Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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 and 654 patients who received lapatinib in combination with letrozole (see section 5.1).

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.

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 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.

Immune system disorders
Rare               Hypersensitivity reactions including anaphylaxis (see section 4.3) Metabolism and nutrition disorders
Very common        Anorexia
Psychiatric disorders
Very common        Insomnia*
TYK API MAR22 V2                                                            EU SmPC Feb22 Nervous system disorders
Very common         Headache†
Common              Headache*
Cardiac disorders
Common              Decreased left ventricular ejection fraction (see section 4.2 - dose reduction – cardiac events and section 4.4).
Not known           Ventricular arrhythmias/Torsades de Pointes, electrocardiogram QT prolonged**
Vascular disorders
Very common         Hot flush†
Respiratory, thoracic and mediastinal disorders
Very common         Epistaxis†, cough†, dyspnoea†.
Uncommon            Interstitial lung disease/pneumonitis.
Not known           Pulmonary arterial hypertension**.
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, dyspepsia*, stomatitis*, constipation*, abdominal pain*.
Common              Constipation†
Hepatobiliary disorders
Common              Hyperbilirubinaemia, hepatotoxicity (see section 4.4).
Skin and subcutaneous tissue disorders
Very common         Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose reduction – other toxicities), dry skin*†, palmar-plantar erythrodysaesthesia*, alopecia†, pruritus†.
Common              Nail disorders including paronychia, skin fissures.
Notknown            Serious cutaneous reactions, including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)**
Musculoskeletal and connective tissue disorders
Very common         Pain in extremity*†, back pain*†, arthralgia†.
General disorders and administration site conditions
Very common         Fatigue, mucosal inflammation*, asthenia†.
*     These adverse reactions were observed when lapatinib was administered in combination with capecitabine.
†     These adverse reactions were observed when lapatinib was administered in combination with letrozole.
**    Adverse reactions from spontaneous reports and literature

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 
TYK API MAR22 V2                                                            EU SmPC Feb22 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 section 4.4).

Diarrhoea

Diarrhoea occurred in approximately 65 % of patients who received lapatinib in combination with capecitabine and in 64 % of patients who received lapatinib in combination with letrozole. 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 section 4.4).
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. 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 section 4.4).

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/.