Tykerb

Tykerb

lapatinib

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Lapatinib ditosylate monohydrate.
Description
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to lapatinib 250 mg. It also contains the following excipients: Microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, macrogol/PEG 400, polysorbate 80, yellow iron oxide, red iron oxide.
Action
ATC Code: L01XE07.
Pharmacology: Pharmacodynamics: Mechanism of Action: Lapatinib is a novel 4-anilinoquinazoline kinase inhibitor with a unique mechanism of action since it is a potent, reversible and selective inhibitor of the intracellular tyrosine kinase domains of both ErbB1 and ErbB2 receptors (estimated Ki(app) values of 3 nanomolar and 13 nanomolar, respectively) with a slow off-rate from these receptors (half-life ≥300 min). This dissociation rate was found to be slower than other 4-anilinoquinazoline kinase inhibitors studied. Lapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models.
In addition to its activity as a single agent, an additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumour cell lines tested. The clinical significance of these in vitro data is unknown.
The combination of lapatinib and trastuzumab may offer complementary mechanisms of action as well as possible non-overlapping mechanisms of resistance. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib 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. These findings suggest noncross-resistance between these 2 ErbB2-directed agents.
Hormone sensitive breast cancer cells [estrogen receptor- (ER) positive and/or progesterone receptor- (PgR) positive] that co-express ErbB2 tend to become resistant to established hormone therapies. Hormone sensitive breast cancer cells initially lack ErbB1 or ErbB2 will up regulate these receptors as the tumour becomes resistant to hormone therapy. Randomised trials in hormone sensitive metastatic breast cancer (MBC) indicate that an ErbB2 or ErbB1 tyrosine kinase inhibitor may potentially improve clinical efficacy when added to hormone therapy.
Clinical Studies: Data have shown that in some settings, Tykerb is less effective than trastuzumab-based treatment regimens. See details as follows.
Combination Treatment with Tykerb and Capecitabine: The efficacy and safety of Tykerb in combination with capecitabine in breast cancer was evaluated in a randomised trial. Patients eligible for enrollment had ErbB2 over-expressing [immunohistochemistry (IHC) 3+ or IHC 2+ and fluorescent in-situ hybridization (FISH) positive], locally advanced or MBC, progressing after prior treatment that included taxanes, anthracyclines and trastuzumab. Left ventricular ejection fraction (LVEF) was evaluated in all patients [using echocardiogram or multigated acquisition scan (MUGA)] prior to initiation of treatment with Tykerb to ensure baseline LVEF was within the institutions normal limits. In clinical trials, LVEF was monitored at approximately 8-week intervals during treatment with lapatinib to ensure it did not decline to below the institutions lower limit of normal. The majority of LVEF decreases (>60% of events) were observed during the first 9 weeks of treatment; however, limited data was available for long-term exposure.
Patients were randomised to receive either Tykerb 1250 mg once daily (continuously) plus capecitabine (2000 mg/m2/day on days 1-14 every 21 days), or to receive capecitabine alone (2500 mg/m2/day on days 1-14 every 21 days). Study treatment was given until disease progression, or withdrawal for another reason. The primary endpoint was time to progression (TTP) and results presented below are based on review by an independent review panel.
A prespecified interim analysis was conducted with a data cutoff of 15 November 2005. This analysis showed an improvement in TTP (51% reduction in the hazard of achieving progression) for patients receiving Tykerb plus capecitabine, compared to capecitabine alone. (See Table 1.)
Key Efficacy Data from Interim Analysis of Study EGF100151 (Tykerb+capecitabine).

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A subsequent analysis was conducted with a data cut-off of 03 April 2006 (the date at which further enrollment was halted). At this time a, total of 399 patients had been enrolled (198 to the combination arm, 201 to the control arm). Analysis by an independent review panel confirmed an improvement in TTP, with a 43% reduction in the hazard of achieving progression for patients receiving Tykerb plus capecitabine, compared to capecitabine alone (p=0.00013). Median TTP was 27.1 and 18.6 weeks, overall response was 23.7% and 13.9%, median duration of response was 32.1 and 30.6 weeks for the Tykerb plus capecitabine and capecitabine alone arms, respectively.
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, as assessed by an independent review panel.
At the time enrollment was halted to EGF100151 (03 April 2006), 399 patients were randomised to study therapy and 9 other patients were being screened. All 9 patients in screening, and all those already receiving capecitabine monotherapy, were offered combination treatment. In total, 207 patients were assigned to the combination therapy and 201 patients were assigned to capecitabine monotherapy.
An analysis of survival data to 01 October 2008 is summarised (see Table 2).

