1. NAME OF THE MEDICINAL PRODUCT, Tyverb 250 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION, Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib. For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM, Film-coated tablet.Oval, biconvex, yellow film-coated tablets, with "GS XJG" debossed on one side.

4.1 Therapeutic indications, Tyverb, in combination with capecitabine, is indicated for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy which must include anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting (see section 5.1).

4.2 Posology and method of administration, Lapatinib treatment should only be initiated by a physician experienced in the administration of anticancer agents. ErbB2 overexpressing tumours are defined by IHC3+, or IHC2+ and gene amplification or gene amplification alone. Gene amplification should be performed using an accurate and validated assay. Lapatinib is taken in combination with capecitabine. The recommended dose of lapatinib is 1250 mg (i.e. five tablets) once daily continuously. The daily dose should not be divided. Lapatinib 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 lapatinib should be standardised in relation to food intake, for example always be taken 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 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.

Cardiac events; Lapatinib 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). Lapatinib may be restarted at a reduced dose (1000 mg/day) after a minimum of 2 weeks and if the LVEF recovers to normal and the patient is asymptomatic. Interstitial lung disease / pneumonitis Lapatinib should be discontinued in patients who experience pulmonary symptoms which are NCI CTCAE grade 3 or greater (see section 4.4).

Other toxicities; Discontinuation or interruption of dosing with lapatinib may be considered when a patient develops toxicity greater than or equal to grade 2 on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Dosing can be restarted at 1250 mg/day when the toxicity improves to grade 1 or less. If the toxicity recurs, then lapatinib should be restarted at a lower dose (1000 mg/day). The prescribing information for capecitabine must be consulted for guidance on dose delay and dose reduction recommendations for capecitabine.

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 lapatinib in this population (see section 5.2),

Hepatic impairment; Lapatinib should be discontinued if changes in liver function are severe and patients should not be retreated (see section 4.4). Administration of lapatinib 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).

Paediatrics; Tyverb is not recommended for use in paediatrics due to insufficient data on safety and efficacy.

Elderly; There are limited data of the use of lapatinib in patients aged 65 years and older.

4.4 Special warnings and precautions for use; Lapatinib has been associated with reports of decreases in left ventricular ejection fraction (LVEF) (see section 4.8). Caution should be taken if lapatinib is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in 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 (see section 4.2). 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 (see section 4.2). Hepatotoxicity has occurred with lapatinib use and may in rare cases be fatal. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before 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. Caution is warranted if lapatinib is prescribed to patients with moderate or severe hepatic impairment (see sections 4.2 and 5.2). Caution is advised if lapatinib is prescribed to patients with severe renal impairment (see sections 4.2 and 5.2). Diarrhoea, including severe diarrhoea, has been reported with lapatinib treatment (see section 4.8). Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of lapatinib therapy (see section 4.2 – dose delay and dose reduction – other toxicities). 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 lapatinib (see section 4.5). Coadministration of lapatinib with medicinal product with narrow therapeutic windows that are substrates of CYP3A4 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).

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 halflife increased 1.7–fold. Coadministration of lapatinib with strong inhibitors of CYP3A4 (e.g.ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Coadministration of lapatinib 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%. Coadministration 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 (rifampin, 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.

Effects of lapatinib on other medicinal products; Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Coadministration of lapatinib with medicines with narrow therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) or CYP2C8 (e.g. repaglinide) should be avoided (see sections 4.4 and 5.2). If lapatinib is administered in combination with paclitaxel (175 mg/m2 every three weeks), severe neutropenia may coincide with diarrhoea. This warrants monitoring and early treatment of diarrhoea. Lapatinib inhibits the transport proteins Pgp, 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 Pgp (e.g. digoxin), BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) (see section 5.2). Concomitant administration of lapatinib with capecitabine or trastuzumab did not meaningfully alter the pharmacokinetics of these agents (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 (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 lapatinib.

