Chemical formula: C₂₉H₂₆ClFN₄O₄S Molecular mass: 581.058 g/mol PubChem compound: 208908
Lapatinib interacts in the following cases:
Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Co-administration of lapatinib with medicinal products with narrow therapeutic windows that are substrates of CYP2C8 (e.g. repaglinide) should be avoided.
Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of this effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin).
Lapatinib is predominantly metabolised by CYP3A.
In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased approximately 72%. Co-administration of lapatinib with known inducers of CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum [St. John’s Wort]) should be avoided.
Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Co-administration of lapatinib with orally administered midazolam resulted in an approximate 45% increase in the AUC of midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed intravenously. Co-administration of lapatinib with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should be avoided.
Lapatinib should be discontinued if changes in liver function are severe and patients should not be retreated.
Administration of lapatinib to patients with moderate to severe hepatic impairment should be undertaken with caution due to increased exposure to the medicinal product. Insufficient data are available in patients with hepatic impairment to provide a dose adjustment recommendation.
Grapefruit juice may inhibit CYP3A4 in the gut wall and increase the bioavailability of lapatinib and should therefore be avoided during treatment with lapatinib.
Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, and erythromycin) and inducers (rifampicin and St. John’s Wort) of these proteins may alter the exposure and/or distribution of lapatinib.
Lapatinib inhibits the transport protein Pgp in vitro at clinically relevant concentrations. Co-administration of lapatinib with orally administered digoxin resulted in an approximate 80% increase in the AUC of digoxin. Caution should be exercised when dosing lapatinib concurrently with medicinal products with narrow therapeutic windows that are substrates of Pgp, and a reduction in the dose of the Pgp substrate should be considered.
Lapatinib is predominantly metabolised by CYP3A.
In healthy volunteers receiving ketoconazole, a strong CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure to lapatinib (100 mg daily) was increased approximately 3.6–fold, and half-life increased 1.7–fold. Co-administration of lapatinib with strong inhibitors of CYP3A4 (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided.
Lapatinib is predominantly metabolised by CYP3A.
Co-administration of lapatinib with moderate inhibitors of CYP3A4 should proceed with caution and clinical adverse reactions should be carefully monitored.
Caution is advised in patients with severe renal impairment as there is no experience of lapatinib in this population.
The solubility of lapatinib is pH-dependent. Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 27% (range: 6% to 49%). This effect decreases with increasing age from approximately 40 to 60 years.
Co-administration of lapatinib with intravenously administered docetaxel did not significantly affect the AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced neutropenia was increased.
Co-administration of lapatinib with irinotecan (when administered as part of the FOLFIRI regimen) resulted in an approximate 40% increase in the AUC of SN-38, the active metabolite of irinotecan. The precise mechanism of this interaction is unknown, but it is assumed to be due to inhibition of one or more transport proteins by lapatinib. Adverse reactions should be carefully monitored if lapatinib is co-administered with irinotecan, and a reduction in the dose of irinotecan should be considered.
Co-administration of lapatinib with intravenous paclitaxel increased the exposure of paclitaxel by 23%, due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity of diarrhoea and neutropenia has been observed with this combination in clinical studies. Caution is advised if lapatinib is co-administered with paclitaxel.
A concentration-dependent increase of the QTc interval was demonstrated in a dedicated placebo-controlled crossover study in subjects with advanced solid tumours.
Caution should be taken if lapatinib is administered to patients with conditions that could result in prolongation of QTc (including hypokalemia, hypomagnesemia, and congenital long QT syndrome), co-administration of other medicinal product known to cause QT prolongation, or conditions that increase the exposure of lapatinib, such as co-administration of strong CYP3A4 inhibitors. Hypokalemia or hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QT measurement should be performed prior to and one to two weeks after the start of lapatinib therapy. When clinically indicated, e.g. after initiation of a concomitant treatment that might affect QT or that may interact with lapatinib, ECG measurement should also be considered.