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After the study was halted, 36 patients crossed over from capecitabine to Tykerb ± capecitabine, of whom 26 crossed over prior to disease progression while on capecitabine alone. To isolate the treatment effect in the presence of crossover, Cox regression analysis considering crossover as a time-dependent covariate and treatment effect was performed. The results from this analysis suggest a clinically relevant reduction in risk of death by 20%, with a treatment effect hazard ratio of 0.8 [95% confidence interval (CI): 0.64, 0.99; p=0.043].
Data from pre-planned interim analysis (N=475) are available on the efficacy and safety of Tykerb in combination with capecitabine relative to trastuzumab in combination with capecitabine. A randomized phase III study (EGF111438) comparing the effect of the 2 regimens on the incidence of CNS as site of 1st relapse in women with HER2-positive MBC  was stopped early. There was a low incidence of CNS events, 2.8% in the Tykerb-containing arm compared with 3.7% in the trastuzumab-containing arm, odds ratio (95% CI) is 0.75 (0.25, 2.2) and superior efficacy of the trastuzumab plus capecitabine arm in terms of progression-free survival (PFS) {median PFS was 6.6 months in the Tykerb-containing arm compared with 8 months in the trastuzumab-containing arm [HR=1.3 (95% CI: 1, 1.7)]}. At the time of the interim analysis, the median overall survival (OS) in the Tykerb plus capecitabine arm was lower than in the trastuzumab plus capecitabine arm [HR=1.58 (95% CI: 1.07, 2.32].
Combination Treatment with Tykerb and Paclitaxel: The efficacy and safety of Tykerb in combination with paclitaxel in breast cancer were evaluated in a randomised trial. Patients had histologically confirmed invasive breast cancer (stage IV disease) tumours with human epidermal growth factor receptor 2 (HER2) overexpression (documented by IHC or FISH) and had not received prior therapy for metastatic disease (EGF 104535).
Patients were randomly assigned to paclitaxel (80 mg/m2 IV on days 1, 8 and 15 of a 28-day schedule) and either Tykerb 1500 mg/day or placebo once daily. Patients received a minimum of 6 cycles of Tykerb plus paclitaxel. After the 6 cycles of combination with paclitaxel were completed, patients continued on Tykerb or placebo until disease progression or an unacceptable toxicity occurred. The primary endpoint was OS. Four hundred forty-four (444) patients were enrolled in this study. Of the 222 patients who were on paclitaxel plusplacebo, 149 patients (67%) with disease progression entered the open-label extension phase of the study and received Tykerb monotherapy. The median age was 50 years and 7% were older than 65 years. Eighty-six percent (86%) were Asian, 8% Hispanic and 5% Caucasian. The OS data are summarised (see Table 3).

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A summary of other efficacy endpoints are provided (see Table 4).

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Another randomised, double-blind, controlled study (EGF 30001) evaluated Tykerb and paclitaxel as 1st-line therapy for MBC in patients with negative or untested ErbB2 status and previously untreated in the metastatic setting. Patients (N=579) were randomly assigned 1:1 to paclitaxel (175 mg/m2 IV over 3 hrs on day 1, every 3 weeks) and either Tykerb 1500 mg/day or placebo once daily. Sixty four percent (64%) were Caucasian, 18% Hispanic and 11% Asian. There were 91 patients (16%) with HER2-positive disease. The primary endpoint was TTP; secondary endpoints included PFS, tumour response rate (RR), clinical benefit rate (CBR), OS and safety. No significant differences in TTP or PFS were observed between treatment arms in unselected intent-to-treat (ITT) population. The median PFS in HER2-positive subgroup was 34.4 weeks (95% CI: 32.1, 41.6) in the Tykerb plus paclitaxel combination compared to 22.6 weeks (95% CI: 20.1, 32.9) in the paclitaxel plus placebo group (hazard ratio of 0.56; 95% CI: 0.34, 0.9; p=0.007). The OS analysis of the ITT population and HER2-positive subgroup are presented (see Table 5).

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Data from a pre-planned interim analysis are available on the efficacy and safety of Tykerb plus taxane, relative to trastuzumab plus taxane. A randomized phase III study (EGF108919) (N=636) comparing the activity of Tykerb plus taxane, followed by Tykerb alone versus trastuzumab plus taxane, followed by trastuzumab as 1st line therapy for women with HER2-positive MBC was stopped early due to superior efficacy of trastuzumab plus taxane in terms of PFS. Results from the interim analysis showed that while the PFS in the Tykerb-containing arm was consistent with a previous study (ie, EGF104535), it was lower than in the trastuzumab-containing arm (median PFS was 8.8 months in the Tykerb-containing arm compared with 11.4 months in the trastuzumab-containing arm; HR=1.33; 95% CI 1.06-1.67, p=0.01). The hazard ratio for OS was 1.1 (95% CI 0.75-1.61; p=0.62) based on 18% (n=115) deaths.
