Tyverb tablets 250 mg No. 70

Instructions for Tyverb tablets 250 mg No. 70

Composition

active ingredient: lapatinib;

1 tablet contains 250 mg of lapatinib in the form of lapatinib ditosylate monohydrate;

excipients: microcrystalline cellulose, povidone K30, sodium starch glycolate (type A), magnesium stearate, Opadry® Yellow YS-1-12524-A (hypromellose, titanium dioxide (E 171), macrogol 400, polysorbate 80, iron oxide yellow (E 172), iron oxide red (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated oval biconvex yellow tablets, flat on one side and marked GS XJG on the other side.

Pharmacotherapeutic group

Antineoplastic agents. Human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors. ATC code L01E H01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action: Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of the EGFR (ErbB1) and HER2 (ErbB2) receptors (estimated Kiapp values of 3 nM and 13 nM, respectively) with slow dissociation from these receptors (half-life ≥ 300 min). Lapatinib inhibits the growth of ErbB-driven tumor cells in vitro and in various animal models.

The combination of lapatinib and trastuzumab may exhibit complementary mechanisms of action, as well as possible different mechanisms of resistance. The growth inhibitory potential of lapatinib was studied in cell lines exposed to trastuzumab. Lapatinib retained significant activity against a HER2-amplified breast cancer cell line selected for long-term growth in trastuzumab-containing medium in vitro and demonstrated an additive effect in combination with trastuzumab in these cell lines.

Pharmacokinetics.

Absorption: After oral administration, lapatinib is incompletely and variably absorbed (AUC coefficient of variation approximately 70%). Serum concentrations appear after a median latency period of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of 1250 mg produces geometric steady-state Cmax values (coefficient of variation) of 2.43 (76%) μg/mL and AUC values of 36.2 (79%) μg*h/mL.

Systemic exposure to lapatinib is increased when administered with food. AUC increases 3- and 4-fold (Cmax approximately 2.5- and 3-fold) when administered with a low-fat (5% fat [500 calories]) or high-fat (50% fat [1000 calories]) meal, respectively, compared to administration in the fasted state. Systemic exposure to lapatinib was also affected by the timing of food intake. When administered 1 hour before a low-fat breakfast, mean AUC values increased approximately 2- and 3-fold when lapatinib was administered 1 hour after a low-fat or high-fat meal, respectively.

Distribution: Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies have shown that lapatinib is a substrate for the transporters BCRP (breast cancer resistance protein) and Pgp (ABCB2). In addition, in vitro, lapatinib inhibited these efflux transporters as well as the hepatic uptake transporter OATP1B1 at clinically relevant concentrations (IC50 values were 2.3 μg/mL). The clinical relevance of these effects on the pharmacokinetics of other drugs, as well as on the pharmacological activity of other anticancer drugs, is unknown.

Biotransformation: Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, and to a lesser extent by CYP2C19 and CYP2C8, to form a variety of oxidized metabolites, none of which accounted for more than 14% of the dose excreted in the feces or 10% of the plasma concentration of lapatinib.

Lapatinib inhibits CYP3A and CYP2C8 in vitro at clinically relevant concentrations. Lapatinib has little inhibitory effect on hepatic microsomal enzymes such as CYP1A2, CYP2C9, CYP2C19 and CYP2D6 or UGT enzymes (in vitro IC50 values ≥ 6.9 μg/mL).

Elimination. The elimination half-life increases dose-dependently with single doses. Steady state is reached after 6–7 days of administration. The steady state half-life is 24 hours. Lapatinib is eliminated primarily by metabolism mediated by CYP3A4/5. Biliary excretion also contributes to elimination. Lapatinib and its metabolites are excreted primarily in the feces. Faecal excretion of unchanged lapatinib accounts for an average of 27% (range 3 to 67%) of the oral dose. Less than 2% of the administered oral dose (as lapatinib and metabolites) is excreted in the urine.

Renal impairment: Specific pharmacokinetic studies of lapatinib in patients with renal impairment or in patients undergoing hemodialysis have not been conducted. Available data indicate that no dose adjustment is required in patients with mild to moderate renal impairment.

