拉帕替尼（lapatinib）—一种新的EGFR靶向治疗药物乳腺癌晚期新药 Tykerb,是葛兰素史克公司研制的。 临床试验显示,对于那些已对罗氏的赫赛汀(Herceptin)产生耐药性的HER2型乳癌患者,这种新药有很好的临床效果。 拉帕替尼（lapatinib）是一种口服的小分子表皮生长因子（EGFR:ErbB-1，ErbB-2）酪氨酸激酶抑制剂。在体外试验中，对Her-2过表达乳腺癌细胞系的生长抑制作用明显。在Her-2过表达的进展期乳腺癌的Ⅰ期临床试验中，拉帕替尼（lapatinib）也具有较高的有效率，且与赫赛汀（曲妥珠单抗）无交叉耐药。因为其结构为小分子，与赫赛汀（曲妥珠单抗）不同，能够透过血脑屏障，对于乳腺癌脑转移有一定的治疗作用。 Spector报告了拉帕替尼（lapatinib）单药（1500mg/d）在难治性炎性乳腺癌（曾用过蒽环类药物或复发）中的Ⅱ期临床结果。病人分为两组A组（ErbB-2过表达）和B组（ErbB-1表达，ErbB-2不表达）。A组使用拉帕替尼（lapatinib）的部分缓解率达62%，B组仅为8.3%。毒性反应主要表现为Ⅰ/Ⅱ级皮肤和胃肠道反应。这表明，拉帕替尼（lapatinib）疗效与HER-2过表达有密切关系。 该药由葛兰素史克公司研制，是一种新型的靶向抗癌药物。所谓靶向治疗药物，是指将某些受体、基因或关键蛋白作为靶点，进而有的放矢地杀灭相关肿瘤细胞的药物。 该药和另外一种乳腺癌治疗药物希罗达一起使用，可以有效控制晚期的转移性HER2阳性乳腺癌。两种药物联合用药疗法适用于那些之前服用过其他药物但治疗无效后乳腺癌转移的患者。 拉帕替尼是一种激酶抑制剂，它的独特之处在于可以通过多种途径发挥作用，乳腺癌癌细胞不能接收到生长所需的信号。 Lapatinib是一种口服的小分子表皮生长因子可逆性的酪氨酸激酶抑制剂，Lapatinib不同于其他酪氨酸激酶抑制剂，它能够同时作用于Her-1和Her-2 两个靶点，这种作用方式所产生的抑制肿瘤细胞增殖和生长的生物学效应要远远大于仅抑制其中一个靶点。Lapatinib 在体外实验中显示了对多种人类肿瘤细胞有活性，在动物实验中还发现与三苯氧胺联合能够抑制三苯氧胺抵抗的 ErbB-2过度表达乳腺癌的生长。而后在Ⅰ/Ⅱ期临床试验确立该药物的剂量范围为每日口服 500～1 600 mg，毒副反应可耐受，主要表现为腹泻（42%）、皮疹（31%），没有观察到IV度毒性，III度毒性发生率仅6%，主要为腹泻和皮疹，并证实了对乳腺癌、头颈部癌、膀胱癌、子宫内膜癌等多种实体肿瘤有效，尤其在对曲妥珠单抗抵抗的局部晚期和转移性乳腺癌患者中显示了较好疗效（Lackey KE.2006；Pandite L，Burris HA，Jones S，et al.2004；Arona A，Scholar EM.205；Nelson MH，Dolder CR.2006）。在体外实验中，对Her-2过表达乳腺癌细胞系的生长抑制作用明显。 Geyer（Geyer A.2006）报道了一项总例数为321人的 Her-2 高表达且对曲妥珠单抗抗拒的转移性乳腺癌分别以卡培他滨或卡培他滨联合lapatinib 治疗的随机开放国际性Ⅲ期临床试验的结果，其中160例给予lapatinib 1 250 mg，每日一次口服，联合卡培他滨每日2 000 mg/m2口服，第1到第14天，每3周重复；另161人卡培他滨每日 2 500 mg/m2口服，第1到第14天，每3周重复。结果显示单用卡培他滨组的中位进展时间为19.7周，而联合组为36.9周，两组结果具有显著的统计学差异，P值为0.000 16，联合组几乎将至进展时间延长1倍。 Lin（Lin NU.2006）等报道了EGF105084扩展研究最新结果，EGF105084原研究入组标准为，Her-2阳性、转移性乳腺癌、目标脑转移病变直径≥10 mm、颅部放疗后脑转移进展、之前接受过曲妥珠单抗治疗、ECOG评分0～2。扩展研究的纳入标准为放射影像学证实拉帕替尼单药治疗后中枢神经系统疾病进展。扩展研究终点包括脑转移对联合治疗的反应率、第一次进展的位置、无进展生存(PFS)、耐受性和脑病变体积缩小≥20%的患者比例。 EGF105084扩展研究纳入原研究(242例患者接受拉帕替尼单药治疗，750 mg bid)中符合上述标准的51例脑转移进展患者。进入扩展研究后患者从单用拉帕替尼治疗转为继续接受拉帕替尼(1 250 mg/d)与卡培他滨(每日2 000 mg/m2，治疗14天，21天为1个疗程)联合治疗。 EGF105084原研究结果显示，单独使用拉帕替尼治疗的患者中位PFS为9.3周，16周时的PFS率为21.4%。扩展研究结果显示,接受联合治疗后完全缓解(CR)患者比例为0，部分缓解(PR)患者比例为20%(10例)，疾病稳定(SD)患者比例为39%(20例)，疾病进展(PD)患者比例为29%(15例)，12%的患者进展情况不详。所有患者中49例接受联合治疗后CNS肿瘤体积缩小，其中20%(10例)患者的肿瘤体积缩小≥ 50%(绝对中位体积缩小7.1 cm3)，37%(18例)患者的肿瘤缩小≥20%(绝对中位体积缩小4.8 cm3)。联合治疗患者的中位PFS为15.8周。肿瘤体积缩小≥20%的患者中位PFS为20周，其他所有患者的PFS为8.21周(HR:0.34，95%CI:0.17～0.68，P =0.001 3)。 从上述两项研究结果中可以看出：Lapatinib能透过血脑屏障，与曲妥珠单抗无交叉耐药；与卡培他滨联用，可缩小Her-2阳性乳腺癌患者的脑转移瘤体积，其单药有治疗脑转移瘤的活性，并与其治疗全身疾病的活性相当；对Her-2的直接靶向治疗与化疗联合具有协同作用等。 Perez（Perez EA，Byrne JA，Hammond IW，et al.2006）对 2 812例使用lapatinib的患者心功能分析结果作了报道，提示有1.3%的患者被检出有LVEF的下降，此现象多发生在用药9周内（68%），持续的平均时间为5周，仅0.1%的患者表现出心功能不全的症状且能被常规的心功能不全治疗手段所逆转，而且92％的患者有既往使用蒽环类药物、曲妥珠单抗、放疗的病史，所以应进一步研究lapatinib 的心脏毒性。 tykerb拉帕替尼英文说明书 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dose of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)]. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. 2.2 Dose Modification Guidelines Cardiac Events: TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. TYKERB may be restarted at a reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic. Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh Class C) should have their TYKERB dose reduced. A dose reduction to 750 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there is no clinical data with this dose adjustment in patients with severe hepatic impairment. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib 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 lapatinib dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).] Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose of lapatinib 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 lapatinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2).] Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be considered when patients develop greater than or equal to Grade 2 NCI CTC toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB should be restarted at a lower dose (1,000 mg/day). See manufacturer’s prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity. 3 DOSAGE FORMS AND STRENGTHS 250 mg tablets — oval, biconvex, orange, film-coated with GS XJG debossed on one side. 4 CONTRAINDICATIONS None. See manufacturer’s prescribing information for capecitabine contraindications. 5 WARNINGS AND PRECAUTIONS 5.1 Decreased Left Ventricular Ejection Fraction TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 weeks of treatment; however, data on long-term exposure are limited. 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 institution’s normal limits. LVEF should continue to be evaluated during treatment with TYKERB to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)]. 