Combination Treatment with Tykerb and Trastuzumab: The efficacy and safety of Tykerb in combination with trastuzumab in MBC were evaluated in a randomized trial. Eligible patients were women with stage IV ErbB2 gene-amplified (or protein overexpressing) MBC 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 in the metastatic setting was 3.
Patients were randomized to receive either oral Tykerb 1000 mg once daily plus trastuzumab 4 mg/kg administered as an IV loading dose, followed by 2 mg/kg IV weekly (N=148), or oral Tykerb 1500 mg once daily (N=148). Patients who had objective disease progression after receiving at least 4 weeks of treatment with Tykerb 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.
The primary objective of this study was to evaluate and compare PFS in patients with MBC treated with Tykerb and trastuzumab compared with Tykerb monotherapy. Other secondary objectives were to evaluate and compare the 2 treatment arms with respect to OS, overall tumor RR, clinical benefit response rate and time to response.
The median age was 51 years and 13% were ≥65 years. Ninety-four percent (94%) were Caucasian. Most patients in both treatment arms had visceral disease [215 (73%) patients overall]. In addition, half of the patients in the study population were ER-negative and PgR-negative [150 (51%) patients overall]. A summary of efficacy endpoints is provided in Table 6 and OS data in Table 7. (See Table 6 and 7.)

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In another supportive randomized study in patients with HER2-positive primary breast cancer, the efficacy and safety of neoadjuvant Tykerb combined with trastuzumab and paclitaxel versus trastuzumab and paclitaxel, versus Tykerb and paclitaxel were studied. The primary endpoint of this study was to evaluate and compare the rate of pathological complete response (pCR) (defined as no invasive cancer in the breast or only noninvasive in situ cancer in the breast) at the time of surgery. A summary of efficacy data is provided in Table 8. (See Table 8.)

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Combination Treatment with Tykerb and Letrozole: Tykerb has been studied in combination with letrozole for the treatment of advanced or MBC in hormone receptor-positive (ER-positive and/or PgR-positive) postmenopausal women.
EGF30008 was a randomised, double-blind, controlled trial in patients with hormone receptor-positive (HR+) locally advanced or MBC, who had not received prior systemic therapy for their metastatic disease. One thousand two hundred eighty six (1286) patients were randomised to letrozole 2.5 mg once daily plus Tykerb 1500 mg once daily or letrozole with placebo. Randomisation was stratified by sites of disease and prior adjuvant antioestrogen therapy. ErbB2 receptor status was retrospectively determined by central laboratory testing. Of all patients randomised to treatment, 219 patients had tumours overexpressing the ErbB2 receptor (the 'ErbB2-positive population'), which was the prespecified primary population for the analysis of efficacy. There were 952 ErbB2-negative patients and a total of 115 patients whose ErbB2 status was unconfirmed.
In the ErbB2-positive population, investigator-determined PFS was significantly greater with letrozole plus Tykerb compared with letrozole plus placebo (see Table 9).

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The benefit of Tykerb plus  letrozole on PFS in the ErbB2-positive population was confirmed in a pre-planned Cox regression analysis [HR=0.65 (95% CI 0.47-0.89) p=0.008]. In addition to a PFS benefit seen in the ErbB2-positive population, combination therapy of Tykerb and letrozole offered an improvement in ORR compared with letrozole treatment alone (27.9% and 14.8%, respectively) and in CBR (47.7% and 28.7%, respectively). Although not yet mature, a trend toward a survival benefit was noted for the Tykerb and letrozole combination, HR=0.77 (95% CI 0.52-1.14) p=0.185.
In the ITT population, investigator-determined PFS was greater between the 2 treatment arms (see Table 6). Although, statistically significant, the difference was not considered clinically relevant.
In the ErbB2-negative population (n=952), the Kaplan-Meier analyses for PFS did not show a significant difference between the 2 treatment arms (see Table 8). However, the pre-planned Cox regression model taking into account a number of baseline covariates for PFS did show an improvement with the Tykerb and letrozole combination in ErbB2-negative population. [HR=0.77 (95% CI 0.64-0.94) p=0.01]. In addition, age, performance status, baseline serum ErbB2 ECD, number of metastatic sites and prior adjuvant antioestrogen stratification were identified as being significant prognostic factors.
Growth factor receptor upregulation occurs with oestrogen therapy resistance. Therefore, the treatment effect in the predefined trial strata of prior hormone therapy was further analysed (<6 months since discontinuation of hormone therapy and ≥6 months since discontinuation of hormone therapy or never having received hormone therapy). Table 10 as follows, describes the PFS in these 2 subgroups of ErbB2-negative population. In addition to the PFS benefit of Tykerb and letrozole therapy in the <6 months stratum, a benefit in CBR was also noted when compared with letrozole treatment alone (43.8% and 31.7%, respectively). (See Table 10.)

