TYVERB 250mg film-coated tablets medication leaflet

Tyverb 250 mg film-coated tablets

Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Oval, biconvex, yellow film-coated tablets, with “GS XJG” debossed on one side.

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 withprogression following prior therapy, which must have included anthracyclines and taxanes andtherapy with trastuzumab in the metastatic setting (see section 5.1).

* in combination with trastuzumab for patients with hormone receptor-negative metastatic diseasethat has progressed on prior trastuzumab therapy(ies) in combination with chemotherapy (seesection 5.1).

* in combination with an aromatase inhibitor for postmenopausal women with hormone receptorpositive metastatic disease, not currently intended for chemotherapy. The patients in theregistration study were not previously treated with trastuzumab or an aromatase inhibitor (seesections 4.4. and 5.1). No data are available on the efficacy of this combination relative totrastuzumab in combination with an aromatase inhibitor in this patient population.

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

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

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 ondays 1-14 in a 21 day cycle (see section 5.1). Capecitabine should be taken with food or within30 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 prescribinginformation 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 dosingdetails.

Dose delay and dose reduction

Tyverb should be discontinued in patients with symptoms associated with decreased left ventricularejection 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 ofnormal (see section 4.4). Tyverb may be restarted at a reduced dose (750 mg/day when administeredwith trastuzumab, 1000 mg/day when administered with capecitabine or 1250 mg/day whenadministered with an aromatase inhibitor) after a minimum of 2 weeks and if the LVEF recovers tonormal 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).

Tyverb dosing should be interrupted in patients with diarrhoea which is NCI CTCAE grade 3 orgrade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomitinggreater 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/dayto 1250 mg/day) when diarrhoea resolves to grade 1 or less. Tyverb dosing should be permanentlydiscontinued 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 developstoxicity greater than or equal to grade 2 on the NCI CTCAE. Dosing can be restarted, when thetoxicity 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 anaromatase inhibitor. If the toxicity recurs, then Tyverb should be restarted at a lower dose (750 mg/daywhen administered with trastuzumab, 1000 mg/day when administered with capecitabine or1250 mg/day when administered with an aromatase inhibitor).

No dose adjustment is necessary in patients with mild to moderate renal impairment. Caution isadvised in patients with severe renal impairment as there is no experience of Tyverb in this population(see section 5.2).

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

Administration of Tyverb to patients with moderate to severe hepatic impairment should beundertaken with caution due to increased exposure to the medicinal product. Insufficient data areavailable in patients with hepatic impairment to provide a dose adjustment recommendation (seesection 5.2).

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 hormonereceptor 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 andletrozole were observed between these patients and patients < 65 years of age.

The safety and efficacy of Tyverb in children below the age of 18 years have not yet been established.

No data are available.

Tyverb is for oral use.

The daily dose of Tyverb should not be divided. Tyverb should be taken either at least one hourbefore, or at least one hour after food. To minimise variability in the individual patient, administrationof Tyverb should be standardised in relation to food intake, for example always to be taken one hourbefore 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 forrelevant details of their posology including any dose reductions, contraindications and safetyinformation.

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

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

Lapatinib has been associated with reports of decreases in LVEF (see section 4.8). Lapatinib has notbeen evaluated in patients with symptomatic cardiac failure. Caution should be taken if Tyverb is to beadministered 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 treatmentwith 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 notdecline to an unacceptable level (see section 4.2). In some cases, LVEF decrease may be severe andlead to cardiac failure. Fatal cases have been reported, causality of the deaths is uncertain. In studiesacross the clinical development programme for lapatinib, cardiac events including LVEF decreaseswere reported in approximately 1% of patients. Symptomatic LVEF decreases were observed inapproximately 0.3% of patients who received lapatinib. However, when lapatinib was administered incombination 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 cardiacevents observed in this study were comparable in nature and severity to those previously seen withlapatinib.

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

Caution should be taken if Tyverb is administered to patients with conditions that could result inprolongation of QTc (including hypokalemia, hypomagnesemia, and congenital long QT syndrome),co-administration of other medicinal product known to cause QT prolongation, or conditions thatincrease the exposure of lapatinib, such as co-administration of strong CYP3A4 inhibitors.

