Tykerb Information
Tykerb (Lapatinib) Warning: Hepatotoxicity
Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain.
Tykerb (Lapatinib) Indications And Usage
Tykerb (Lapatinib) is indicated in combination with:
Tykerb (Lapatinib) in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.
Tykerb (Lapatinib) Dosage And Administration
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Hepatic Impairment:
Other Toxicities:
See manufacturer’s prescribing information for the coadministered product dosage adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
Tykerb (Lapatinib) Dosage Forms And Strengths
250 mg tablets — oval, biconvex, orange, film-coated with GS XJG debossed on one side.
Tykerb (Lapatinib) Contraindications
Tykerb (Lapatinib) is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.
Tykerb (Lapatinib) Warnings And Precautions
Tykerb (Lapatinib) can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Tykerb (Lapatinib) is expected to result in adverse reproductive effects. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth .
There are no adequate and well-controlled studies with Tykerb (Lapatinib) in pregnant women. Women should be advised not to become pregnant when taking Tykerb (Lapatinib) . 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.
Tykerb (Lapatinib) Adverse Reactions
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 (Lapatinib) 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 CTCAE v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.
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Hormone Receptor Positive, Metastatic Breast Cancer:
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The following adverse reactions have been identified during post-approval use of Tykerb (Lapatinib) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders:
Tykerb (Lapatinib) Drug Interactions
Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing Tykerb (Lapatinib) concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. 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.
Midazolam:
Paclitaxel:
Digoxin:
Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly . Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes .
Ketoconazole:
Carbamazepine:
Tykerb (Lapatinib) Use In Specific Populations
Pregnancy Category D
Based on findings in animals, Tykerb (Lapatinib) can cause fetal harm when administered to a pregnant woman. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses. There are no adequate and well-controlled studies with Tykerb (Lapatinib) in pregnant women. Women should be advised not to become pregnant when taking Tykerb (Lapatinib) . 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.
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 following 1,250 mg dose of lapatinib plus capecitabine), 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 following 1,250 mg dose of lapatinib plus capecitabine). 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 following 1,250 mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
Tykerb (Lapatinib) Overdosage
There is no known antidote for overdoses of Tykerb (Lapatinib) . The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of Tykerb (Lapatinib) 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.
Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG) and/or mucosal inflammation.
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.
Treatment of overdose with Tykerb (Lapatinib) should consist of general supportive measures.
Tykerb (Lapatinib) 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 -(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 CHClFNOS (CHOS) HO and a molecular weight of 943.5. Lapatinib ditosylate monohydrate has the following chemical structure:
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 (Lapatinib) 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 (Lapatinib) are: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Orange film-coat: FD&C yellow No. 6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide.
Tykerb (Lapatinib) Clinical Pharmacology
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 K 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.
Hormone receptor positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.
Absorption:
max
At the dose of 1,250 mg daily, steady state geometric mean (95% confidence interval) values of C 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 (Lapatinib) 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 (C 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:
Metabolism:
Elimination:
Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (
Effects of Age, Gender, or Race:
Tykerb (Lapatinib) Clinical Studies
The efficacy and safety of Tykerb (Lapatinib) in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) overexpressing (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 (Lapatinib) 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m/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 4 months after the interim analysis are presented in Table 5, Figure 1, and Figure 2.
TTP = Time to progression.
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At the time of above efficacy analysis, the overall survival data were not mature (32% events). However, based on the TTP results, the study was unblinded and patients receiving capecitabine alone were allowed to cross over to Tykerb (Lapatinib) plus capecitabine treatment. The survival data were followed for an additional 2 years to be mature and the analysis is summarized in Table 6.
CI = confidence interval
The efficacy and safety of Tykerb (Lapatinib) in combination with letrozole were evaluated in a double-blind, placebo-controlled, multi-center study. A total of 1,286 postmenopausal women with hormone receptor positive (ER positive and/or PgR positive) metastatic breast cancer, who had not received prior therapy for metastatic disease, were randomly assigned to receive either Tykerb (Lapatinib) (1,500 mg once daily) plus letrozole (2.5 mg once daily) (n = 642) or letrozole (2.5 mg once daily) alone (n = 644). Of all patients randomized to treatment, 219 (17%) patients had tumors overexpressing the HER2 receptor, defined as fluorescence in situ hybridization (FISH) (≥2 or 3+ immunohistochemistry (IHC). There were 952 (74%) patients who were HER2 negative and 115 (9%) patients did not have their HER2 receptor status confirmed. The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2 positive population. Progression-free survival was defined as the interval of time between date of randomization and the earlier date of first documented sign of disease progression or death due to any cause.
The baseline demographic and disease characteristics were balanced between the two treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty-four percent (84%) of the patients were White. Approximately 50% of the HER2 positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients had prior trastuzumab.
In the HER2 positive subgroup (n = 219), the addition of Tykerb (Lapatinib) to letrozole resulted in an improvement in PFS. In the HER2 negative subgroup, there was no improvement in PFS of the Tykerb (Lapatinib) plus letrozole combination compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the Tykerb (Lapatinib) plus letrozole combination therapy. The overall survival (OS) data were not mature. Efficacy analyses for the hormone receptor positive, HER2 positive and HER2 negative subgroups are presented in Table 7 and Figure 3.
PFS = progression-free survival; CI = confidence interval.
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Tykerb (Lapatinib) How Supplied/storage And Handling
The 250 mg tablets of Tykerb (Lapatinib) 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].
Tykerb (Lapatinib) Patient Counseling Information
See FDA-approved patient labeling (17.2).
Tykerb (Lapatinib)
Tykerb (Lapatinib)
Tykerb (Lapatinib)