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Pharmacokinetics: Absorption: Absorption following oral administration of lapatinib is incomplete and variable (approximately 50-100% coefficient of variation in AUC). Serum concentrations appear after a median lag time of 0.25 hrs (range 0-1.5 hrs). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hrs after administration. Daily dosing of 1250 mg produces steady-state geometric mean (95% CI) Cmax values of 2.43 (1.57-3.77) mcg/mL and AUC values of 36.2 (23.4-56) mcg·hr/mL.
Systemic exposure to lapatinib is increased when administered with food (see Dosage & Administration and Interactions). Lapatinib 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 (1000 calories)] meal, respectively.
Distribution: Lapatinib is highly bound (>99%) to albumin and α1-acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer resistance protein (BCRP, ABCG2) and p-glycoprotein (Pgp, ABCB1). Lapatinib has also been shown to inhibit Pgp (IC50 2.3 mcg/mL), BCRP (IC50 0.014 mcg/mL) and the hepatic uptake transporter organic anion-transporting polypeptide (OATP) 1B1 (IC50 2.3 mcg/mL), in vitro, at clinically relevant concentrations. The clinical significance of these effects on the pharmacokinetics of other drugs or the pharmacological activity of other anticancer agents is not known. Lapatinib does not significantly inhibit the OAT or organic cation-transporter (OCT) renal transporters (in vitro IC50 values were ≥6.9 mcg/mL).
Metabolism: Lapatinib 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 >14% of the dose recovered in the faeces or 10% of lapatinib concentration in plasma.
Lapatinib inhibits CYP3A (Ki 0.6-2.3 mcg/mL) and CYP2C8 (0.3 mcg/mL) in vitro at clinically relevant concentrations. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6 or UGT enzymes (in vitro IC50 values were ≥6.9 mcg/mL).
In healthy volunteers receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure to lapatinib was increased approximately 3.6-fold, and half-life increased by 1.7-fold.
In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased by approximately 72%.
Elimination: The half-life of lapatinib measured after single doses increases with increasing dose. However, daily dosing of lapatinib results in achievement of steady state within 6-7 days, indicating an effective half-life of 24 hrs. Lapatinib is predominantly eliminated through metabolism by CYP3A4/5. The primary route of elimination for lapatinib and its metabolites is in faeces, with <2% of the dose (as lapatinib and metabolites) excreted in urine. Recovery of lapatinib in faeces accounts for a median 27% (range 3-67%) of an oral dose.
Special Patient Populations: Renal Impairment: Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing haemodialysis. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that <2% of an administered dose (as unchanged lapatinib and metabolites) is eliminated by the kidneys.
Hepatic Impairment: The pharmacokinetics of lapatinib were examined in subjects with moderate (n=8) or severe (n=4) hepatic impairment and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100-mg dose increased approximately 56% and 85% in subjects with moderate and severe hepatic impairment, respectively. Administration of Tykerb in patients with hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction is recommended for patients with severe preexisting hepatic impairment. In patients who develop severe hepatotoxicity while on therapy, Tykerb should be discontinued and patients should not be retreated with Tykerb (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: Lapatinib was studied in pregnant rats and rabbits given oral doses of 30, 60 and 120 mg/kg/day. There were no teratogenic effects, however, minor anomalies (left-sided umbilical artery, cervical rib and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (6.4 times the expected clinical exposure in humans given lapatinib 1250 mg and capecitabine 2000 mg/m2). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (6.5% and 19% of the expected clinical exposure in humans given lapatinib 1250 mg and capecitabine 2000 mg/m2, respectively) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased foetal body weights and minor skeletal variations. In the rat pre- and postnatal development study, a decrease in pup survival occurred between birth and postnatal day 21 at doses of ≥60 mg/kg/day (3.3 times the expected clinical exposure in humans given lapatinib 1250 mg and capecitabine 2000 mg/m2). The highest no-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 tested which produced exposures based on AUC up to 1.7-fold in mice and male rats, and up to 12-fold in female rats, compared to humans given lapatinib 1250 mg and capecitabine 2000 mg/m2. 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, but was within background range. There was also an increase in renal infarcts and papillary necrosis in female rats at exposures 6- and 8-fold compared to humans given lapatinib 1250 mg and capecitabine 2000 mg/m2. The relevance of these findings for humans is uncertain.
Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay. There were no effects on male or female rat gonadal function, mating or fertility at doses up to 120 mg/kg/day (females) and up to 180 mg/kg/day (males) (8 and 3 times the expected human clinical exposure, respectively). The effect on human fertility is unknown.
Indications/Uses
Tykerb, in combination with capecitabine, is indicated for the treatment of patients with advanced or metastatic breast cancer (MBC) whose tumours overexpress ErbB2 (HER2+/neu) and whose tumour have progressed after treatment with trastuzumab (see Pharmacology: Clinical Studies under Actions).
