactions

Decreased left ventricular ejection fraction and QT interval prolongation

Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of patients receiving lapatinib and were asymptomatic in more than 70% of cases. LVEF decreases resolved or improved in more than 70 % of cases, in approximately 60 % of these on discontinuation of treatment with lapatinib, and in approximately 40 % of cases lapatinib was continued. Symptomatic LVEF decreases were observed in approximately 0.3% of patients who received lapatinib monotherapy or in combination with other anti-cancer medicinal products. Observed adverse reactions included dyspnoea, cardiac failure and palpitations. Overall 58 % of these symptomatic patients recovered. LVEF decreases were reported in 2.5 % of patients who received lapatinib in combination with capecitabine, as compared to 1.0 % with capecitabine alone. LVEF decreases were reported in 3.1 % of patients who received lapatinib in combination with letrozole as compared to 1.3 % of patients receiving letrozole plus placebo. LVEF decreases were reported in 6.7 % of patients who received lapatinib in combination with trastuzumab, as compared to 2.1 % of patients who received lapatinib alone.

A concentration dependent increase in QTcF (maximum mean ΔΔQTcF 8.75 ms; 90% CI 4.08, 13.42) was observed in a dedicated QT study in patients with advanced solid tumours (see section 4.4).

Diarrhoea

Diarrhoea occurred in approximately 65 % of patients who received lapatinib in combination with capecitabine, in 64 % of patients who received lapatinib in combination with letrozole and in 62 % of patients who received lapatinib in combination with trastuzumab. Most cases of diarrhoea were grade 1 or 2 and did not result in discontinuation of treatment with lapatinib. Diarrhoea responds well to proactive management (see section 4.4). However, a few cases of acute renal failure have been reported secondary to severe dehydration due to diarrhoea.

Rash

Rash occurred in approximately 28 % of patients who received lapatinib in combination with capecitabine, in 45 % of patients who received lapatinib in combination with letrozole and in 23 % of patients who received lapatinib in combination with trastuzumab. Rash was generally low grade and did not result in discontinuation of treatment with lapatinib. Prescribing physicians are advised to perform a skin examination prior to treatment and regularly during treatment. Patients experiencing skin reactions should be encouraged to avoid exposure to sunlight and apply broad spectrum sunscreens with a Sun Protection Factor (SPF) ≥ 30. If a skin reaction occurs a full body examination should be performed at every visit until one month after resolution. Patients with extensive or persistent skin reactions should be referred to a dermatologist.

Hepatotoxicity

The risk of lapatinib-induced hepatotoxicity was associated with carriage of the HLA alleles DQA1*02:01 and DRB1*07:01 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 Tyverb. In patients who took up to 5000 mg of lapatinib, symptoms observed include known lapatinib associated events (see section 4.8) and in some cases sore scalp and/or mucosal inflammation. In a single case of a patient who took 9000 mg of Tyverb, 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.