Hepatic impairment. The pharmacokinetics of lapatinib were studied in subjects with moderate (n = 8) and severe (n = 4) hepatic impairment compared to subjects with normal hepatic function (n = 8) in healthy volunteers. Systemic exposure (AUC) of lapatinib following a single 100 mg dose was increased by 56% and 85% in subjects with moderate and severe hepatic impairment, respectively. Lapatinib should be used with caution in patients with hepatic impairment.

Indication

Treatment of adult patients with HER2 (ErbB2) overexpressing breast cancer:

as part of combination therapy with capecitabine for patients with advanced or metastatic cancer who have progressed on prior therapy with trastuzumab in combination with anthracyclines and taxanes for metastatic disease;

as part of combination therapy with trastuzumab in patients with metastatic, hormone-negative cancer that progresses after trastuzumab-containing chemotherapy;

as part of combination therapy with an aromatase inhibitor for postmenopausal women with metastatic, hormone-positive cancer who are not candidates for chemotherapy; patients in the registration study were not previously treated with trastuzumab or aromatase inhibitors; there are no data on the efficacy of this combination compared with trastuzumab in combination with an aromatase inhibitor in this group of patients.

Contraindication

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other types of interactions

Effects of other medicinal products on lapatinib

Lapatinib is metabolized primarily by CYP3A (see Pharmacokinetics).

When co-administered with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 7 days) in healthy volunteers, the systemic exposure of lapatinib (100 mg daily) increased approximately 3.6-fold and the half-life increased 1.7-fold. Co-administration of Tyverb with strong CYP3A4 inhibitors (such as ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Caution should be exercised when co-administering Tyverb with moderate CYP3A4 inhibitors and the patient's clinical status and possible adverse reactions should be closely monitored.

When co-administered with the CYP3A4 inducer carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days) in healthy volunteers, systemic exposure to lapatinib was reduced by approximately 72%. Co-administration of Tyverb with known CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, or St. John's wort) should be avoided.

Lapatinib is a substrate for the transport proteins Pgp and BCRP (breast cancer resistance protein). Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin, St. John's wort) of these proteins may alter the exposure and/or disposition of lapatinib (see section 5.2).

Lapatinib solubility is pH-dependent. Co-administration with agents that increase gastric pH should be avoided as solubility and absorption of lapatinib may be reduced. Pretreatment with a proton pump inhibitor (esomeprazole) reduces lapatinib exposure by an average of 27% (range 6 to 49%). This effect decreases with increasing patient age from 40 to 60 years.

Effects of lapatinib on other medicinal products

Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Co-administration of Tyverb with oral midazolam increased the AUC of midazolam by approximately 45%. No clinically relevant increase in midazolam AUC was observed when midazolam was administered intravenously. Co-administration of lapatinib with oral drugs with a narrow therapeutic index that are substrates for CYP3A4, such as cisapride, pimozide, or quinidine, should be avoided (see sections 4.4 and 5.2).

Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of Tyverb with drugs with a narrow therapeutic index that are substrates for CYP2C8 (e.g. repaglinide) should be avoided (see sections 4.4 and 5.2).

Concomitant use of lapatinib with intravenous paclitaxel increases paclitaxel exposure by 23% due to inhibition of CYP2C8 and/or P-glycoprotein (Pgp) by lapatinib. In clinical studies, this combination has been shown to increase the incidence and severity of diarrhea and neutropenia. Lapatinib should be used with caution in combination with paclitaxel.

Co-administration of lapatinib with intravenous docetaxel did not significantly affect the AUC or Cmax of either active substance. However, the incidence of docetaxel-induced neutropenia was increased.

Co-administration of Tyverb with irinotecan (as part of the FOLFIRI regimen) increases the AUC of SN-38, the active metabolite of irinotecan, by approximately 40%. The exact mechanism of this interaction is unknown, but it is thought to be related to inhibition of one or more transport proteins by lapatinib. Tyverb should be used with caution in combination with irinotecan, with careful monitoring for adverse reactions and consideration of the need for a dose reduction of irinotecan.

Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical significance of these effects has not been studied. It cannot be excluded that lapatinib may affect the pharmacokinetics of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) substrates (see section 5.2).

Co-administration of Tyverb with capecitabine, letrozole, or trastuzumab does not significantly affect the pharmacokinetics of these drugs (or metabolites of capecitabine) or lapatinib.

Interactions with food and drink

The bioavailability of lapatinib is increased up to 4-fold when administered with food, depending on the fat content of the food. Furthermore, depending on the type of food, the bioavailability of lapatinib is approximately 2-3-fold higher when administered 1 hour after a meal compared to when administered 1 hour before the first meal of the day (see sections 4.2 and 5.2).

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

Application features

The data indicate that the combination of Tyverb with chemotherapy is less effective than the combination of trastuzumab with chemotherapy.

Cardiotoxicity

Decreased left ventricular ejection fraction has been reported with lapatinib (see section 4.8). Lapatinib has not been evaluated in patients with symptomatic heart failure. Lapatinib should be used with caution in patients with impaired left ventricular function (including concomitant use with potentially cardiotoxic drugs). Left ventricular ejection fraction should be determined in all patients before initiating treatment with Tyverb to ensure that the baseline value is within the established range. Ejection fraction should be monitored during treatment with Tyverb to avoid a decrease below the acceptable range (see section 4.2). In some cases, decreased left ventricular ejection fraction may be severe and result in heart failure. Fatalities have been reported, although the cause remains unknown. In the lapatinib clinical trial program, cardiac adverse reactions, including decreased left ventricular ejection fraction, were observed in approximately 1% of patients treated with lapatinib. Symptomatic decreases in left ventricular ejection fraction were observed in approximately 0.3% of patients treated with lapatinib. However, in a pivotal clinical trial, lapatinib in combination with trastuzumab in patients with metastatic disease had a higher incidence of cardiac adverse reactions, including decreased left ventricular ejection fraction (7%) than lapatinib monotherapy (2%). The nature and severity of cardiac adverse reactions in this study were similar to those previously observed with lapatinib.

Concentration-dependent prolongation of the QTc interval was demonstrated in a dedicated placebo-controlled crossover study in patients with advanced solid tumors.

Therefore, caution should be exercised when administering Tyverb to patients with potential QT prolongation (such as hypokalemia, hypomagnesemia, and congenital QT prolongation) or concomitantly with other medicinal products that may prolong the QT interval or increase lapatinib exposure, such as potent CYP3A4 inhibitors.

Hypokalemia or hypomagnesemia should be corrected before starting treatment. Electrocardiography with QT interval measurement should be performed before starting treatment and 1–2 weeks after starting treatment with Tyverb.

ECG should be performed as clinically indicated, for example after initiation of concomitant medications that may affect the QT interval or interact with lapatinib.

Interstitial lung diseases and pneumonitis

Lapatinib has been associated with pulmonary toxicity, including interstitial lung disease and pneumonitis (see Adverse Reactions). Patients should be monitored for symptoms of pulmonary toxicity (dyspnea, cough, fever) and treatment should be discontinued in patients who develop Grade 3 or greater (National Cancer Institute Adverse Reactions). Pulmonary toxicity can be severe and may result in respiratory failure. Fatalities have been reported, although the causes of these events remain unclear.

Hepatotoxicity, which in rare cases can be fatal, has been reported during treatment with Tyverb. Hepatotoxicity can occur within a few days to several months after initiation of treatment. Patients should be informed of the potential for hepatotoxicity at the start of treatment. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored prior to initiation of treatment, monthly during treatment, and as clinically indicated. If liver function changes are severe, Tyverb treatment should be discontinued and not restarted. Patients who carry the HLA allele DQA1*02:01 and DRB1*07:01 are at increased risk of hepatotoxicity associated with Tyverb. In a large randomized clinical trial of Tyverb monotherapy (1194 patients), the overall risk of severe liver injury (ALT ≥5 times the upper limit of normal, National Cancer Institute Grade 3 adverse reaction) was 2.8% after 1 year of treatment. The overall incidence in carriers of the DQA1*02:01 and DRB1*07:01 alleles was 10.3%, compared with 0.5% in patients who did not carry these alleles. HLA allele carriage is common (15–25%) in Caucasians, Asians, African Americans, and Hispanics, but is lower (1%) in Japanese.