5.2 Patients with Severe Hepatic Impairment If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. 5.3 Diarrhea Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB. 5.4 QT Prolongation QT prolongation measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4)]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration. The prescriber should consider baseline and on-treatment electrocardiograms with QT measurement. 5.5 Pregnancy Pregnancy Category D TYKERB can cause fetal harm when administered to a pregnant woman. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC). Lapatinib was studied for effects on embryo-fetal development 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 (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations. There are no adequate and well-controlled studies with TYKERB in pregnant women. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14).] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication. The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2. Table 1. Adverse Reactions Occurring in ≥10% of Patients * National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. † Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine group. Table 2. Selected Laboratory Abnormalities * National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See Warnings and Precautions (5.1).] 7 DRUG INTERACTIONS 7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown. Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)]. Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%. 7.3 Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised. 7.4 Other Chemotherapy Agents In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)]. 8.3 Nursing Mothers 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 serious adverse reactions in nursing infants from TYKERB, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TYKERB in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine (N = 198), 17% were 65 years of age and older, and 1% were 75 years of age and older. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with TYKERB in patients with severe renal impairment. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys. 8.7 Hepatic Impairment The pharmacokinetics of lapatinib were examined in subjects with moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100 mg-dose increased approximately 14% and 63% in subjects with moderate and severe hepatic impairment, respectively. Administration of TYKERB in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 10 OVERDOSAGE There is no known antidote for overdoses of TYKERB. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of TYKERB could result in serum concentrations exceeding those observed in clinical trials and could result in increased toxicity. Therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose. There has been a report of one patient who took 3,000 mg of TYKERB for 10 days. This patient had Grade 3 diarrhea and vomiting on Day 10. The event resolved following IV hydration and interruption of treatment with TYKERB and letrozole. Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib. 11 DESCRIPTION Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. It is present as the monohydrate of the ditosylate salt, with chemical name N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. It has the molecular formula C29H26ClFN4O4S (C7H8O3S)2 H2O and a molecular weight of 943.5. Lapatinib ditosylate monohydrate has the following chemical structure:  (分子式) Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 0.001 mg/mL at 25°C. Each 250 mg tablet of TYKERB contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base. The inactive ingredients of TYKERB are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow No. 6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models. 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 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. 12.3 Pharmacokinetics Absorption: Absorption following oral administration of TYKERB is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hour). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of TYKERB results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours. At the dose of 1,250 mg daily, steady state geometric mean (95% confidence interval) values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.hr/mL (23.4 to 56 mcg.hr/mL). Divided daily doses of TYKERB resulted in approximately 2-fold higher exposure at steady state (steady state AUC) compared to the same total dose administered once daily. Systemic exposure to lapatinib is increased when administered with food. 