Lapatinib Tablets USP 250mg Taj Pharma

  1. Name of the medicinal product

Lapatinib Tablets USP 250mg Taj Pharma

  1. Qualitative and quantitative composition

Lapatinib Tablets USP 250mg Taj Pharma
Each film-coated tablet contains:
Lapatinib Ditosylate monohydrate USP
Equivalent to Lapatinib 250mg
Excipients: Q.S.
Colours: Titanium Dioxide, Iron oxide of Red, Iron oxide of Yellow,

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet (tablet).

  1. Clinical particulars

4.1 Therapeutic indications

Lapatinib Taj Pharma Tablets USP 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.
  • Posology and method of administration

Lapatinib Taj Pharma Tablets USP 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

Lapatinib Taj Pharma Tablets USP / capecitabine combination posology

The recommended dose of Lapatinib Taj Pharma Tablets USP is 1250mg (i.e. five tablets) once daily continuously.

The recommended dose of capecitabine is 2000mg/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.

Lapatinib Taj Pharma Tablets USP / trastuzumab combination posology

The recommended dose of Lapatinib Taj Pharma Tablets USP is 1000mg (i.e. four tablets) once daily continuously.

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

Lapatinib Taj Pharma Tablets USP / aromatase inhibitor combination posology

The recommended dose of Lapatinib Taj Pharma Tablets USP is 1500mg (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

Lapatinib Taj Pharma Tablets USP 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 Taj Pharma Tablets USP may be restarted at a reduced dose (750mg/day when administered with trastuzumab, 1000mg/day when administered with capecitabine or 1250mg/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

Lapatinib Taj Pharma Tablets USP should be discontinued in patients who experience pulmonary symptoms which are NCI CTCAE grade 3 or greater (see section 4.4).

Diarrhoea

Lapatinib Taj Pharma Tablets USP 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). Lapatinib Taj Pharma Tablets USP may be reintroduced at a lower dose (reduced from 1000mg/day to 750mg/day, from 1250mg/day to 1000mg/day or from 1500mg/day to 1250mg/day) when diarrhoea resolves to grade 1 or less. Lapatinib Taj Pharma Tablets USP dosing should be permanently discontinued in patients with diarrhoea which is NCI CTCAE grade 4.

Other toxicities

Discontinuation or interruption of dosing with Lapatinib Taj Pharma Tablets USP 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 1000mg/day when administered with trastuzumab, 1250mg/day when administered with capecitabine or 1500mg/day when administered with an aromatase inhibitor. If the toxicity recurs, then Lapatinib Taj Pharma Tablets USP should be restarted at a lower dose (750mg/day when administered with trastuzumab, 1000mg/day when administered with capecitabine or 1250mg/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 Lapatinib Taj Pharma Tablets USP in this population (see section 5.2).

Hepatic impairment

Lapatinib Taj Pharma Tablets USP should be discontinued if changes in liver function are severe and patients should not be retreated (see section 4.4).

Administration of Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP / capecitabine and Lapatinib Taj Pharma Tablets USP / trastuzumab in patients aged ≥ 65 years.

In the phase III clinical study of Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP and letrozole were observed between these patients and patients < 65 years of age.

Paediatric population

The safety and efficacy of Lapatinib Taj Pharma Tablets USP in children below the age of 18 years have not yet been established. No data are available.

Method of administration

Lapatinib Taj Pharma Tablets USP is for oral use.

The daily dose of Lapatinib Taj Pharma Tablets USP should not be divided. Lapatinib Taj Pharma Tablets USP 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 Taj Pharma Tablets USP 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.

  • Contraindications

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

  • Special warnings and precautions for use

Data have shown that Lapatinib Taj Pharma Tablets USP combined with chemotherapy is less effective than trastuzumab when combined with chemotherapy.

Cardiac toxicity

Lapatinib Taj Pharma has been associated with reports of decreases in LVEF (see section 4.8). Lapatinib Taj Pharma has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if Lapatinib Taj Pharma Tablets USP is to be administered to patients with conditions that could impair left ventricular function (including co-administration with potentially cardiotoxic medicinal products). Evaluation of cardiac function, including LVEF determination, should be conducted for all patients prior to initiation of treatment with Lapatinib Taj Pharma Tablets USP 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 Taj Pharma Tablets USP 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 Taj Pharma, 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 Taj Pharma. However, when Lapatinib Taj Pharma was administered in combination with trastuzumab in the metastatic setting, the incidence of cardiac events including LVEF decreases was higher (7%) versus the Lapatinib Taj Pharma 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 Taj Pharma.

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 Lapatinib Taj Pharma Tablets USP 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 Taj Pharma, 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 Lapatinib Taj Pharma Tablets USP therapy. When clinically indicated, e.g. after initiation of a concomitant treatment that might affect QT or that may interact with Lapatinib Taj Pharma, ECG measurement should also be considered.