Hypokalemia or hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QTmeasurement 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 thatmay 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 andpneumonitis (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 has occurred with Tyverb use and may in rare cases be fatal. The hepatotoxicity mayoccur days to several months after initiation of treatment. At the initiation of treatment, patients shouldbe advised of the potential for hepatotoxicity. Liver function (transaminases, bilirubin and alkalinephosphatase) should be monitored before the initiation of treatment and monthly thereafter, or asclinically indicated. Tyverb dosing should be discontinued if changes in liver function are severe andpatients should not be retreated. Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01have increased risk of Tyverb-associated hepatotoxicity. In a large, randomised clinical trial of Tyverbmonotherapy (n=1,194), the cumulative frequency of severe liver injury (ALT >5 times the upper limitof 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 ofthe HLA risk alleles is common (15 to 25%) in Caucasian, Asian, African and Hispanic populationsbut lower (1%) in Japanese populations.

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

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 generallyoccurs early during Tyverb treatment, with almost half of those patients with diarrhoea firstexperiencing it within 6 days. This usually lasts 4-5 days. Tyverb-induced diarrhoea is usuallylow-grade, with severe diarrhoea of NCI CTCAE grades 3 and 4 occurring in <10% and <1% ofpatients, 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 allowidentification 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 severecases 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 casesof diarrhoea may require administration of oral or intravenous electrolytes and fluids, use ofantibiotics such as fluoroquinolones (especially if diarrhoea is persistent beyond 24 hours, there isfever, or grade 3 or 4 neutropenia) and interruption or discontinuation of Tyverb therapy (seesection 4.2 - dose delay and dose reduction -diarrhoea).

Serious cutaneous reactions

Serious cutaneous reactions have been reported with Tyverb. If erythema multiforme orlife-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 exposureto lapatinib (see section 4.5).

Concomitant treatment with strong inhibitors of CYP3A4 should be avoided due to risk of increasedexposure 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 therapeuticwindows 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 lapatinibsolubility 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’.

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 for7 days, systemic exposure to lapatinib (100 mg daily) was increased approximately 3.6-fold, andhalf-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 CYP3A4should 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 daysand 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 increasegastric pH should be avoided, as lapatinib solubility and absorption may decrease. Pre-treatment witha 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 Tyverbwith orally administered midazolam resulted in an approximate 45% increase in the AUC ofmidazolam. There was no clinically meaningful increase in AUC when midazolam was dosedintravenously. Co-administration of Tyverb with orally administered medicinal products with narrowtherapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should beavoided (see sections 4.4 and 5.2).

Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of Tyverbwith 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 by23%, due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity ofdiarrhoea and neutropenia has been observed with this combination in clinical studies. Caution isadvised if lapatinib is co-administered with paclitaxel.

Co-administration of lapatinib with intravenously administered docetaxel did not significantly affectthe AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced neutropeniawas 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 oneor more transport proteins by lapatinib. Adverse reactions should be carefully monitored if Tyverb isco-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 withmedicinal products with narrow therapeutic windows that are substrates of Pgp, and a reduction in thedose of the Pgp substrate should be considered.

Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of thiseffect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics ofsubstrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) (see section 5.2).

Concomitant administration of Tyverb with capecitabine, letrozole or trastuzumab did notmeaningfully alter the pharmacokinetics of these medicinal products (or the metabolites ofcapecitabine) 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 fatcontent in the meal. Furthermore, depending on type of food the bioavailability is approximately2-3 times higher when lapatinib is taken 1 hour after food compared with 1 hour before the first mealof the day (see sections 4.2 and 5.2).

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

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

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

Tyverb should not be used during pregnancy unless clearly necessary.

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

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

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

The safety of lapatinib has been evaluated as monotherapy or in combination with otherchemotherapies for various cancers in more than 20,000 patients, including 198 patients who receivedlapatinib in combination with capecitabine, 149 patients who received lapatinib in combination withtrastuzumab 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 alsocommon (>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. Diarrhoeawas the most common adverse reaction resulting in discontinuation of treatment when lapatinib wasadministered in combination with capecitabine, or with letrozole.