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-1,000 calories) meal, respectively. Distribution: Lapatinib is highly bound (>99%) to albumin and alpha-1 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 in vitro to inhibit these efflux transporters, as well as the hepatic uptake transporter OATP 1B1, at clinically relevant concentrations. 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 accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. Elimination: At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours. Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3 to 67%) of an oral dose. Effects of Age, Gender, or Race: Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed. 12.4 QT Prolongation The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-label dose escalation study in advanced cancer patients. Eighty-one patients received daily doses of lapatinib ranging from 175 mg/day to 1,800 mg/day. Serial ECGs were collected on Day 1 and Day 14 to evaluate the effect of lapatinib on QT intervals. Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the Friedericia method) >480 msec or an increase in QTcF >60 msec by automated machine-read evaluation of ECG. Analysis of the data suggested a relationship between lapatinib concentration and the QTc interval. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with lapatinib are ongoing. Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays. There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human clinical exposure based on AUC, respectively). 14 CLINICAL STUDIES The efficacy and safety of TYKERB in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) over-expressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab. Patients were randomized to receive either TYKERB 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m2/day on Days 1-14 every 21 days. The endpoint was time to progression (TTP). TTP was defined as time from randomization to tumor progression or death related to breast cancer. Based on the results of a pre-specified interim analysis, further enrollment was discontinued. Three hundred and ninety-nine (399) patients were enrolled in this study. The median age was 53 years and 14% were older than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven percent (97%) had stage IV breast cancer, 48% were estrogen receptor+ (ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation. Approximately 95% of patients had prior treatment with anthracyclines, taxanes, and trastuzumab. Efficacy analyses four months after the interim analysis are presented in Table 3, Figure 1, and Figure 2. Table 3. Efficacy Results TTP = Time to progression. * The time from last tumor assessment to the data cut-off date was >100 days in approximately 30% of patients in the independent assessment. The pre-specified assessment interval was 42 or 84 days. Figure 1. Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression Figure 2. Kaplan-Meier Estimates for Investigator Assessment Time to Progression At the time of updated analysis, 30% of patients had died and the data for survival analysis are not mature. Fifty-five patients (28%) in the TYKERB plus capecitabine group and 64 subjects (32%) in the capecitabine group had died. 16 HOW SUPPLIED/STORAGE AND HANDLING The 250 mg tablets of TYKERB are oval, biconvex, orange, and film-coated with GS XJG debossed on one side and are available in: Bottles of 150 tablets: NDC 0173-0752-00 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (17.6). 17.1 Decreased Left Ventricular Ejection Fraction Patients should be informed that TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB. 17.2 Diarrhea Patients should be informed that TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with TYKERB. 17.3 Drug Interactions TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products. 17.4 Food Patients should be informed of the importance of taking TYKERB at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food. 17.5 Divided Dosing The dose of TYKERB should not be divided. Patients should be advised of the importance of taking TYKERB once daily, in contrast to capecitabine which is taken twice daily. 