Interstitial lung disease and pneumonitis

Lapatinib Taj Pharma 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 Lapatinib Taj Pharma Tablets USP use and may in rare cases be fatal. The hepatotoxicity may occur days to several months after initiation of treatment. At the initiation of treatment, patients should be advised of the potential for hepatotoxicity. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before the initiation of treatment and monthly thereafter, or as clinically indicated. Lapatinib Taj Pharma Tablets USP dosing should be discontinued if changes in liver function are severe and patients should not be retreated. Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of Lapatinib Taj Pharma Tablets USP-associated hepatotoxicity. In a large, randomised clinical trial of Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP treatment, with almost half of those patients with diarrhoea first experiencing it within 6 days. This usually lasts 4-5 days. Lapatinib Taj Pharma Tablets USP-induced diarrhoea is usually low-grade, with severe diarrhoea of NCI CTCAE grades 3 and 4 occurring in <10% and <1% of patients, respectively. At the start of therapy, the patients bowel pattern and any other symptoms (e.g. fever, cramping pain, nausea, vomiting, dizziness and thirst) should be determined, to allow identification of changes during treatment and to help identify patients at greater risk of diarrhoea. Patients should be instructed to promptly report any change in bowel patterns. In potentially severe cases of diarrhoea the measuring of neutrophil counts and body temperature should be considered. Proactive management of diarrhoea with anti-diarrhoeal medicinal product is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhoea is persistent beyond 24 hours, there is fever, or grade 3 or 4 neutropenia) and interruption or discontinuation of Lapatinib Taj Pharma Tablets USP therapy (see section 4.2 – dose delay and dose reduction –diarrhoea).

Serious cutaneous reactions

Serious cutaneous reactions have been reported with Lapatinib Taj Pharma Tablets USP. 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 Lapatinib Taj Pharma Tablets USP.

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 Taj Pharma (see section 4.5).

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

Grapefruit juice should be avoided during treatment with Lapatinib Taj Pharma Tablets USP (see section 4.5).

Co-administration of Lapatinib Taj Pharma Tablets USP 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 Taj Pharma solubility and absorption may decrease (see section 4.5).

  • Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on Lapatinib Taj Pharma

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

In healthy volunteers receiving ketoconazole, a strong CYP3A4 inhibitor, at 200mg twice daily for 7 days, systemic exposure to Lapatinib Taj Pharma (100mg daily) was increased approximately 3.6–fold, and half-life increased 1.7–fold. Co-administration of Lapatinib Taj Pharma Tablets USP with strong inhibitors of CYP3A4 (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Co-administration of Lapatinib Taj Pharma Tablets USP 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 100mg twice daily for 3 days and 200mg twice daily for 17 days, systemic exposure to Lapatinib Taj Pharma was decreased approximately 72%. Co-administration of Lapatinib Taj Pharma Tablets USP with known inducers of CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum [St John’s Wort]) should be avoided.

Lapatinib Taj Pharma 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 Taj Pharma (see section 5.2).

The solubility of Lapatinib Taj Pharma is pH-dependent. Concomitant treatment with substances that increase gastric pH should be avoided, as Lapatinib Taj Pharma solubility and absorption may decrease. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased Lapatinib Taj Pharma 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 Taj Pharma on other medicinal products

Lapatinib Taj Pharma inhibits CYP3A4 in vitro at clinically relevant concentrations. Co-administration of Lapatinib Taj Pharma Tablets USP with orally administered midazolam resulted in an approximate 45% increase in the AUC of midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed intravenously. Co-administration of Lapatinib Taj Pharma Tablets USP 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 Taj Pharma inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of Lapatinib Taj Pharma Tablets USP 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 Taj Pharma with intravenous paclitaxel increased the exposure of paclitaxel by 23%, due to Lapatinib Taj Pharma 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 Taj Pharma is co-administered with paclitaxel.

Co-administration of Lapatinib Taj Pharma with intravenously administered docetaxel did not significantly affect the AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced neutropenia was increased.

Co-administration of Lapatinib Taj Pharma Tablets USP 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 Taj Pharma. Adverse reactions should be carefully monitored if Lapatinib Taj Pharma Tablets USP is co-administered with irinotecan, and a reduction in the dose of irinotecan should be considered.

Lapatinib Taj Pharma inhibits the transport protein Pgp in vitro at clinically relevant concentrations. Co-administration of Lapatinib Taj Pharma with orally administered digoxin resulted in an approximate 80% increase in the AUC of digoxin. Caution should be exercised when dosing Lapatinib Taj Pharma 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 Taj Pharma 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 Taj Pharma will affect the pharmacokinetics of substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) (see section 5.2).

Concomitant administration of Lapatinib Taj Pharma Tablets USP with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these medicinal products (or the metabolites of capecitabine) or Lapatinib Taj Pharma.

Interactions with food and drink

The bioavailability of Lapatinib Taj Pharma 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 Taj Pharma 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 Taj Pharma and should therefore be avoided during treatment with Lapatinib Taj Pharma Tablets USP.

  • 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 Lapatinib Taj Pharma Tablets USP and for at least 5 days after the last dose.

Pregnancy

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

Lapatinib Taj Pharma Tablets USP should not be used during pregnancy unless clearly necessary.

Breast-feeding

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

Fertility

There are no adequate data from the use of Lapatinib Taj Pharma Tablets USP in women of childbearing potential.

  • Effects on ability to drive and use machines

Lapatinib Taj Pharma Tablets USP 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 Taj Pharma. The clinical status of the patient and the safety profile of Lapatinib Taj Pharma should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor or cognitive skills.