No additional adverse reactions were reported to be associated with lapatinib in combination withtrastuzumab. There was an increased incidence of cardiac toxicity, but these events were comparablein 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 pivotaltrial.

The following adverse reactions have been reported to have a causal association with lapatinib aloneor 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 veryrare (<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.

Rare Hypersensitivity reactions including anaphylaxis (see section 4.3)

Very common Anorexia

Very common Insomnia*

Very common Headache†

Common Headache*

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 QTprolonged**

Very common Hot flush†

Very common Epistaxis†, cough†, dyspnoea†.

Uncommon Interstitial lung disease/pneumonitis.

Not known Pulmonary arterial hypertension**.

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

Common Constipation†

Common Hyperbilirubinaemia, hepatotoxicity (see section 4.4).

Very common Rash (including dermatitis acneiform) (see section 4.2 - dose delay anddose reduction - other toxicities), dry skin*†, palmar-plantarerythrodysaesthesia*, alopecia†, pruritus†.

Common Nail disorders including paronychia, skin fissures.

Not known Serious cutaneous reactions, including Stevens Johnson syndrome (SJS)and toxic epidermal necrolysis (TEN)**

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

Very common Fatigue, mucosal inflammation*, asthenia†.

* These adverse reactions were observed when lapatinib was administered in combination withcapecitabine.† These adverse reactions were observed when lapatinib was administered in combination withletrozole.

** Adverse reactions from spontaneous reports and literature

Decreased left ventricular ejection fraction and QT interval prolongation

Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% ofpatients receiving lapatinib and were asymptomatic in more than 70% of cases. LVEF decreasesresolved or improved in more than 70 % of cases, in approximately 60 % of these on discontinuationof 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 lapatinibmonotherapy or in combination with other anti-cancer medicinal products. Observed adverse reactionsincluded dyspnoea, cardiac failure and palpitations. Overall 58 % of these symptomatic patientsrecovered. LVEF decreases were reported in 2.5 % of patients who received lapatinib in combinationwith capecitabine, as compared to 1.0 % with capecitabine alone. LVEF decreases were reported in3.1 % of patients who received lapatinib in combination with letrozole as compared to 1.3 % ofpatients receiving letrozole plus placebo. LVEF decreases were reported in 6.7 % of patients whoreceived lapatinib in combination with trastuzumab, as compared to 2.1 % of patients who receivedlapatinib 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 occurred in approximately 65 % of patients who received lapatinib in combination withcapecitabine, in 64 % of patients who received lapatinib in combination with letrozole and in 62 % ofpatients who received lapatinib in combination with trastuzumab. Most cases of diarrhoea weregrade 1 or 2 and did not result in discontinuation of treatment with lapatinib. Diarrhoea responds wellto proactive management (see section 4.4). However, a few cases of acute renal failure have beenreported secondary to severe dehydration due to diarrhoea.

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

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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for the inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosinephosphorylation. The maximum oral dose of lapatinib that has been administered in clinical studies is1800 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 lapatinibassociated events (see section 4.8) and in some cases sore scalp and/or mucosal inflammation. In asingle 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, thereforehaemodialysis would not be expected to be an effective method to enhance the elimination oflapatinib.

Further management should be as clinically indicated or as recommended by the national poisonscentre, where available.

Pharmacotherapeutic group: Antineoplastic agents, human epidermal growth factor receptor 2 (HER2)tyrosine kinase inhibitors, ATC code: L01EH01.

Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both

EGFR (ErbB1) and of HER2 (ErbB2) 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 combination of lapatinib and trastuzumab may offer complementary mechanisms of action as wellas possible non-overlapping mechanisms of resistance. The growth inhibitory effects of lapatinib wereevaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against

HER2-amplified breast cancer cell lines selected for long-term growth in trastuzumab-containingmedium in vitro and was synergistic in combination with trastuzumab in these cell lines.