In combination with trastuzumab, is indicated for the treatment of patients with MBC whose tumours overexpress ErbB2 (HER2/neu) and whose tumour have progressed after treatment with trastuzumab therapy(s) in the metastatic setting and for whom trastuzumab is not appropriate (see Pharmacology: Clinical Studies under Actions).
In combination with paclitaxel, is indicated for the 1st line treatment of patients with MBC whose tumours overexpress ErbB2 (HER2/neu) and for whom trastuzumab is not appropriate (see Pharmacology: Clinical Studies under Actions).
In combination with an aromatase inhibitor, is indicated for the treatment of postmenopausal women with hormone receptor-positive, ErbB2 (HER2/neu) overexpressing advanced or MBC, and for whom hormone therapy is indicated (see Pharmacology: Clinical Studies under Actions).
Dosage/Direction for Use
Tykerb treatment should only be initiated by a physician experienced in the administration of anticancer agents.
Prior to the initiation of treatment, LVEF must be evaluated to ensure that the baseline LVEF is within the institutional limits of normal (see Precautions). LVEF must continue to be monitored during treatment with Tykerb to ensure that LVEF does not decline below the institutional lower limit of normal (see Dose Delay and Dose Reduction: Cardiac Events as follows).
Tykerb should be taken at least 1 hr before or at least 1 hr after food (see Pharmacology: Pharmacokinetics: Absorption under Actions and Interactions).
Missed doses should not be replaced and the dosing should resume with the next scheduled daily dose (see Overdosage).
Consult the full prescribing information of the co-administered medicinal product for relevant details of their dosage and administration, contraindications and safety information.
In Combination with Capecitabine: Recommended Dose: 1250 mg (5 tabs) once daily continuously with capecitabine.
The recommended dose of capecitabine is 2000 mg/m2/day taken in 2 doses 12 hrs apart on days 1-14 in a 21-day cycle (see Pharmacology: Clinical Studies under Actions). Capecitabine should be taken with food or within 30 min after food.
In Combination with Trastuzumab: Recommended Dose: 1000 mg (4 tabs) once daily continuously in combination with trastuzumab.
The recommended dose of trastuzumab is 4 mg/kg administered as an IV loading dose, followed by 2 mg/kg IV weekly (see Pharmacology: Clinical Studies under Actions).
In Combination with Paclitaxel: Recommended Dose: 1500 mg (6 tabs) once daily continuously in combination with paclitaxel.
When co-administered with Tykerb, the recommended dose of paclitaxel is 80 mg/m2 on days 1, 8 and 15 of a 28-day schedule. Alternatively, paclitaxel may be given at a dose of 175 mg/m2 every 21 days (see Pharmacology: Clinical Studies under Actions).
In Combination with an Aromatase Inhibitor: Recommended Dose: 1500 mg (6 tabs) once daily continuously when taken in combination with an aromatase inhibitor.
When Tykerb is co-administered with the aromatase inhibitor letrozole, the recommended dose of letrozole is 2.5 mg once daily. If Tykerb is co-administered with an alternative aromatase inhibitor, please refer to the FPI of the medicinal product for dosing details.
Dose Delay and Dose Reduction: Cardiac Events (see Precautions): Tykerb should be discontinued in patients with symptoms associated with decreased LVEF that are National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) ≥grade 3 or if their LVEF drops below the institutions lower limit of normal. Tykerb may be restarted at a lower dose (reduced from 1000 mg/day to 750 mg/day, from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day) after a minimum of 2 weeks, and if the LVEF recovers to normal and patient is asymptomatic. Based on current data, the majority of LVEF decreases occur within the first 12 weeks of treatment, however, there is limited data on long-term exposure.
Interstitial Lung Disease/Pneumonitis (see Precautions and Adverse Reactions): Tykerb should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are NCI CTCAE ≥grade 3.
Diarrhea (see Precautions and Adverse Reactions): Tykerb dosing should be interrupted in patients with diarrhea which is NCI CTCAE grade 3 or grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration). Tykerb may be reintroduced at a lower dose (reduced from 1000 mg/day to 750 mg/day, from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day) when diarrhea resolves to ≤grade 1. Tykerb dosing should be permanently discontinued in patients with diarrhea which is NCI CTCAE grade 4.
Other Toxicities: Discontinuation or interruption of dosing with Tykerb may be considered when a patient develops toxicity ≥grade 2 on the NCI CTCAE. Dosing can be restarted at the standard dose of 1000 mg/day, 1250 mg/day or 1500 mg/ day, when the toxicity improves to ≤grade 1. If the toxicity recurs, then Tykerb should be restarted at a lower dose (reduced from 1000 mg/day to 750 mg/day, from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day).
Population: Renal Impairment: There is no experience of Tykerb in patients with severe renal impairment, however, patients with renal impairment are unlikely to require dose modification of Tykerb given that <2% of an administered dose (lapatinib and metabolites) is eliminated by the kidneys (see Pharmacology: Pharmacokinetics Special Patient Populations under Actions).