  • Undesirable effects

Summary of the safety profile

The safety of Lapatinib Taj Pharma 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 Taj Pharma in combination with capecitabine, 149 patients who received Lapatinib Taj Pharma in combination with trastuzumab and 654 patients who received Lapatinib Taj Pharma in combination with letrozole (see section 5.1).

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

No additional adverse reactions were reported to be associated with Lapatinib Taj Pharma 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 Taj Pharma 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 Taj Pharma alone or Lapatinib Taj Pharma 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.
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 Taj Pharma was administered in combination with capecitabine.

 These adverse reactions were observed when Lapatinib Taj Pharma 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 Taj Pharma 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 Taj Pharma, and in approximately 40 % of cases Lapatinib Taj Pharma was continued. Symptomatic LVEF decreases were observed in approximately 0.3% of patients who received Lapatinib Taj Pharma 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 Taj Pharma in combination with capecitabine, as compared to 1.0 % with capecitabine alone. LVEF decreases were reported in 3.1 % of patients who received Lapatinib Taj Pharma 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 Taj Pharma in combination with trastuzumab, as compared to 2.1 % of patients who received Lapatinib Taj Pharma 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 Taj Pharma in combination with capecitabine, in 64 % of patients who received Lapatinib Taj Pharma in combination with letrozole and in 62 % of patients who received Lapatinib Taj Pharma in combination with trastuzumab. Most cases of diarrhoea were grade 1 or 2 and did not result in discontinuation of treatment with Lapatinib Taj Pharma. 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 Taj Pharma in combination with capecitabine, in 45 % of patients who received Lapatinib Taj Pharma in combination with letrozole and in 23 % of patients who received Lapatinib Taj Pharma in combination with trastuzumab. Rash was generally low grade and did not result in discontinuation of treatment with Lapatinib Taj Pharma. 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 Taj Pharma-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.

  • Overdose

There is no specific antidote for the inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine phosphorylation. The maximum oral dose of Lapatinib Taj Pharma that has been administered in clinical studies is 1800mg once daily.

Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with Lapatinib Taj Pharma Tablets USP. In patients who took up to 5000mg of Lapatinib Taj Pharma, symptoms observed include known Lapatinib Taj Pharma 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 9000mg of Lapatinib Taj Pharma Tablets USP, sinus tachycardia (with otherwise normal ECG) was also observed.

Lapatinib Taj Pharma 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 Taj Pharma.

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

  1. Pharmacological properties
  • Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents, protein kinase inhibitors.

Mechanism of action

Lapatinib Taj Pharma, 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 Taj Pharma inhibits ErbB-driven tumour cell growth in vitro and in various animal models.

The combination of Lapatinib Taj Pharma and trastuzumab may offer complementary mechanisms of action as well as possible non-overlapping mechanisms of resistance. The growth inhibitory effects of Lapatinib Taj Pharma were evaluated in trastuzumab-conditioned cell lines. Lapatinib Taj Pharma retained significant activity against HER2-amplified breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro and was synergistic in combination with trastuzumab in these cell lines.

Clinical efficacy and safety

Combination treatment with Lapatinib Taj Pharma Tablets USP and capecitabine

The efficacy and safety of Lapatinib Taj Pharma Tablets USP in combination with capecitabine in breast cancer patients with good performance status was evaluated in a randomised, phase III study. Patients eligible for enrolment had HER2-overexpressing, locally advanced or metastatic breast cancer, progressing after prior treatment that included taxanes, anthracyclines and trastuzumab. LVEF was evaluated in all patients (using echocardiogram [Echo] or multi gated acquisition scan [MUGA]) prior to initiation of treatment with Lapatinib Taj Pharma Tablets USP to ensure baseline LVEF was within the institutions normal limits. In the clinical study LVEF was monitored at approximately eight week intervals during treatment with Lapatinib Taj Pharma Tablets USP 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 Lapatinib Taj Pharma Tablets USP 1250mg once daily (continuously) plus capecitabine (2000mg/m2/day on days 1-14 every 21 days), or to receive capecitabine alone (2500mg/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 Taj Pharma Tablets USP 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 end of enrolment is presented in Table 1.

Table 1 Time to progression data from Study EGF100151 (Lapatinib Taj Pharma Tablets USP / capecitabine)

Investigator assessment
Lapatinib Taj Pharma Tablets USP (1250mg/day)+ capecitabine (2000mg/m2/day, days 1-14 q21 days) Capecitabine (2500mg/m2/day, 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 Lapatinib Taj Pharma Tablets USP when given in combination with 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 (Lapatinib Taj Pharma Tablets USP / capecitabine)

Lapatinib Taj Pharma Tablets USP (1250mg/day)+ capecitabine (2000mg/m2/day, days 1-14 q21 days) Capecitabine (2500mg/m2/day, days 1-14 q21 days)
(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.

Data are available on the efficacy and safety of Lapatinib Taj Pharma Tablets USP in combination with capecitabine relative to trastuzumab 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 Lapatinib Taj Pharma Tablets USP 1250mg once daily (continuously) plus capecitabine (2000mg/m2/day on days 1-14 every 21 days), or trastuzumab (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 trastuzumab treatment and number of prior treatments for metastatic disease. The study was halted as the interim analysis (N=475) showed a low incidence of CNS events and, superior efficacy of the trastuzumab plus capecitabine arm in terms of progression-free survival and overall survival (see results of final analysis in Table 3).