17.6 FDA-Approved Patient Labeling PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT ------------------------------------------------------------------------------------------------------------- PATIENT INFORMATION TYKERB® (TIE-curb) (lapatinib) tablets Read this leaflet before you start taking TYKERB and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. What is TYKERB? TYKERB is used with the medicine capecitabine for the treatment of patients with advanced or metastatic breast cancer that is HER2 positive, and who have already had certain other breast cancer treatments. Before you start taking TYKERB, tell your doctor about all of your medical conditions, including if you: • have heart problems. • have liver problems. You may need a lower dose of TYKERB. • are pregnant or may become pregnant. TYKERB may harm an unborn baby. If you become pregnant during treatment with TYKERB, tell your doctor as soon as possible. • are breastfeeding. It is not known if TYKERB passes into your breast milk or if it can harm your baby. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines and herbal and dietary supplements. TYKERB and many other medicines may interact with each other. Your doctor needs to know what medicines you take so he or she can choose the right dose of TYKERB for you. Especially tell your doctor if you take: • antibiotics and anti-fungals (drugs used to treat infections) • HIV (AIDS) treatments • anticonvulsant drugs (drugs used to treat seizures) • calcium channel blockers (drugs used to treat certain heart disorders or high blood pressure) • antidepressants • drugs used for stomach ulcers • St. John’s Wort or other herbal supplements Know the medicines you take. Keep a list of your medicines with you to show your doctor. Do not take other medicines during treatment with TYKERB without first checking with your doctor. Because TYKERB is given with another drug called capecitabine, you should also discuss with your doctor or pharmacist any medicines that should be avoided when taking capecitabine. How should I take TYKERB? • Take TYKERB exactly as your doctor has told you. TYKERB and capecitabine are taken in 21 day cycles. The usual dose of TYKERB is 1,250 mg (5 tablets) taken by mouth, one time a day on days 1 to 21. Your doctor will tell you the dose of capecitabine you should take and when you should take it. • TYKERB should be taken at least one hour before, or at least one hour after food. • Do not eat or drink grapefruit products while taking TYKERB. • Your doctor may adjust your dose of TYKERB depending on how you tolerate the treatment. • If you forget to take your dose of TYKERB, take it as soon as you remember that day. If you miss a day, do not double your dose the next day. Just skip the missed dose. What are the possible side effects of TYKERB? Serious side effects include: • heart problems • decreased pumping of blood from the heart • abnormal heartbeat Call your doctor right away if you have palpitations or are short of breath. • severe diarrhea, which may lead to you becoming dehydrated Common side effects of TYKERB in combination with capecitabine include: • diarrhea • red, painful hands and feet • nausea • rash • vomiting • tiredness • mouth sores • loss of appetite • indigestion Tell your doctor about any side effect that gets serious or that does not go away. These are not all the side effects with TYKERB. Ask your doctor or pharmacist for more information. You may also get side effects from capecitabine. Talk to your doctor about possible side effects with capecitabine. How should I store TYKERB tablets? • Store TYKERB tablets at room temperature between 59° and 86°F (15° to 30°C). Keep the container closed tightly. • Do not keep medicine that is out of date or that you no longer need. Be sure that if you throw any medicine away, it is out of the reach of children. • Keep TYKERB and all medicines out of the reach of children. General information about TYKERB Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use TYKERB for any other condition for which it was not prescribed. Do not give TYKERB to other people, even if they have the same condition that you have. It may harm them. This leaflet summarizes the most important information about TYKERB. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about TYKERB that is written for health professionals. For more information you can call toll-free 1-888-825-5249. What are the ingredients in TYKERB? Active Ingredient: Lapatinib. Inactive Ingredients: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow #6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide. TYKERB tablets are oval, biconvex, orange, film-coated with GS XJG printed on one side. 药样 Revised: March 2007 GlaxoSmithKline Research Triangle Park, NC 27709 ©2007, GlaxoSmithKline. All rights reserved. TKB:1PIL TYKERB is a trademark of GlaxoSmithKline.