Hepatic Impairment: Lapatinib is metabolised in the liver. Moderate and severe hepatic impairment have been associated with 56% and 85% increases in systemic exposure, respectively. Administration of Tykerb to patients with hepatic impairment should be undertaken with caution due to increased exposure to the drug. (See Pharmacology: Pharmacokinetics under Actions and Precautions.)
Patients with severe hepatic impairment (Child-Pugh class C) should have their dose of Tykerb reduced. A dose reduction from 1250 mg/day to 750 mg/day or from 1500 mg/day to 1000 mg/day in patients with severe hepatic impairment is predicted to adjust the AUC to the normal range. However, there is no clinical data with this dose adjustment in patients with severe hepatic impairment (see Pharmacokinetics: Special Patient Populations under Actions and Precautions).
Elderly: There are limited data on the use of Tykerb in patients ≥65 years. (See Table 11.)

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No overall differences in the safety or efficacy of these regimens on the basis of age were observed. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Greater sensitivity of elderly individuals cannot be ruled out.
Overdosage
There is no specific antidote for the inhibition of epidermal growth factor receptor (EGFR) ErbB1 and/or ErbB2+ tyrosine phosphorylation. The maximum oral dose of Tykerb that has been administered in clinical trials is 1800 mg once daily.
More frequent ingestion of Tykerb could result in serum concentrations exceeding those observed in clinical trials, therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose (see Dosage & Administration).
Symptoms: Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with Tykerb. Symptoms observed include known Tykerb-associated events (see Adverse Reactions) and in some cases, sore scalp, sinus tachycardia (with otherwise normal ECG) and/or mucosal inflammation.
Treatment: Tykerb 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 Tykerb.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Contraindications
History of hypersensitivity reactions to lapatinib or to any of the excipients of Tykerb.
Special Precautions
Cardiac Toxicity: Tykerb has been associated with reports of decreases in LVEF (see Adverse Reactions). Caution should be taken if Tykerb is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Tykerb to ensure that the patient has a baseline LVEF that is within the institutions normal limits. LVEF should be continuously evaluated during treatment with Tykerb to ensure that LVEF does not decline to an unacceptable level (see Pharmacology: Clinical Studies under Actions and Dose Delay and Dose Reduction: Cardiac Events under Dosage & Administration).
In studies across the clinical development program for Tykerb, 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 Tykerb. However, when Tykerb was administered in combination with trastuzumab in the metastatic setting, the incidence of cardiac events including LVEF decreases was higher (7%) versus the Tykerb 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 Tykerb.
Interstitial Lung Disease and Pneumonitis: Tykerb has been associated with reports of interstitial lung disease and pneumonitis (see Adverse Reactions). Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease/pneumonitis (see Dosage & Administration).
Hepatotoxicity:
Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and post-marketing experience. The hepatotoxicity may be severe and deaths have been reported, although the relationship to Tykerb is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin and alkaline phosphatase) should be monitored before initiation of treatment, every 4-6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Tykerb should be discontinued and patients should not be retreated with Tykerb (see Adverse Reactions). Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of lapatinib-associated hepatotoxicity. In a large, randomized clinical trial of Tykerb monotherapy (n=1194), the overall risk of severe liver injury (ALT >5 times the upper limit of normal, NCI CTCAE grade 3) was 2% (1:50), the risk in DQA1*02:01 and DRB1*07:01 allele carriers was 8% (1:12) and the risk in non-carriers was 0.5% (1:200). Carriage of the HLA risk alleles is common (15-25%) in Caucasian, Asian, African and Hispanic populations but lower (1%) in Japanese populations.
If Tykerb is to be administered to patients with severe preexisting hepatic impairment, dose reduction is recommended. In patients who develop severe hepatotoxicity while on therapy, Tykerb should be discontinued and patients should not be re-treated with Tykerb (see Pharmacokinetics: Special Patient Populations under Pharmacology under Actions and Dosage & Administration).
Diarrhea: Diarrhea, including severe diarrhea, has been reported with Tykerb treatment (see Adverse Reactions). Diarrhea generally occurs early during Tykerb treatment, with almost half of those patients with diarrhea 1st experiencing it within 6 days. This usually lasts 4-5 days. Tykerb-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE grades 3 and 4 occurring in <10% and <1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with antidiarrheal agents eg, loperamide after the 1st unformed stool, is recommended. Severe cases of diarrhea may require administration of oral or IV electrolytes and fluids, use of antibiotics eg, fluoroquinolones (especially if diarrhea is persistent beyond 24 hrs, there is fever, or grade 3 or 4 neutropenia) and interruption or discontinuation of Tykerb therapy (see Dose Delay and Dose Reduction: Diarrhea under Dosage & Administration).