In the Lapatinib Taj Pharma Tablets USP 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 Taj Pharma effect on CNS metastasis

Lapatinib Taj Pharma has in terms of objective responses demonstrated modest activity in the treatment of established CNS metastases. In the prevention of CNS metastases in the metastatic and early breast cancer settings the observed activity was limited.

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

Investigator-assessed PFS Overall survival
Lapatinib Taj Pharma Tablets USP (1,250mg/day) + capecitabine (2000mg/m2/day, days 1-14 q21 days) Trastuzumab (loading dose of 8mg/kg followed by 6mg/kg q3 weekly infusions) + capecitabine (2500mg/m2/day, days 1-14 q21 days) Lapatinib Taj Pharma Tablets USP (1,250mg/day) + capecitabine (2000mg/m2/day, days 1-14 q21 days) Trastuzumab (loading dose of 8mg/kg followed by 6mg/kg q3 weekly infusions) + capecitabine (2500mg/m2/day, days 1-14 q21 days)
ITT population
N 271 269 271 269
Number (%) with event1 160 (59) 134 (50) 70 (26) 58 (22)
Kaplan-Meier estimate, months a
Median (95% CI) 6.6 (5.7, 8.1) 8.0 (6.1, 8.9) 22.7 (19.5, -) 27.3 (23.7, -)
Stratified Hazard ratio b
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 (%) with event1 103 (62) 86 (54) 43 (26) 38 (24)
Median (95% CI) 6.6 (5.7, 8.3) 6.1 (5.7, 8.0) 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 (%) with event1 57 (55) 48 (44) 27 (26) 20 (18)
Median (95% CI) 6.3 (5.6, 8.1) 10.9 (8.3, 15.0) 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 or death from any cause, or to the date of censor.

b. Pike estimate of the treatment hazard ratio, <1 indicates a lower risk for Lapatinib Taj Pharma Tablets USP plus capecitabine compared 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 Lapatinib Taj Pharma Tablets USP and trastuzumab

The efficacy and safety of Lapatinib Taj Pharma in combination with trastuzumab in metastatic breast cancer were evaluated in a randomised trial. Eligible patients were women with Stage IV ErbB2 gene amplified (or protein overexpressing) metastatic breast cancer who had been exposed to treatment with anthracyclines and taxanes. In addition, per the protocol, patients were to be reported by the investigators as having progressed on their most recent trastuzumab containing regimen in the metastatic setting. The median number of prior trastuzumab-containing regimens was three. Patients were randomised to receive either oral Lapatinib Taj Pharma 1,000mg once daily plus trastuzumab 4mg/kg administered as an intravenous loading dose, followed by 2mg/kg intravenous weekly (N = 148), or oral Lapatinib Taj Pharma 1500mg once daily (N = 148). Patients who had objective disease progression after receiving at least 4 weeks of treatment with Lapatinib Taj Pharma monotherapy were eligible to crossover to combination therapy. Of the 148 patients who received monotherapy treatment, 77 (52%) patients elected 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 overall survival (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. A summary of efficacy endpoints and overall survival data is provided in Table 4. Subgroup analysis results based on predefined stratification factor (hormone receptor status) is also shown in Table 5.

Table 4 Progression-free survival and overall survival data (Lapatinib Taj Pharma Tablets USP / trastuzumab)

Lapatinib Taj Pharma plus trastuzumab

(N=148)

Lapatinib Taj Pharma alone

(N=148 )

Median PFS1, weeks

(95% CI)

12.0

(8.1, 16.0)

8.1

(7.6, 9.0)

Hazard ratio (95% CI) 0.73 (0.57, 0.93)
P value 0.008
Response rate, %

(95% CI)

10.3

(5.9, 16.4)

6.9

(3.4, 12.3)

Died 105 113
Median overall survival1, months

(95% CI)

14.0

(11.9, 17.2)

9.5

(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 Lapatinib Taj Pharma Tablets USP and letrozole

Lapatinib Taj Pharma Tablets USP has been studied in combination with letrozole for the treatment of postmenopausal women with 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 study enrolled patients who had not received prior therapy for their metastatic disease.

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

Patients were randomised to letrozole 2.5mg once daily plus Lapatinib Taj Pharma Tablets USP 1500mg once daily or letrozole with placebo. Randomisation was stratified by sites of disease and by time from discontinuation of prior adjuvant anti-oestrogen therapy. HER2 receptor status was retrospectively determined by central laboratory testing. Of all patients randomised to treatment, 219 patients had tumours overexpressing the 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 HER2 status 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 Lapatinib Taj Pharma Tablets USP compared with letrozole plus placebo. In the HER2-negative population, there was no benefit in PFS when letrozole plus Lapatinib Taj Pharma Tablets USP was compared with letrozole plus placebo (see Table 6).