Tyverb should be used with caution in patients with moderate or severe hepatic impairment and in patients with severe renal impairment (see sections 4.2 and 5.2).

Diarrhea

Diarrhea, including severe cases, has been reported with Tyverb (see Adverse Reactions). Diarrhea can be potentially life-threatening if accompanied by dehydration, renal failure, neutropenia and/or electrolyte imbalance. Fatalities have been reported. Diarrhea usually occurs early in Tyverb treatment, with approximately half of patients with diarrhea experiencing the first episode within 6 days. Diarrhea usually lasts 4 to 5 days. Diarrhea associated with Tyverb is usually mild, with severe diarrhea of National Cancer Institute Grade 3 and 4 occurring in < 10% and < 1% of patients, respectively. At the beginning of treatment, the patient's stool pattern and any other symptoms (fever, cramping pain, nausea, vomiting, dizziness, and thirst) should be recorded in order to monitor changes during treatment and to identify patients at increased risk of developing diarrhea. Patients should be advised to report any changes in bowel habits immediately. In potentially severe cases of diarrhea, neutrophil counts and body temperature should be measured. Prompt treatment of diarrhea with antidiarrheal medications is essential. In severe cases, oral or intravenous administration of electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhea lasts more than 24 hours, there is fever or grade 3 or 4 neutropenia), interruption or discontinuation of Tyverb may be required (see section “Method of administration and dosage” – “Discontinuation or dose reduction” – “Diarrhea”).

Severe skin reactions

Severe skin reactions have been reported with Tyverb. If erythema multiforme or life-threatening reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal lesions) are suspected, Tyverb treatment should be discontinued.

Concomitant use with CYP3A4 inhibitors and inducers

Concomitant use of lapatinib with CYP3A4 inhibitors and inducers should be undertaken with caution due to increased or decreased lapatinib concentrations, respectively (see section 4.5).

Grapefruit juice should be avoided during treatment with lapatinib (see section 4.5).

Co-administration of Tyverb with other medicinal products with a narrow therapeutic index that are substrates for CYP3A4 and/or CYP2C8 should be avoided (see section “Interaction with other medicinal products and other forms of interaction”).

Concomitant use with substances that increase gastric pH should be avoided as the solubility and absorption of lapatinib may be reduced (see section 4.5).

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Women of reproductive age

Women of childbearing potential should be advised to use appropriate contraception and avoid pregnancy during treatment with Tyverb and for at least 5 days after the last dose.

Pregnancy

There are no data on the use of Tyverb in pregnant women. Animal studies have shown reproductive toxicity (see section 5.1). The potential risk to humans is unknown.

Breast-feeding

The safety of Tyverb during breastfeeding has not been established. It is not known whether lapatinib is excreted in human milk. In rats, growth retardation was observed in offspring exposed to lapatinib via breast milk. Women receiving Tyverb should discontinue breastfeeding during treatment and for at least 5 days after the last dose.

Fertility

There are no data on the use of Tyverb in women of reproductive age.

Ability to influence reaction speed when driving vehicles or other mechanisms

Tyverb does not affect the ability to drive or use machines. Given the pharmacological properties of lapatinib, its adverse effects on such activities are unlikely. However, when deciding on the patient's ability to perform work that requires increased concentration and speed of psychomotor reactions, attention should be paid to the patient's clinical condition and the nature of adverse reactions.

Method of administration and doses

A course of treatment with Tyverb is prescribed only by a doctor who has experience in the use of anticancer drugs.

HER2 (ErbB2) overexpression status should be established by the presence of IHC3+ or IHC2+ with gene amplification or by gene amplification alone. HER2 status should be determined using accurate and validated methods.