4.6 Pregnancy and lactation; There are no adequate data from the use of lapatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is not known. Lapatinib should not be used during pregnancy unless clearly necessary. Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with lapatinib. The safe use of lapatinib during lactation 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 lapatinib.

4.7 Effects on ability to drive and use machines ; No studies on the effects on the ability to drive and use machines have been performed. A detrimental effect on such activities cannot be predicted from the pharmacology of lapatinib. The clinical status of the patient and the adverse event 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: Safety of lapatinib has been evaluated as monotherapy or in combination with other chemotherapies for various cancers including patients who received lapatinib in combination with capecitabine (see section 5.1). The most common adverse reactions (>25%) during therapy with lapatinib plus capecitabine were gastrointestinal (diarrhoea, nausea, and vomiting) or dermatologic (palmar-plantar erythrodysesthesia [PPE] and rash). The incidence of PPE was similar in both lapatinib plus capecitabine and capecitabine alone treatment arms. Diarrhoea was the most common adverse reaction resulting in discontinuation of treatment and this had a similar incidence in both treatment groups (lapatinib plus capecitabine: 5%, capecitabine: 3%). The following convention has been utilised for the classification of frequency: Very common ((¡Ý1/10), Common (¡Ý1/100 to <1/10), Uncommon (¡Ý1/1,000 to <1/100), Rare (¡Ý1/10,000 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. The following adverse reactions have been reported to be associated with lapatinib:

Cardiac disorders; Common Decreased left ventricular ejection fraction (see section 4.2 - dose reduction – cardiac events and section 4.4)

Respiratory, thoracic and mediastinal disorders; Uncommon Interstitial lung disease/pneumonitis

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

Skin and subcutaneous tissue disorders; Very common Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose reduction – other toxicities)

Metabolism and nutrition disorders; Very common Anorexia

General disorders and administration site conditions; Very common Fatigue

Hepatobiliary disorders; Common Hyperbilirubinaemia, hepatotoxicity

The following additional adverse reactions have been reported to be associated with lapatinib in combination with capecitabine with a frequency difference of greater than 5% compared to capecitabine alone.

Gastrointestinal disorders Very common Dyspepsia

Nervous system disorders Common Headache

Gastrointestinal disorders Very common Stomatitis, constipation, abdominal pain

Skin and subcutaneous tissue disorders Very common Palmar-plantar erythro dysaesthesia

Musculoskeletal and connective tissue disorders Very common Pain in extremity, back pain

General disorders and administrative site conditions Very common Mucosal inflammation

Psychiatric disorders Very common Insomnia

Decreased left ventricular ejection fraction Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of patients receiving lapatinib and were asymptomatic in more than 90% of cases. LVEF decreases resolved or improved in more than 60% of cases on discontinuation of treatment with lapatinib.Symptomatic LVEF decreases were observed in approximately 0.1% of patients who received lapatinib monotherapy. Observed symptoms included dyspnoea, cardiac failure and palpitations. All events resolved promptly on discontinuation of lapatinib. LVEF decreases were reported in 2.5% of patients who received lapatinib in combination with capecitabine, as compared to 1.0% with capecitabine alone.

Diarrhoea occurred in approximately 65 % of patients who received lapatinib in combination with capecitabine. 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).

Rash occurred in approximately 28 % of patients who received lapatinib in combination with capecitabine. Rash was generally low grade and did not result in discontinuation of treatment with lapatinib.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Protein kinase inhibitor, ATC code: L01XE07 This medicinal product has been authorised under a so-called "conditional approval" scheme. This means that furrther evidence on this medicinal product is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.

Mechanism of action Lapatinib a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of ErbB2 (HER2) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes). Lapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models. 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.