Table 6 Progression free survival data from Study EGF30008 (Lapatinib Taj Pharma Tablets USP / letrozole)

HER2-overexpressing population HER2-negative population
N = 111 N = 108 N = 478 N = 474
Lapatinib Taj Pharma Tablets USP 1500mg / day + Letrozole 2.5mg /day Letrozole 2.5mg /day + placebo Lapatinib Taj Pharma Tablets USP 1500mg / day + Letrozole 2.5mg /day Letrozole 2.5mg /day + placebo
Median PFS, weeks (95% CI) 35.4

(24.1, 39.4)

13.0

(12.0, 23.7)

59.7

(48.6, 69.7)

58.3

(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 rate (ORR) 27.9% 14.8% 32.6% 31.6%
Odds ratio 0.4 (0.2, 0.9) 0.9 (0.7, 1.3)
P-value 0.021 0.26
Clinical benefit rate (CBR) 47.7% 28.7% 58.2% 31.6%
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 data were 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-positive population only)

Lapatinib Taj Pharma Tablets USP 1500mg / day + Letrozole 2.5mg /day

N=111

Letrozole 2.5mg /day + placebo

N=108

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 adjusting for important prognostic factors.

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

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

Cardiac electrophysiology

The effect of Lapatinib Taj Pharma on the QT-interval was evaluated in a single-blind, placebo-controlled, single sequence (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 were administered 12 hours apart in the morning and evening on Day 1 and in the morning on Day 2. This was followed by three doses of Lapatinib Taj Pharma 2000mg administered in the same way. Measurements, including electrocardiograms (ECGs) and pharmacokinetic samples, were taken at baseline and at the same 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 Taj Pharma 2000mg. The ΔΔQTcF exceeded the 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 the evaluable population (maximum ΔΔQTcF (90% CI) of 7.91 ms (4.13, 11.68) observed 10 hours after ingestion of the third dose of Lapatinib Taj Pharma 2000mg).

There is a positive relationship between Lapatinib Taj Pharma plasma concentrations and ΔΔQTcF. Lapatinib Taj Pharma produced 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 dosing regimens. An additional increase in peak exposure of Lapatinib Taj Pharma can be expected when Lapatinib Taj Pharma is taken repeatedly with food (see sections 4.2 and 5.2) or concomitantly with strong CYP3A4 inhibitors. When Lapatinib Taj Pharma is taken in combination with strong CYP3A4 inhibitors the QTc interval can be expected to be prolonged by 16.1 ms (12.6-20.3 ms) as demonstrated in a model-based prediction (see section 4.4).

Food effects on Lapatinib Taj Pharma exposure

The bioavailability and thereby the plasma concentrations of Lapatinib Taj Pharma are increased by food, in relation to the content and timing of the meal. Dosing of Lapatinib Taj Pharma one hour after a meal results in approximately 2-3 times higher systemic exposure, compared to dosing one hour before a meal (see sections 4.5 and 5.2).

The European Medicines Agency has waived the obligation to submit the results of studies with Lapatinib Taj Pharma Tablets USP in all subsets of the paediatric population in the treatment of breast carcinoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The absolute bioavailability following oral administration of Lapatinib Taj Pharma is unknown, but it is incomplete and variable (approximately 70% coefficient of variation in AUC). Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of Lapatinib Taj Pharma are achieved approximately 4 hours after administration. Daily dosing of 1250mg produces steady state geometric mean (coefficient of variation) Cmax values of 2.43 (76%) µg/ml and AUC values of 36.2 (79%) µg*hr/ml.

Systemic exposure to Lapatinib Taj Pharma is increased when administered with food. Lapatinib Taj Pharma AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5 and 3–fold higher) when administered with 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 Taj Pharma is also affected by the timing of administration in relation to food intake. Relative to dosing 1 hour before a low fat breakfast, mean AUC values were approximately 2- and 3-fold higher when Lapatinib Taj Pharma was administered 1 hour after a low fat or high fat meal, respectively.

Distribution

Lapatinib Taj Pharma is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that Lapatinib Taj Pharma is a substrate for the transporters BCRP (ABCG1) and p-glycoprotein (ABCB1). Lapatinib Taj Pharma has also been shown in vitro to inhibit these efflux transporters, as well as the hepatic uptake transporter OATP 1B1, at clinically relevant concentrations (IC50 values were equal to 2.3 µg/ml). The clinical significance of these effects on the pharmacokinetics of other medicinal products or the pharmacological activity of other anti-cancer medicinal products is not known.

Biotransformation

Lapatinib Taj Pharma undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which account for more than 14% of the dose recovered in the faeces or 10% of Lapatinib Taj Pharma concentration in plasma.

Lapatinib Taj Pharma inhibits CYP3A (Ki 0.6 to 2.3 µg/ml) and CYP2C8 (0.3 µg/ml) in vitro at clinically relevant concentrations. Lapatinib Taj Pharma did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes (in vitro IC50 values were greater than or equal to 6.9 µg/ml).

Elimination

The half-life of Lapatinib Taj Pharma measured after single doses increases with increasing dose. However, daily dosing of Lapatinib Taj Pharma results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours. Lapatinib Taj Pharma is predominantly eliminated through metabolism by CYP3A4/5. Biliary excretion may also contribute to the elimination. The primary route of excretion for Lapatinib Taj Pharma and its metabolites is in faeces. Recovery of unchanged Lapatinib Taj Pharma 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 Taj Pharma and metabolites) excreted in urine.