Concomitant Treatment with CYP3A4 Inhibitors or Inducers: Concomitant treatment with inhibitors or inducers of CYP3A4 should proceed with caution due to risk of increased or decreased exposure to lapatinib, respectively (see Interactions).
Effects on the Ability to Drive or Operate Machinery: There have been no studies to investigate the effect of Tykerb on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of Tykerb. The clinical status of the patient and the adverse event profile of Tykerb should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.
Impairment of Fertility: No relevant information.
Use in Pregnancy: There are no adequate and well-controlled studies of Tykerb in pregnant women. The effect of Tykerb on human pregnancy is unknown. Tykerb should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with Tykerb.
Tykerb was not teratogenic when studied in pregnant rats and rabbits but caused minor abnormalities at doses which were maternally toxic (see Toxicology under Pharmacology under Actions).
Use in Lactation: It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfeeding infants from lapatinib, it is recommended that breastfeeding be discontinued in women who are receiving therapy with Tykerb.
Use in Children: The safety and efficacy of Tykerb in paediatric patients has not been established.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate and well-controlled studies of Tykerb in pregnant women. The effect of Tykerb on human pregnancy is unknown. Tykerb should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with Tykerb.
Tykerb was not teratogenic when studied in pregnant rats and rabbits but caused minor abnormalities at doses which were maternally toxic (see Toxicology under Pharmacology under Actions).
Use in Lactation: It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfeeding infants from lapatinib, it is recommended that breastfeeding be discontinued in women who are receiving therapy with Tykerb.
Adverse Reactions
Clinical Trial Data: The safety of Tykerb has been evaluated as monotherapy and in combination with other chemotherapeutic agents for various cancers in >20,000 patients including 198 patients who received Tykerb in combination with capecitabine, 149 patients who received Tykerb in combination with trastuzumab, 222 patients who received Tykerb in combination with paclitaxel, 293 patients who received Tykerb in combination with paclitaxel (175 mg/m2 every 3 weeks), and 654 patients who received Tykerb in combination with letrozole (see Pharmacokinetics: Clinical Studies under Pharmacology under Actions).
The following convention has been utilized for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000).
Adverse Reactions with Tykerb Monotherapy: The following adverse reactions have been reported to be associated with Tykerb.
Metabolism and Nutrition Disorders: Very Common: Anorexia.
Cardiac Disorders: Common: Decreased LVEF1 (see Dose Delay and Dose Reduction: Cardiac Events under Dosage & Administration and Precautions).
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Interstitial lung disease/pneumonitis.
Gastrointestinal Disorders: Very Common: Diarrhea2, which may lead to dehydration3 (see Dose Delay and Dose Reduction: Diarrhea under Dosage & Administration and Precautions), nausea, vomiting.
Hepatobiliary Disorders: Uncommon: Hyperbilirubinemia4, hepatotoxicity.
Skin and Subcutaneous Tissue Disorders: Very Common: Rash2 (including acneiform dermatitis) (see Dose Delay and Dose Reduction: Other Toxicities under Dosage & Administration). Common: Nail disorders including paronychia.
Immune System Disorders: Rare: Hypersensitivity reactions including anaphylaxis (see Contraindications).
General Disorders and Administration Site Conditions: Very Common: Fatigue.
1LVEF decreases have been reported in approximately 1% of patients and were asymptomatic in >70% of cases. LVEF decreases resolved or improved in >70% of cases on discontinuation of treatment with Tykerb. Symptomatic LVEF decreases were observed in approximately 0.3% of patients who received Tykerb. Observed adverse events included dyspnea, cardiac failure and palpitations.
2Diarrhea and rash were generally low grade and did not result in discontinuation of treatment with Tykerb. Diarrhea responds well to proactive management (see Precautions). Rash was transient in the majority of cases.
3Most events of diarrhea were grade 1 or 2.
4Elevated bilirubin may be due to lapatinib inhibition of hepatic uptake by OATP1B1 or inhibition of excretion into bile by P-gp or BCRP.
Adverse Reactions with Tykerb in Combination with Capecitabine: In addition to the adverse reactions observed with Tykerb monotherapy, the following additional adverse reactions have been reported to be associated with Tykerb in combination with capecitabine with a frequency difference of >5% compared to capecitabine alone. These data are based on exposure to this combination in 198 patients.
Gastrointestinal Disorders: Very Common: Dyspepsia.
Skin and Subcutaneous Tissue Disorders: Very Common: Dry skin.
The following adverse reactions were reported to be associated with Tykerb in combination with capecitabine but were seen at a similar frequency in the capecitabine alone arm.
Gastrointestinal Disorders: Very Common: Stomatitis, constipation, abdominal pain.
Skin and Subcutaneous Tissue Disorders: Very Common: Palmar-plantar erythrodysaesthesia.