Combination treatment with Tyverb and capecitabine

The efficacy and safety of Tyverb in combination with capecitabine in breast cancer patients withgood performance status was evaluated in a randomised, phase III study. Patients eligible forenrolment had HER2-overexpressing, locally advanced or metastatic breast cancer, progressing afterprior treatment that included taxanes, anthracyclines and trastuzumab. LVEF was evaluated in allpatients (using echocardiogram [Echo] or multi gated acquisition scan [MUGA]) prior to initiation oftreatment with Tyverb to ensure baseline LVEF was within the institutions normal limits. In theclinical study LVEF was monitored at approximately eight week intervals during treatment with

Tyverb to ensure it did not decline to below the institutions lower limit of normal. The majority of

LVEF decreases (greater than 60 % of events) were observed during the first nine weeks of treatment,however limited data was available for long term exposure.

Patients were randomised to receive either Tyverb 1250 mg once daily (continuously) pluscapecitabine (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, blindedto treatment. The study was halted based on the results of a pre-specified interim analysis that showedan improvement in TTP for patients receiving Tyverb plus capecitabine. An additional 75 patientswere enrolled in the study between the time of the interim analysis and the end of the enrolment.

Investigator analysis on data at the end of enrolment is presented in Table 1.

Table 1 Time to progression data from Study EGF100151 (Tyverb/capecitabine)

Investigator assessment

Tyverb (1250 mg/day)+ Capecitabine (2500 mg/m2/day,capecitabine (2000 mg/m2/day, days 1-14 q21 days)days 1-14 q21 days)(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 Tyverb when given in combinationwith capecitabine significantly increased time to progression (Hazard Ratio 0.57 [95 % CI 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

Table 2.

Table 2 Overall survival data from Study EGF100151 (Tyverb/capecitabine)

Tyverb (1250 mg/day)+ Capecitabine (2500 mg/m2/day,capecitabine (2000 mg/m2/day, days 1-14 q21 days)days 1-14 q21 days)(N = 207) (N = 201)

Number of subjects who 148 154died

Median overall survival, 74.0 65.9weeks

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 comparedwith the 13 (6%) progressions on the capecitabine alone arm.

Data are available on the efficacy and safety of Tyverb in combination with capecitabine relative totrastuzumab in combination with capecitabine. A randomised Phase III study (EGF111438) (N=540)compared the effect of the two regimens on the incidence of CNS as site of first relapse in women with

HER2 overexpressing metastatic breast cancer. Patients were randomised to either Tyverb 1250 mgonce daily (continuously) plus capecitabine (2000 mg/m2/day on days 1-14 every 21 days), ortrastuzumab (loading dose of 8mg/kg followed by 6mg/kg q3 weekly infusions) plus capecitabine(2500mg/m2/day, days 1-14, every 21 days). Randomisation was stratified by prior trastuzumabtreatment and number of prior treatments for metastatic disease. The study was halted as the interimanalysis (N=475) showed a low incidence of CNS events and, superior efficacy of the trastuzumabplus capecitabine arm in terms of progression-free survival and overall survival (see results of finalanalysis in Table 3).

In the Tyverb plus capecitabine arm 8 patients (3.2%) experienced CNS as site of first progression,compared with 12 patients (4.8%) in the trastuzumab plus capecitabine arm.

Lapatinib effect on CNS metastasis

Lapatinib has in terms of objective responses demonstrated modest activity in the treatment ofestablished CNS metastases. In the prevention of CNS metastases in the metastatic and early breastcancer settings the observed activity was limited.

Table 3 Analyses of investigator-assessed progression-free survival and overall survival

Investigator-assessed PFS Overall survival

Tyverb Trastuzumab Tyverb Trastuzumab(1250 mg/day) + (loading dose of (1250 mg/day) + (loading dose ofcapecitabine 8mg/kg followed capecitabine 8mg/kg followed(2000 mg/m2/day, by 6mg/kg q3 (2000 mg/m2/day, by 6mg/kg q3days 1-14 q21 weekly infusions) days 1-14 q21 weekly infusions)days) + days) +capecitabine capecitabine(2500 mg/m2/day, (2500 mg/m2/day,days 1-14 q21 days 1-14 q21days) days)

ITT population

N 271 269 271 269

Number (%) 160 (59) 134 (50) 70 (26) 58 (22)with event1

Kaplan-Meierestimate,months a

Median (95% 6.6 (5.7, 8.1) 8.0 (6.1, 8.9)