Renal impairment

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

Hepatic impairment

The pharmacokinetics of Lapatinib Taj Pharma 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 control patients. Systemic exposure (AUC) to Lapatinib Taj Pharma after a single oral 100mg dose increased approximately 56% and 85% in patients with moderate and severe hepatic impairment, respectively. Administration of Lapatinib Taj Pharma in patients with hepatic impairment should be undertaken with caution (see sections 4.2 and 4.4).

5.3 Preclinical safety data

Lapatinib Taj Pharma was studied in pregnant rats and rabbits given oral doses of 30, 60, and 120mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib and precocious ossification) occurred in rats at ≥60mg/kg/day (4 times the expected human clinical exposure). In rabbits, Lapatinib Taj Pharma was associated with maternal toxicity at 60 and 120mg/kg/day (8% and 23% of the expected human clinical exposure, respectively) and abortions at 120mg/kg/day. At ≥60mg/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 60mg/kg/day or higher (5 times the expected human clinical exposure). The highest no-effect dose for this study was 20mg/kg/day.

In oral carcinogenicity studies with Lapatinib Taj Pharma, severe skin lesions were seen at the highest doses tested which produced exposures based on AUC up to 2-fold in mice and male rats, and up to 15-fold in female rats, compared to humans given 1250mg of Lapatinib Taj Pharma once daily. There was no evidence of carcinogenicity in mice. In rats, the incidence of benign haemangioma of the mesenteric lymph nodes was higher in some groups than in concurrent controls. There was also an increase in renal infarcts and papillary necrosis in female rats at exposures 7 and 10-fold compared to humans given 1250mg of Lapatinib Taj Pharma 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 to 120mg/kg/day (females) and up to 180mg/kg/day (males) (8 and 3 times the expected human clinical exposure, respectively). The effect on human fertility is unknown.

Lapatinib Taj Pharma 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.

  1. Pharmaceutical particulars

6.1. List of excipients

Tablet core

Microcrystalline cellulose, Povidone (K30), Sodium starch glycolate (Type A), Magnesium stearate

Tablet coating

Hypromellose, Titanium dioxide , Macrogol (400), Polysorbate 80, Iron oxide yellow, Iron oxide red

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister packs

2 years

Bottles

3 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Lapatinib Taj Pharma Tablets USP is supplied in either blister packs or bottles.

Blister packs
Each pack contains 5, 10, 15, 30, 40, 60 film-coated Tablets.
Each box contains 30, 60, 120, 240, 360 and 500 film-coated tablets.

Lapatinib Taj Pharma Tablets USP / aromatase inhibitor combination posology

Bottles

Lapatinib Taj Pharma Tablets USP is also supplied in high density polyethylene bottles (HDPE) with a child resistant polypropylene closure containing 70, 84, 105, 140, 360 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

Lapatinib Tablets USP 250mg Taj Pharma
(film-coated tablets)

Package leaflet: Information for the user

Lapatinib Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Don’t pass it on to others. It may harm them, even if their signs of illness seem the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Lapatinib Taj Pharma Tablets USP is and what it is used for
  2. What you need to know before you take Lapatinib Taj Pharma Tablets USP
  3. How to take Lapatinib Taj Pharma Tablets USP
  4. Possible side effects
  5. How to store Lapatinib Taj Pharma Tablets USP
  6. Contents of the pack and other information

1.What Lapatinib Taj Pharma Tablets USP is and what it is used for

Lapatinib Taj Pharma Tablets USP is used to treat certain types of breast cancer (HER2-overexpressing) which have spread beyond the original tumour or to other organs (advanced or metastatic breast cancer). It may slow or stop cancer cells from growing, or may kill them.

Lapatinib Taj Pharma Tablets USP is prescribed to be taken in combination with another anti-cancer medicine.

Lapatinib Taj Pharma Tablets USP is prescribed in combination with capecitabine, for patients who have had treatment for advanced or metastatic breast cancer before. This previous treatment for metastatic breast cancer must have included trastuzumab.

Lapatinib Taj Pharma Tablets USP is prescribed in combination with trastuzumab, for patients who have hormone receptornegative metastatic breast cancer and have had other treatment for advanced or metastatic breast cancer before.

Lapatinib Taj Pharma Tablets USP is prescribed in combination with an aromatase inhibitor, for patients with hormone sensitive metastatic breast cancer (breast cancer that is more likely to grow in the presence of hormones), who are not currently intended for chemotherapy.

Information about these medicines is described in separate patient information leaflets. Ask your doctor to give you information about these other medicines.

  1. What you need to know before you take Lapatinib Taj Pharma Tablets USP

Do not take Lapatinib Taj Pharma Tablets USP

 if you are allergic to Lapatinib Taj Pharma or any of the other ingredients of this medicine (listed in Section 6).

Take special care with Lapatinib Taj Pharma Tablets USP

Your doctor will run tests to check that your heart is working properly before and during your treatment with Lapatinib Taj Pharma Tablets USP.

Tell your doctor if you have any heart problems before you take Lapatinib Taj Pharma Tablets USP.

Your doctor also needs to know before you take Lapatinib Taj Pharma Tablets USP:

  • if you have lung disease
  • if you have inflammation of the lung
  • if you have any liver problems
  • if you have any kidney problems
  • if you have diarrhoea (see section 4).