General Disorders and Administrative Site Conditions: Very Common: Mucosal inflammation.
Musculoskeletal and Connective Tissue Disorders: Very Common: Pain in extremity, back pain.
Nervous System Disorders: Common: Headache.
Psychiatric Disorders: Very Common: Insomnia.
Adverse Reactions with Tykerb in Combination with Trastuzumab: No additional adverse reactions were reported to be associated with Tykerb 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 Tykerb clinical program (see Cardiac Toxicity under Precautions). These data are based on exposure to this combination in 149 patients in the pivotal trial.
Adverse Reactions with Tykerb in Combination with Paclitaxel: In addition to the adverse reactions observed with Tykerb monotherapy, the following additional adverse reactions have been reported to be associated with Tykerb in combination with paclitaxel (80 mg/m2 weekly) with a frequency difference of >5% compared to paclitaxel alone. These data are based on exposure to this combination in 222 patients.
Blood and Lymphatic System Disorders: Very Common: Neutropenia, leukopenia, anemia.
Nervous System Disorders: Very Common: Peripheral neuropathy*.
Musculoskeletal and Connective Tissue Disorders: Very Common: Myalgia*.
*Additional adverse reactions reported in 293 patients on Tykerb in combination with paclitaxel (175 mg/m2 every 3 weeks) with a frequency difference of >5% compared to paclitaxel alone.
Adverse Reactions with Tykerb in Combination with Letrozole: In addition to the adverse reactions observed with Tykerb monotherapy, the following additional adverse reactions have been reported to be associated with Tykerb in combination with letrozole with a frequency difference of >5% compared to letrozole alone. These data are based on exposure to this combination in 654 patients.
Respiratory, Thoracic and Mediastinal Disorders: Very Common: Epistaxis.
Skin and Subcutaneous Tissue Disorders: Very Common: Alopecia, dry skin.
Drug Interactions
Lapatinib is predominantly metabolised by CYP3A4 (see Pharmacology: Pharmacokinetics under Actions). Therefore, inhibitors or inducers of these enzymes may alter the pharmacokinetics of lapatinib.
Co-administration of Tykerb with known inhibitors of CYP3A4 (eg, ketoconazole, itraconazole or grapefruit juice) should proceed with caution and clinical response and adverse events should be carefully monitored (see Precautions). If patients must be co-administered with a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to Tykerb 500 mg/day is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Tykerb dose is adjusted upward to the indicated dose.
Co-administration of Tykerb with known inducers of CYP3A4 (eg, rifampin, carbamazepine or phenytoin) should proceed with caution and clinical response and adverse events should be carefully monitored (see Precautions). If patients must be co-administered with a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of Tykerb should be titrated gradually from 1250-4500 mg/day or from 1500-5500 mg/day based on tolerability. This dose of Tykerb is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, the Tykerb dose should be reduced over approximately 2 weeks to the indicated dose.
Pretreatment with a proton-pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 27% (range: 6-49%). This effect decreases with increasing age from approximately 40-60 years. Therefore, caution should be used when Tykerb is used in patients pretreated with a proton-pump inhibitor.
Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Co-administration of Tykerb 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 IV. Caution should be exercised when dosing Tykerb concurrently with orally administered medications with narrow therapeutic windows that are substrates of CYP3A4 (see Pharmacology: Pharmacokinetics under Actions).
Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised when dosing Tykerb concurrently with medications with narrow therapeutic windows that are substrates of CYP2C8 (see Pharmacology: Pharmacokinetics under Actions).
Co-administration of Tykerb with IV paclitaxel increased the exposure of paclitaxel by 23%, due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity of diarrhoea and neutropenia has been observed with this combination in clinical trials. Caution is advised when Tykerb is co-administered with paclitaxel.
Co-administration of Tykerb with IV 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 Tykerb 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. Caution is advised if Tykerb is co-administered with irinotecan.
Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors and inducers of these proteins may alter the exposure and/or distribution of lapatinib (see Pharmacology: Pharmacokinetics under Actions).
Lapatinib inhibits the transport protein Pgp in vitro at clinically relevant concentrations. Co-administration of Tykerb with orally administered digoxin resulted in an approximate 98% increase in the AUC of digoxin. Caution should be exercised when dosing Tykerb concurrently with medications with narrow therapeutic windows that are substrates of Pgp.
Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of this effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of substrates of BCRP (eg, topotecan) and OATP1B1 (eg, rosuvastatin) (see Pharmacokinetics under Actions).
Concomitant administration of Tykerb with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these agents (or the metabolites of capecitabine) or lapatinib.
The bioavailability of lapatinib is affected by food (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Storage
Do not store above 30°C.
ATC Classification
L01EH01 - lapatinib ; Belongs to the class of human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 250 mg (yellow, oval, biconvex, with one side plain, opposite side debossed with 'GS XJG') x 70's.
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