CI) 22.7 (19.5, -) 27.3 (23.7, -)

Stratified

Hazard ratiob

HR (95% CI) 1.30 (1.04, 1.64) 1.34 (0.95, 1.90)p-value 0.021 0.095

Subjects who had received prior trastuzumab*

N 167 159 167 159

Number (%) 103 (62) 86 (54) 43 (26) 38 (24)with event1

Median (95% 6.6 (5.7, 8.3) 6.1 (5.7, 8.0)

CI) 22.7 (20.1,-) 27.3 (22.5, 33.6)

HR (95% CI) 1.13 (0.85, 1.50) 1.18 (0.76, 1.83)

Subjects who had not received prior trastuzumab*

N 104 110 104 110

Number (%) 57 (55) 48 (44) 27 (26) 20 (18)with event1

Median (95% 6.3 (5.6, 8.1) 10.9 (8.3, 15.0)

CI) NE2 (14.6, -) NE2 (21.6, -)

HR (95% CI) 1.70 (1.15, 2.50) 1.67 (0.94, 2.96)

CI = confidence interval

a. PFS was defined as the time from randomisation to the earliest date of disease progression ordeath from any cause, or to the date of censor.

b. Pike estimate of the treatment hazard ratio, <1 indicates a lower risk for Tyverb plus capecitabinecompared with Trastuzumab plus capecitabine.

1. PFS event is Progressed or Died and OS event is Died due to any cause.

2. NE=median was not reached.

* Post hoc analysis

Combination treatment with Tyverb and trastuzumab

The efficacy and safety of lapatinib in combination with trastuzumab in metastatic breast cancer wereevaluated in a randomised trial. Eligible patients were women with Stage IV ErbB2 gene amplified (orprotein overexpressing) metastatic breast cancer who had been exposed to treatment withanthracyclines and taxanes. In addition, per the protocol, patients were to be reported by theinvestigators as having progressed on their most recent trastuzumab containing regimen in themetastatic setting. The median number of prior trastuzumab-containing regimens was three. Patientswere randomised to receive either oral lapatinib 1000 mg once daily plus trastuzumab 4 mg/kgadministered as an intravenousloading dose, followed by 2 mg/kg intravenous weekly (N = 148), ororal lapatinib 1500 mg once daily (N = 148). Patients who had objective disease progression afterreceiving at least 4 weeks of treatment with lapatinib monotherapy were eligible to crossover tocombination therapy. Of the 148 patients who received monotherapy treatment, 77 (52%) patientselected at the time of disease progression to receive combination treatment.

Progression-free survival (PFS) was the primary endpoint of the study with response rate and overallsurvival (OS) as secondary endpoints. The median age was 51 years and 13% were 65 years or older.

Ninety-four percent (94%) were Caucasian. Most patients in both treatment arms had visceral disease(215 [73%] patients overall). In addition, 150 [50%] of patients were hormone receptor negative. Asummary of efficacy endpoints and overall survival data is provided in Table 4. Subgroup analysisresults based on predefined stratification factor (hormone receptor status) is also shown in Table 5.

Table 4 Progression-free survival and overall survival data (Tyverb/trastuzumab)

Lapatinib plustrastuzumab Lapatinib alone(N=148) (N=148 )

Median PFS1, weeks 12.0 8.1(95% CI) (8.1, 16.0) (7.6, 9.0)

Hazard ratio (95% CI) 0.73 (0.57, 0.93)

P value 0.008

Response rate, % 10.3 6.9(95% CI) (5.9, 16.4) (3.4, 12.3)

Died 105 113

Median overall survival1, months 14.0 9.5(95% CI) (11.9, 17.2) (7.6, 12.0)

Hazard ratio (95% CI) 0.74 (0.57, 0.97)

P value 0.026

PFS = progression-free survival; CI = confidence interval.1Kaplan-Meier estimates

Table 5 Summary of PFS and OS in studies with hormone receptor negative

Median PFS Median OS

Lap+Tras 15.4 wks (8.4, 16.9) 17.2 mos (13.9, 19.2)

Lap 8.2 wks (7.4, 9.3) 8.9 mos (6.7, 11.8)

HR (95% CI) 0.73 (0.52, 1.03) 0.62 (0.42, 0.90)

Combination treatment with Tyverb and letrozole

Tyverb has been studied in combination with letrozole for the treatment of postmenopausal womenwith hormone receptor-positive (oestrogen receptor [ER] positive and/or progesterone receptor [PgR]positive) advanced or metastatic breast cancer.