Your doctor will run tests to check that your liver is working properly before and during your treatment with Lapatinib Taj Pharma Tablets USP.

Tell your doctor if any of these apply to you.

Serious skin reactions

Serious skin reactions have been seen with Lapatinib Taj Pharma Tablets USP. Symptoms may include skin rash, blisters and skin peeling.

Tell your doctor as soon as possible if you get any of these symptoms.

Other medicines and Lapatinib Taj Pharma Tablets USP

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes herbal medicines and other medicines you bought without a prescription.

It is especially important to tell your doctor if you are taking, or have recently taken any of the following medicines. Some medicines may affect the way Lapatinib Taj Pharma Tablets USP works or Lapatinib Taj Pharma Tablets USP may affect how other medicines work. These medicines include some medicines in the following groups:

  • St John’s Wort – a herb extract used to treat depression
  • erythromycin, ketoconazole, itraconazole, posaconazole, voriconazole, rifabutin, rifampicin, telithromycin – medicines used to treat infections
  • cyclosporine – a medicine used to suppress the immune system for example after organ transplantations
  • ritonavir, saquinavir – medicines used to treat HIV
  • phenytoin, carbamazepine – medicines used to treat seizures
  • cisapride – a medicine used to treat certain digestive system problems
  • pimozide – a medicine used to treat certain mental health problems
  • quinidine, digoxin – medicines used to treat certain heart problems
  • repaglinide – a medicine used to treat diabetes
  • verapamil – a medicine used to treat high blood pressure or heart problems (angina)
  • nefazodone – a medicine used to treat depression
  • topotecan, paclitaxel, irinotecan, docetaxel – medicines used to treat certain types of cancer
  • rosuvastatin – a medicine used to treat high cholesterol
  • medicines that decrease stomach acidity – used to treat stomach ulcers or indigestion

Tell your doctor if you are taking, or have recently taken, any of these.

Your doctor will review the medicines you are currently taking to make sure you are not taking something that can’t be taken with the Lapatinib Taj Pharma Tablets USP. Your doctor will advise you whether an alternative is available.

Lapatinib Taj Pharma Tablets USP with food and drink

Don’t drink grapefruit juice while you are being treated with Lapatinib Taj Pharma Tablets USP. It can affect the way the medicine works.

Pregnancy and breast-feeding

The effect of Lapatinib Taj Pharma Tablets USP during pregnancy is not known. You should not use Lapatinib Taj Pharma Tablets USP if you are pregnant unless your doctor specifically recommends it.

 If you are pregnant or planning to become pregnant, tell your doctor.

 Use a reliable method of contraception to avoid becoming pregnant while you’re taking Lapatinib Taj Pharma Tablets USP and for at least 5 days after the last dose.

 If you become pregnant during treatment with Lapatinib Taj Pharma Tablets USP, tell your doctor.

It is not known whether Lapatinib Taj Pharma Tablets USP passes into breast-milk. Do not breast-feed while taking Lapatinib Taj Pharma Tablets USP and for at least 5 days after the last dose.

 If you are breast-feeding or planning to breast-feed, tell your doctor.

Ask your doctor or pharmacist for advice before taking Lapatinib Taj Pharma Tablets USP if you are unsure.

Driving and using machines

You are responsible to decide if you are able to drive a motor vehicle or perform other tasks that require increased concentration. Because of the possible side effects of Lapatinib Taj Pharma Tablets USP, your ability to drive or operate machines could be affected. These effects are described in section 4, ‘Possible side effects’.

  1. How to take Lapatinib Taj Pharma Tablets USP

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you’re not sure.

Your doctor will decide on the correct dose of Lapatinib Taj Pharma Tablets USP depending on the type of breast cancer being treated.

If you are prescribed Lapatinib Taj Pharma Tablets USP in combination with capecitabine, the usual dose is 5 Lapatinib Taj Pharma Tablets USP tablets a day, as a single dose.

If you are prescribed Lapatinib Taj Pharma Tablets USP in combination with trastuzumab, the usual dose is 4 Lapatinib Taj Pharma Tablets USP tablets a day, as a single dose.

If you are prescribed Lapatinib Taj Pharma Tablets USP in combination with an aromatase inhibitor, the usual dose is 6 Lapatinib Taj Pharma Tablets USP tablets a day, as a single dose.

Take the prescribed dose every day for as long as your doctor tells you to.

Your doctor will advise you about the dose of your other anti-cancer medicine, and how to take it.

Taking your tablets

  • Swallow the tablets whole with water, one after the other, at the same time each day.
  • Take Lapatinib Taj Pharma Tablets USP either at least one hour before or at least one hour after food. Take Lapatinib Taj Pharma Tablets USP at the same time in relation to food each day – for example, you could always take your tablet one hour before breakfast.

While you are taking Lapatinib Taj Pharma Tablets USP

  • Depending on the side effects you experience, your doctor may recommend lowering your dose or temporarily stopping your treatment.
  • Your doctor will also carry out tests to check your heart and liver function before and during treatment with Lapatinib Taj Pharma Tablets USP.

If you take too much Lapatinib Taj Pharma Tablets USP

Contact a doctor or pharmacist immediately. If possible, show them the pack.

