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4.8 Undesirable effects
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The following adverse reactions have been reported to be associated with lapatinib:
Cardiac disorders
Common
Decreased left ventricular ejection fraction (see section 4.2 - dose reduction – cardiac events and section 4.4)
Respiratory, thoracic and mediastinal disorders
Uncommon
Interstitial lung disease/pneumonitis
Gastrointestinal disorders
Very common
Diarrhoea, which may lead to dehydration (see section 4.2 - dose delay and dose reduction – other toxicities and section 4.4).
Nausea
Vomiting
Skin and subcutaneous tissue disorders
Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose reduction – other toxicities)
Nail disorders including paronychia
Immune System Disorders
Rare
Hypersensitivity reactions including anaphylaxis (see Contraindications)
Metabolism and nutrition disorders
Anorexia
General disorders and administration site conditions
Fatigue
Hepatobiliary disorders
Hyperbilirubinaemia, hepatotoxicity
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5.3 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 60 mg/kg/day (4 times the expected human clinical exposure). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (8% and 23% of the expected human clinical exposure, respectively) and abortions at 120 mg/kg/day. At 60 mg/kg/day there were 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 or higher (5 times the expected human clinical exposure). 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 2-fold in mice and male rats, and up to 15-fold in female rats, compared to humans given 1250 mg of lapatinib once daily. 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. There was also an increase in renal infarcts and papillary necrosis in female rats at exposures 7 and 10-fold compared to humans given 1250 mg of lapatinib once daily. The relevance of these findings for humans is uncertain.
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.
Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.