The Phase III study (EGF30008) was randomised, double-blind, and placebo controlled. The studyenrolled patients who had not received prior therapy for their metastatic disease.

In the HER2-overexpressing population, only 2 patients were enrolled who had received priortrastuzumab, 2 patients had received prior aromatase inhibitor therapy, and approximately half hadreceived tamoxifen.

Patients were randomised to letrozole 2.5 mg once daily plus Tyverb 1500 mg once daily or letrozolewith placebo. Randomisation was stratified by sites of disease and by time from discontinuation ofprior adjuvant anti-oestrogen therapy. HER2 receptor status was retrospectively determined by centrallaboratory testing. Of all patients randomised to treatment, 219 patients had tumours overexpressingthe HER2 receptor, and this was the pre-specified primary population for the analysis of efficacy.

There were 952 patients with HER2-negative tumours, and a total of 115 patients whose tumour HER2status was unconfirmed (no tumour sample, no assay result, or other reason).

In patients with HER2-overexpressing MBC, investigator-determined progression-free survival (PFS)was significantly greater with letrozole plus Tyverb compared with letrozole plus placebo. In the

HER2-negative population, there was no benefit in PFS when letrozole plus Tyverb was comparedwith letrozole plus placebo (see Table 6).

Table 6 Progression free survival data from Study EGF30008 (Tyverb/letrozole)

HER2-overexpressing population HER2-negative population

N = 111 N = 108 N = 478 N = 474

Tyverb Tyverb1500 mg/day Letrozole 1500 mg/day Letrozole+ Letrozole 2.5 mg /day + Letrozole 2.5 mg /day2.5 mg /day + placebo 2.5 mg /day + placebo

Median PFS, weeks 35.4 13.0 59.7 58.3(95% CI) (24.1, 39.4) (12.0, 23.7) (48.6, 69.7) (47.9, 62.0)

Hazard ratio 0.71 (0.53, 0.96) 0.90 (0.77, 1.05)

P-value 0.019 0.188

Objective response 27.9% 14.8% 32.6% 31.6%rate (ORR)

Odds ratio 0.4 (0.2, 0.9) 0.9 (0.7, 1.3)

P-value 0.021 0.26

Clinical benefit rate 47.7% 28.7% 58.2% 31.6%(CBR)

Odds ratio 0.4 (0.2, 0.8) 1.0 (0.7, 1.2)

P-value 0.003 0.199

CI= confidence interval

HER2 overexpression = IHC 3+ and/or FISH positive; HER2 negative = IHC 0, 1+ or 2+ and/or

FISH negative

Clinical benefit rate was defined as complete plus partial response plus stable disease for6 months.

At the time of the final PFS analysis (with median follow-up of 2.64 years), the overall survival datawere not mature and there was no significant difference between treatment groups in the

HER2-positive population; this had not changed with additional follow-up (>7.5 years median follow-up time; Table 7).

Table 7 Overall survival (OS) results from study EGF30008 (in the HER2-positivepopulation only)

Tyverb 1500 mg/day Letrozole 2.5 mg /day+ Letrozole 2.5 mg + placebo/day N=108

N=111

Pre-planned OS analysis (conducted at the time of the final PFS analysis, 03 June 2008)

Median follow-up (yrs) 2,64 2,64

Deaths (%) 50 (45) 54 (50)

Hazard ratioa (95% CI), p-valueb 0,77 (0,52; 1,14); 0,185

Final OS analysis (post-hoc analysis, 07 August 2013)

Median follow-up (yrs) 7,78 7,55

Deaths (%) 86 (77) 78 (72)

Hazard ratio (95% CI), p-value 0,97 (0,07; 1,33); 0,848

Median values from Kaplan-Meier analysis; HR and p-values from Cox regression models adjustingfor important prognostic factors.

a. Estimate of the treatment hazard ratio, where <1 indicates a lower risk with letrozole 2.5 mg +lapatinib 1500 mg compared with letrozole 2.5 mg + placebo.

b. P-value from Cox regression model, stratifying for site of disease and prior anti-adjuvanttherapy at screening.