If you forget to take Lapatinib Taj Pharma Tablets USP

Don’t take a double dose to make up for a forgotten dose. Just take the next dose at the scheduled time.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

A severe allergic reaction is a rare side effect (may affect up to 1 in 1,000 people) and may develop rapidly.

Symptoms may include:

  • skin rash (including itchy, bumpy rash)
  • unusual wheezing, or difficulty in breathing
  • swollen eyelids, lips or tongue
  • pains in muscles or joints
  • collapse or blackout.

Tell your doctor immediately if you get any of these symptoms. Don’t take any more tablets.

Very common side effects (may affect more than 1 in 10 people):

  • diarrhoea (which may make you dehydrated and lead to more severe complications)

Tell your doctor immediately at the first sign of diarrhoea (loose stool), as it is important that this is treated right away. Also tell your doctor immediately if your diarrhoea worsens. There is more advice on reducing the risk of diarrhoea at the end of section 4.

  • rash, dry skin, itching

Tell your doctor if you get a skin rash. There is more advice on reducing the risk of skin rash at the end of section 4.

Other very common side effects

  • loss of appetite
  • feeling sick (nausea)
  • being sick (vomiting)
  • tiredness, feeling weak
  • indigestion
  • constipation
  • sore mouth/mouth ulcers
  • stomach pain
  • trouble sleeping
  • back pain
  • pain in hands and feet
  • joint or back pain
  • a skin reaction on the palms of the hands or soles of the feet (including tingling, numbness, pain, swelling or reddening)
  • cough, shortness of breath
  • headache
  • nose bleed
  • hot flush
  • unusual hair loss or thinning

Tell your doctor if any of these side effects get severe or troublesome.

Common side effects (may affect up to 1 in 10 people):

  • an effect on how your heart works

In most cases, the effect on your heart will not have any symptoms. If you do experience symptoms associated with this side effect, these are likely to include an irregular heartbeat and shortness of breath.

  • liver problems, which may cause itching, yellow eyes or skin (jaundice), or dark urine or pain or discomfort in the right upper area of the stomach.
  • nail disorders – such as a tender infection and swelling of the cuticles

Tell your doctor if you get any of these symptoms.

Uncommon side effects (may affect up to 1 in 100 people):

  • treatment-induced lung inflammation, which may cause shortness of breath or cough

Tell your doctor immediately if you get either of these symptoms.

Other uncommon side effects include:

  • blood tests results that show changes in liver function (usually mild and temporary)

Rare side effects (may affect up to 1 in 1,000 people):

  • severe allergic reactions (see the beginning of section 4)

The frequency of some side effects is not known (it cannot be estimated from the available data):

  • irregular heart-beat (change in the electrical activity of the heart)
  • severe skin reaction that might include: rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever or any combination of these
  • pulmonary arterial hypertension (increased blood pressure in the arteries (blood vessels) of the lungs)

If you get other side effects

Tell your doctor or pharmacist if you notice any side effects not listed in this leaflet.

Reducing the risk of diarrhoea and skin rash

Lapatinib Taj Pharma Tablets USP can cause severe diarrhoea

If you suffer from diarrhoea while taking Lapatinib Taj Pharma Tablets USP:

  • drink plenty of fluids (8 to 10 glasses a day), such as water, sports drinks or other clear liquids
  • eat low-fat, high protein foods instead of fatty or spicy foods
  • eat cooked vegetables instead of raw vegetables and remove the skin from fruits before eating
  • avoid milk and milk products (including ice cream)
  • avoid herbal supplements (some may cause diarrhoea).

Tell your doctor if your diarrhoea continues.

Lapatinib Taj Pharma Tablets USP can cause skin rash

Your doctor will check your skin before and during treatment.

To care for sensitive skin:

  • wash with a soap-free cleanser
  • use fragrance free, hypoallergenic beauty products
  • Use sunscreen (Sun Protection Factor [SPF] 30 or higher).

Tell your doctor if you get a skin rash.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

  1. How to store Lapatinib Taj Pharma Tablets USP

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister or bottle and the carton.

Do not store above 30ºC.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

  1. Contents of the pack and other information

What Lapatinib Taj Pharma Tablets USP contains

  • The active substance in Lapatinib Taj Pharma Tablets USP is Lapatinib Taj Pharma. Each film-coated tablet contains Lapatinib Taj Pharma ditosylate monohydrate, equivalent to 250mg Lapatinib Taj Pharma.
  • The other ingredients are: microcrystalline cellulose, povidone (K30), sodium starch glycolate (Type A), magnesium stearate, hypromellose, titanium dioxide, macrogol (400), polysorbate 80, iron oxide yellow, and iron oxide red.

What Lapatinib Taj Pharma Tablets USP looks like and contents of the pack

Lapatinib Taj Pharma Tablets USP is supplied in either blisters packs or bottles:

Blister packs

Each pack contains 5, 10, 15, 30, 40, 60 film-coated Tablets.
Each box contains 30, 60, 120, 240, 360 and 500 film-coated tablets.

Bottles

Lapatinib Taj Pharma Tablets USP is also supplied in high density polyethylene bottles (HDPE) with a child resistant polypropylene closure containing 70, 84, 105, 140, 360 and 500 film-coated tablets.

Not all pack sizes may be marketed.

Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)