Clinical studies The efficacy and safety of lapatinib in combination with capecitabine in breast cancer patients with good performance status was evaluated in a randomized, phase III trial. Patients eligible for enrolment had ErbB2 (HER2)-over-expressing, locally advanced or metastatic breast cancer, progressing after prior treatment that included taxanes, anthracyclines and trastuzumab. LVEF was evaluated in all patients (using echocardiogram or MUGA) prior to initiation of treatment with lapatinib to ensure baseline LVEF was within the institutions normal limits. In clinical trials LVEF was monitored at approximately eight week intervals during treatment with lapatinib to ensure it did not decline to below the institutions lower limit of normal. The majority of LVEF decreases (greater than 60 %) were observed during the first nine weeks of treatment, however limited data was available for long term exposure. Patients were randomized to receive either lapatinib 1250 mg once daily (continuously) plus capecitabine (2000 mg/m2/day on days 1-14 every 21 days), or to receive capecitabine alone (2500 mg/m2/day on days 1-14 every 21 days). The primary endpoint was time to progression (TTP). Assessments were undertaken by the study investigators and by an independent review panel, blinded to treatment. The study was halted based on the results of a pre-specified interim analysis that showed an improvement in TTP for patients receiving lapatinib plus capecitabine. An additional 75 patients were enrolled in the study between the time of the interim analysis and the end of the enrolment.Investigator analysis on data at the stop of enrolment is presented in the following table.

Investigator assessment Lapatinib (1,250 mg/day)+capecitabine (2,000 mg/m2/day), Capecitabine (2,500 mg/m2/day),(N = 198) (N = 201), Number of TTP events 121 126, Median TTP, weeks 23.9 18.3,Hazard Ratio 0.72,(95% CI) (0.56, 0.92),p value 0.008,The independent assessment of the data also demonstrated that lapatinib when given in combination, with capecitabine significantly increased time to progression (Hazard Ratio 0.57 [95 % Cl 0.43, 0.77], p=0.0001) compared to capecitabine alone. Results of an updated analysis of the overall survival data to 28 September 2007 are presented in the table below.

Lapatinib (1,250 mg/day)+ capecitabine (2,000 mg/m2/day),Capecitabine (2,500 mg/m2/day),(N = 207) (N = 201). Number of subjects who died 148 154, Median overall survival, weeks 74.0 65.9, Hazard Ratio 0.9 (95% CI) (0.71, 1.12), p value 0.3, On the combination arm, there were 4 (2%) progressions in the central nervous system as compared with the 13 (6%) progressions on the capecitabine alone arm.

5.3 Preclinical safety data Lapatinib was studied in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib and precocious ossification) occurred in rats at ¡Ý60 mg/kg/day (4 times the expected human clinical exposure). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (8% and 23% of the expected human clinical exposure, respectively) and abortions at 120 mg/kg/day. At ¡Ý60 mg/kg/day there were decreased foetal body weights, and minor skeletal variations. In the rat pre- and postnatal development study, a decrease in pup survival occurred between birth and postnatal day 21 at doses of 60 mg/kg/day or higher (5 times the expected human clinical exposure). The highest no effect dose for this study was 20 mg/kg/day. There were no effects on male or female rat gonadal function, mating, or fertility at doses up to 120 mg/kg/day (females) and up to 180 mg/kg/day (males) (8 and 3 times the expected human clinical exposure, respectively). The effect on human fertility is unknown. Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.

6.1 List of excipients Tablet core, Microcrystalline cellulose, Povidone (K30), Sodium starch glycolate (Type A), Magnesium stearate, Tablet coating Hypromellose, Titanium dioxide (E171), Macrogol 400 Polysorbate 80 Iron oxide yellow (E172) Iron oxide red (E172)

6.2 Incompatibilities  Not applicable.

6.3 Shelf life 2 years

6.4 Special precautions for storage Do not store above 30ºC.

6.5 Nature and contents of container Each pack of Tyverb contains 70 tablets in foil blisters (polyamide / aluminium / polyvinyl chloride / aluminium) of 10 tablets each. Each foil has a perforation down the middle to allow the blisters to be separated into a daily dose of 5 tablets.

6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.

8. MARKETING AUTHORISATION NUMBER(S) EU/1/07/440/001

10 June 2008 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu./>