Tykerb Adverse Reactions

Summary of the safety profile: The safety of lapatinib has been evaluated as monotherapy or in combination with other chemotherapies for various cancers in more than 20,000 patients, including 198 patients who received lapatinib in combination with capecitabine, 149 patients who received lapatinib in combination with trastuzumab and 654 patients who received lapatinib in combination with letrozole (see Pharmacology: Pharmacodynamics under Actions).
The most common adverse reactions (>25%) during therapy with lapatinib were gastrointestinal events (such as diarrhoea, nausea, and vomiting) and rash. Palmar-plantar erythrodysesthesia (PPE) was also common (>25%) when lapatinib was administered in combination with capecitabine. The incidence of PPE was similar in the lapatinib plus capecitabine and capecitabine alone treatment arms. Diarrhoea was the most common adverse reaction resulting in discontinuation of treatment when lapatinib was administered in combination with capecitabine, or with letrozole.
No additional adverse reactions were reported to be associated with lapatinib in combination with trastuzumab. There was an increased incidence of cardiac toxicity, but these events were comparable in nature and severity to those reported from the lapatinib clinical programme (see Cardiac toxicity under Precautions). These data are based on exposure to this combination in 149 patients in the pivotal trial.
Tabulated list of adverse reactions: The following adverse reactions have been reported to have a causal association with lapatinib alone or lapatinib in combination with capecitabine, trastuzumab or letrozole.
The following convention has been utilised for the classification of frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 8.)

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Description of selected adverse reactions: Decreased left ventricular ejection fraction and QT interval prolongation: Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of patients receiving lapatinib and were asymptomatic in more than 70% of cases. LVEF decreases resolved or improved in more than 70% of cases, in approximately 60% of these on discontinuation of treatment with lapatinib, and in approximately 40% of cases lapatinib was continued. Symptomatic LVEF decreases were observed in approximately 0.3% of patients who received lapatinib monotherapy or in combination with other anti-cancer medicinal products. Observed adverse reactions included dyspnoea, cardiac failure and palpitations. Overall 58% of these symptomatic patients recovered. LVEF decreases were reported in 2.5% of patients who received lapatinib in combination with capecitabine, as compared to 1.0% with capecitabine alone. LVEF decreases were reported in 3.1% of patients who received lapatinib in combination with letrozole as compared to 1.3% of patients receiving letrozole plus placebo. LVEF decreases were reported in 6.7% of patients who received lapatinib in combination with trastuzumab, as compared to 2.1% of patients who received lapatinib alone.
A concentration dependent increase in QTcF (maximum mean ΔΔQTcF 8.75 ms; 90% CI 4.08, 13.42) was observed in a dedicated QT study in patients with advanced solid tumours (see Precautions).
Diarrhoea: Diarrhoea occurred in approximately 65% of patients who received lapatinib in combination with capecitabine, in 64% of patients who received lapatinib in combination with letrozole and in 62% of patients who received lapatinib in combination with trastuzumab. Most cases of diarrhoea were grade 1 or 2 and did not result in discontinuation of treatment with lapatinib. Diarrhoea responds well to proactive management (see Precautions). However, a few cases of acute renal failure have been reported secondary to severe dehydration due to diarrhoea.
Rash: Rash occurred in approximately 28% of patients who received lapatinib in combination with capecitabine, in 45% of patients who received lapatinib in combination with letrozole and in 23% of patients who received lapatinib in combination with trastuzumab. Rash was generally low grade and did not result in discontinuation of treatment with lapatinib. Prescribing physicians are advised to perform a skin examination prior to treatment and regularly during treatment. Patients experiencing skin reactions should be encouraged to avoid exposure to sunlight and apply broad spectrum sunscreens with a Sun Protection Factor (SPF) ≥30. If a skin reaction occurs a full body examination should be performed at every visit until one month after resolution. Patients with extensive or persistent skin reactions should be referred to a dermatologist.
Hepatotoxicity: The risk of lapatinib-induced hepatotoxicity was associated with carriage of the HLA alleles DQA1*02:01 and DRB1*07:01 (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.