Doses

Tyverb in combination with capecitabine

The recommended dose of Tyverb is 1250 mg (5 tablets) once daily.

The recommended dose of capecitabine is 2000 mg/m2/day in 2 divided doses (every 12 hours) each day from day 1 to day 14 of a 21-day treatment cycle. It is recommended to take capecitabine with food or within 30 minutes after a meal (see the capecitabine Summary of Product Characteristics).

Tyverb in combination with trastuzumab

The recommended dose of Tyverb is 1000 mg (4 tablets) once daily.

The recommended dose of trastuzumab is 4 mg/kg body weight as an intravenous loading dose, followed by 2 mg/kg body weight intravenously once a week (see the instructions for medical use of trastuzumab).

Tyverb in combination with an aromatase inhibitor

The recommended dose of Tyverb is 1500 mg (6 tablets) once daily.

When using Tyverb with an alternative aromatase inhibitor, it is necessary to read the instructions for medical use of this drug.

Discontinuation or dose reduction

Cardiovascular system disorders

Treatment with Tyverb should be discontinued if symptoms associated with a decrease in left ventricular ejection fraction to grade 3 or greater (according to the National Cancer Institute classification) appear or if the ejection fraction has fallen below the acceptable normal level (see section "Special instructions for use"). Treatment with Tyverb can be resumed at a reduced dose (1000 mg/day when used with capecitabine, 750 mg/day when used with trastuzumab or 1250 mg/day when used with an aromatase inhibitor) no earlier than after 2 weeks and only when the level of left ventricular ejection fraction is within the normal range and the patient does not have symptoms associated with a decrease in left ventricular ejection fraction.

Interstitial lung disease/pneumonitis

Treatment with Tyverb should be discontinued if pulmonary symptoms suggestive of interstitial lung disease/pneumonitis grade 3 or higher (National Cancer Institute Adverse Reactions Classification) occur (see section 4.4).

Diarrhea

Treatment with Tyverb should be discontinued for Grade 3 diarrhea or Grade 1 or 2 diarrhea (according to the National Cancer Institute Adverse Reaction Classification) with signs of complications (moderate to severe abdominal cramps, nausea or vomiting greater than or equal to Grade 2 (according to the National Cancer Institute Adverse Reaction Classification), decreased performance status, fever, sepsis, neutropenia, overt bleeding, or dehydration) (see sections 4.4 and 4.8). Tyverb treatment may be resumed at a reduced dose (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 I or less. Treatment with Tyverb should be permanently discontinued if the patient develops Grade 4 diarrhea (National Cancer Institute Adverse Reaction Classification).

Other manifestations of drug toxicity

A decision to discontinue or interrupt treatment may be made if the patient experiences toxicity greater than or equal to Grade 2 on the National Cancer Institute Adverse Reactions List. Treatment may be resumed at the standard dose of 1250 mg/day with capecitabine, 1000 mg with trastuzumab, or 1500 mg/day with an aromatase inhibitor if toxicity resolves to Grade 1 or less. If toxicity recurs, the dose of Tyverb may be reduced to 1000 mg/day with capecitabine, 750 mg/day with trastuzumab, or 1250 mg/day with an aromatase inhibitor.

Patients with mild to moderate renal impairment do not require dose adjustment. Tyverb should be used with caution in patients with severe renal impairment as there is no experience in this patient group. Hepatic impairment

If changes in liver function are severe, the use of Tyverb should be discontinued and never resumed (see section "Special warnings and precautions for use").

Due to increased drug exposure, Tyverb should be administered with caution to patients with moderate or severe hepatic impairment. There are currently insufficient data to provide dose adjustment recommendations for patients with hepatic impairment.

Elderly patients

Data on the use of Tyverb in combination with capecitabine and Tyverb in combination with trastuzumab in patients aged 65 years and older are limited.