The effect of lapatinib on the QT-interval was evaluated in a single-blind, placebo-controlled, singlesequence (placebo and active treatment) crossover study in patients with advanced solid tumours(EGF114271) (n=58). During the 4-day treatment period, three doses of matching placebo wereadministered 12 hours apart in the morning and evening on Day 1 and in the morning on Day 2. Thiswas followed by three doses of lapatinib 2000 mg administered in the same way. Measurements,including electrocardiograms (ECGs) and pharmacokinetic samples, were taken at baseline and at thesame time points on Day 2 and Day 4.

In the evaluable population (n=37), the maximum mean ΔΔQTcF (90% CI) of 8.75 ms (4.08, 13.42)was observed 10 hours after ingestion of the third dose of lapatinib 2000 mg. The ΔΔQTcF exceededthe 5 ms threshold and the upper bound 90% CIs exceeded the 10 ms threshold at multiple time points.

The results for the pharmacodynamics population (n=52) were consistent with those from theevaluable population (maximum ΔΔQTcF (90% CI) of 7.91 ms (4.13, 11.68) observed 10 hours afteringestion of the third dose of lapatinib 2000 mg).

There is a positive relationship between lapatinib plasma concentrations and ΔΔQTcF. Lapatinibproduced a maximum mean concentration of 3920 (3450-4460) ng/ml (geometric mean/95% CI),exceeding the geometric mean Cmax.ss and 95% CI values observed following the approved dosingregimens. An additional increase in peak exposure of lapatinib can be expected when lapatinib is takenrepeatedly with food (see sections 4.2 and 5.2) or concomitantly with strong CYP3A4 inhibitors.

When lapatinib is taken in combination with strong CYP3A4 inhibitors the QTc interval can beexpected to be prolonged by 16.1 ms (12.6-20.3 ms) as demonstrated in a model-based prediction (seesection 4.4).

Food effects on lapatinib exposure

The bioavailability and thereby the plasma concentrations of lapatinib are increased by food, inrelation to the content and timing of the meal. Dosing of lapatinib one hour after a meal results inapproximately 2-3 times higher systemic exposure, compared to dosing one hour before a meal (seesections 4.5 and 5.2).

The European Medicines Agency has waived the obligation to submit the results of studies with

Tyverb in all subsets of the paediatric population in the treatment of breast carcinoma (see section 4.2for information on paediatric use).

The absolute bioavailability following oral administration of lapatinib is unknown, but it is incompleteand variable (approximately 70% coefficient of variation in AUC). Serum concentrations appear aftera median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinibare achieved approximately 4 hours after administration. Daily dosing of 1250 mg produces steadystate geometric mean (coefficient of variation) Cmax values of 2.43 (76%) µg/ml and AUC values of36.2 (79%) µg*hr/ml.

Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values wereapproximately 3- and 4-fold higher (Cmax approximately 2.5 and 3-fold higher) when administeredwith a low fat (5% fat [500 calories]) or with a high fat (50% fat [1,000 calories]) meal, respectively,as compared with administration in the fasted state. Systemic exposure to lapatinib is also affected bythe timing of administration in relation to food intake. Relative to dosing 1 hour before a low fatbreakfast, mean AUC values were approximately 2- and 3-fold higher when lapatinib wasadministered 1 hour after a low fat or high fat meal, respectively.

Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitrostudies indicate that lapatinib is a substrate for the transporters BCRP (ABCG1) and p-glycoprotein(ABCB1). Lapatinib has also been shown in vitro to inhibit these efflux transporters, as well as thehepatic uptake transporter OATP 1B1, at clinically relevant concentrations (IC50 values were equal to2.3 µg/ml). The clinical significance of these effects on the pharmacokinetics of other medicinalproducts or the pharmacological activity of other anti-cancer medicinal products is not known.