In a phase III clinical trial of Tyverb in combination with letrozole in patients with hormone receptor-positive metastatic breast cancer (all randomised patients by treatment assignment, N = 642), 44% of participants were aged 65 years or older. There were no overall differences in the efficacy and safety of Tyverb in combination with letrozole between these patients and patients aged <65 years.

Method of application

Tyverb is intended for oral use.

The daily dose of Tyverb should not be divided. Tyverb should be taken at least one hour before or at least one hour after a meal. To reduce individual variability in each individual patient, Tyverb administration should be standardized with respect to food intake, e.g. always taking the drug one hour before a meal (see sections “Interaction with other medicinal products and other forms of interaction”, “Pharmacokinetics” for information on absorption).

Missed doses of the drug should not be taken additionally, the next dose should be taken according to the application schedule (see the section "Overdose").

When used concomitantly with other drugs, the prescribing information for these drugs should be consulted for dosage instructions, including dose reduction, contraindications, and safety information.

Children

The safety and efficacy of Tyverb in children (under 18 years of age) have not been established. Data are not available.

Overdose

There is no specific antidote for inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine phosphorylation. The maximum daily dose used in studies was 1800 mg.

There have been reports of asymptomatic or symptomatic overdose in patients treated with Tyverb. In patients receiving up to 5000 mg of lapatinib, symptoms included known adverse reactions associated with Tyverb (see section 4.8), and in some cases scalp lesions and/or mucosal inflammation, sinus tachycardia (with normal ECG) and/or mucosal inflammation. In one case, sinus tachycardia (with normal ECG) was also observed in a patient receiving 9000 mg of Tyverb.

Renal excretion is not a significant route of elimination of Tyverb, and the drug is highly bound to plasma proteins, so hemodialysis may not be an effective method of eliminating Tyverb. Symptomatic therapy should be administered according to the clinical condition or according to national guidelines for the treatment of poisoning.

Side effects

The safety of Tyverb has been studied both as monotherapy and in combination with other chemotherapeutic agents for the treatment of various types of cancer in more than 20,000 patients, including 198 patients who received lapatinib in combination with capecitabine, 149 patients who received lapatinib in combination with trastuzumab, and 654 patients who received lapatinib in combination with letrozole (see section 5.1).

The most common adverse reactions (> 25%) during treatment with lapatinib were gastrointestinal events (such as diarrhea, nausea, and vomiting) and rash. Palmar-plantar erythrodysesthesia [PPE] was also commonly observed (> 25%) when lapatinib was used in combination with capecitabine. The incidence of PPE was similar between the lapatinib plus capecitabine and capecitabine monotherapy groups. Diarrhea was the most common adverse reaction leading to treatment discontinuation when lapatinib was used in combination with capecitabine or with letrozole.

No additional adverse reactions were reported when lapatinib was used in combination with trastuzumab. An increased incidence of cardiac toxicity was noted, but these events were similar in nature and severity to those observed in the lapatinib clinical trial program (see section 4.4. Cardiotoxicity). These data are based on exposure to this combination in 149 patients in the pivotal trial.

Tabulated list of adverse reactions

The following classification of the frequency of side effects is used: very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1000 - < 1/100); rare (< 1/10000); frequency unknown (frequency cannot be estimated from the available data).

Within each grouping, adverse reactions are presented in order of decreasing seriousness.

* These adverse reactions have been observed when lapatinib was used in combination with capecitabine.

† These adverse reactions have been observed with lapatinib in combination with letrozole.

** Adverse reactions that were obtained from spontaneous reports and publications.

Description of selected adverse reactions

Decreased left ventricular ejection fraction and prolonged QT interval

Decreased left ventricular ejection fraction (LVEF) was observed in approximately 1% of patients treated with lapatinib, with more than 70% of cases being asymptomatic. The condition improved or recovered in more than 70% of cases, of which nearly 60% were treated with lapatinib, and approximately 40% were treated with lapatinib for continuation. Symptomatic decreases in LVEF were observed in 0.3% of patients treated with lapatinib as monotherapy or in combination with other anticancer drugs. Symptoms included dyspnea, heart failure, and palpitations. Overall, 58% of these patients, who were not