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minorcontributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of whichaccount for more than 14% of the dose recovered in the faeces or 10% of lapatinib concentration inplasma.

Lapatinib inhibits CYP3A (Ki 0.6 to 2.3 µg/ml) and CYP2C8 (0.3 µg/ml) in vitro at clinically relevantconcentrations. Lapatinib did not significantly inhibit the following enzymes in human livermicrosomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes (in vitro IC50 values weregreater than or equal to 6.9 µg/ml).

The half-life of lapatinib measured after single doses increases with increasing dose. However, dailydosing of lapatinib results in achievement of steady state within 6 to 7 days, indicating an effectivehalf-life of 24 hours. Lapatinib is predominantly eliminated through metabolism by CYP3A4/5.

Biliary excretion may also contribute to the elimination. The primary route of excretion for lapatiniband its metabolites is in faeces. Recovery of unchanged lapatinib in faeces accounts for a median 27%(range 3 to 67%) of an oral dose. Less than 2% of the administered oral dose (as lapatinib andmetabolites) excreted in urine.

Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or inpatients undergoing haemodialysis. Available data suggest that no dose adjustment is necessary inpatients with mild to moderate renal impairment.

The pharmacokinetics of lapatinib were examined in patients with moderate (n = 8) or severe (n = 4)hepatic impairment (Child-Pugh scores of 7-9, or greater than 9, respectively) and in 8 healthy controlpatients. Systemic exposure (AUC) to lapatinib after a single oral 100 mg dose increasedapproximately 56% and 85% in patients with moderate and severe hepatic impairment, respectively.

Administration of lapatinib in patients with hepatic impairment should be undertaken with caution (seesections 4.2 and 4.4).

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 riband precocious ossification) occurred in rats at ≥60 mg/kg/day (4 times the expected human clinicalexposure). 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≥60 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 postnatalday 21 at doses of 60 mg/kg/day or higher (5 times the expected human clinical exposure). The highestno-effect dose for this study was 20 mg/kg/day.

In oral carcinogenicity studies with lapatinib, severe skin lesions were seen at the highest doses testedwhich produced exposures based on AUC up to 2-fold in mice and male rats, and up to 15-fold infemale rats, compared to humans given 1250 mg of lapatinib once daily. There was no evidence ofcarcinogenicity in mice. In rats, the incidence of benign haemangioma of the mesenteric lymph nodeswas higher in some groups than in concurrent controls. There was also an increase in renal infarcts andpapillary necrosis in female rats at exposures 7 and 10-fold compared to humans given 1250 mg oflapatinib once daily. The relevance of these findings for humans is uncertain.

There were no effects on male or female rat gonadal function, mating, or fertility at doses up to120 mg/kg/day (females) and up to 180 mg/kg/day (males) (8 and 3 times the expected human clinicalexposure, respectively). The effect on human fertility is unknown.

Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamsterchromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay andan in vivo rat bone marrow chromosome aberration assay.

Microcrystalline cellulose

Povidone (K30)

Sodium starch glycolate (Type A)

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Macrogol (400)

Polysorbate 80

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

Blister packs2 years

Bottles3 years

Do not store above 30ºC.

Tyverb is supplied in either blister packs or bottles.

Blister packs

Tyverb/capecitabine combination posology

Each pack of Tyverb contains 70 film-coated tablets in foil blisters (polyamide/aluminium /polyvinyl chloride/aluminium) of 10 tablets each. Each foil has a perforation down the middle toallow the blisters to be separated into a daily dose of 5 tablets.

Multipacks contain 140 (2 packs of 70) film-coated tablets.

Tyverb/aromatase inhibitor combination posology

Each pack of Tyverb contains 84 film-coated tablets in foil blisters (polyamide/aluminium /polyvinyl chloride/aluminium) of 12 tablets each. Each foil has a perforation down the middle toallow the blisters to be separated into a daily dose of 6 tablets.

Tyverb is also supplied in high density polyethylene bottles (HDPE) with a child resistantpolypropylene closure containing 70, 84, 105 or 140 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/07/440/001-007

Date of first authorisation: 10 June 2008

Date of latest renewal: 19 September 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.