Lapatinib has been associated with reports of decreases in LVEF. Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if lapatinib is to be administered to patients with conditions that could impair left ventricular function (including co-administration with potentially cardiotoxic medicinal products). Evaluation of cardiac function, including LVEF determination, should be conducted for all patients prior to initiation of treatment with lapatinib to ensure that the patient has a baseline LVEF that is within the institutions normal limits. LVEF should continue to be evaluated during treatment with lapatinib to ensure that LVEF does not decline to an unacceptable level. In some cases, LVEF decrease may be severe and lead to cardiac failure. Fatal cases have been reported, causality of the deaths is uncertain.
Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis. Patients should be monitored for symptoms of pulmonary toxicity (dyspnoea, cough, fever) and treatment discontinued in patients who experience symptoms which are NCI CTCAE grade 3 or greater. Pulmonary toxicity may be severe and lead to respiratory failure. Fatal cases have been reported, causality of the deaths is uncertain.
Serious cutaneous reactions have been reported with lapatinib. 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, discontinue treatment with lapatinib.
Hepatotoxicity has occurred with lapatinib use and may in rare cases be fatal. The hepatotoxicity may occur days to several months after initiation of treatment. At the initiation of treatment, patients should be advised of the potential for hepatotoxicity. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before the initiation of treatment and monthly thereafter, or as clinically indicated. Lapatinib dosing should be discontinued if changes in liver function are severe and patients should not be retreated. Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of lapatinib-associated hepatotoxicity.
Diarrhoea, including severe diarrhoea, has been reported with lapatinib treatment. Diarrhoea can be potentially life-threatening if accompanied by dehydration, renal insufficiency, neutropenia and/or electrolyte imbalances and fatal cases have been reported. Diarrhoea generally occurs early during lapatinib treatment, with almost half of those patients with diarrhoea first experiencing it within 6 days. This usually lasts 4-5 days. Lapatinib-induced diarrhoea is usually low-grade, with severe diarrhoea of NCI CTCAE grades 3 and 4 occurring in <10% and <1% of patients, respectively. At the start of therapy, the patients bowel pattern and any other symptoms (e.g. fever, cramping pain, nausea, vomiting, dizziness and thirst) should be determined, to allow identification of changes during treatment and to help identify patients at greater risk of diarrhoea. Patients should be instructed to promptly report any change in bowel patterns. In potentially severe cases of diarrhoea the measuring of neutrophil counts and body temperature should be considered. Proactive management of diarrhoea with anti-diarrhoeal medicinal product is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhoea is persistent beyond 24 hours, there is fever, or grade 3 or 4 neutropenia) and interruption or discontinuation of lapatinib therapy.
Lapatinib dosing should be interrupted in patients with diarrhoea which is NCI CTCAE grade 3 or grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration). Lapatinib may be reintroduced at a lower dose (reduced 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 diarrhoea resolves to grade 1 or less. Lapatinib dosing should be permanently discontinued in patients with diarrhoea which is NCI CTCAE grade 4.
There are no adequate data from the use of lapatinib in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is not known. Lapatinib should not be used during pregnancy unless clearly necessary.
The safe use of lapatinib during breast-feeding has not been established. It is not known whether lapatinib is excreted in human milk. In rats, growth retardation was observed in pups which were exposed to lapatinib via breast milk. Breast-feeding must be discontinued in women who are receiving therapy with lapatinib and for at least 5 days after the last dose.
Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with lapatinib and for at least 5 days after the last dose.
There are no adequate data from the use of lapatinib in women of childbearing potential.
Lapatinib has no influence on the ability to drive and use machines. A detrimental effect on such activities cannot be predicted from the pharmacology of lapatinib. The clinical status of the patient and the safety profile of lapatinib should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor or cognitive skills.
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.
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. These data are based on exposure to this combination in 149 patients in the pivotal trial.
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.
Rare: Hypersensitivity reactions including anaphylaxis
Very common: Anorexia
Very common: Insomnia*
Very common: Headache†
Common: Headache*
Common: Decreased left ventricular ejection fraction
Not known: Ventricular arrhythmias/Torsades de Pointes, electrocardiogram QT prolonged**
Very common: Hot flush†
Very common: Epistaxis†, cough†, dyspnoea†.
Uncommon: Interstitial lung disease/pneumonitis.
Not known: Pulmonary arterial hypertension**.
Very common: Diarrhoea, which may lead to dehydration, nausea, vomiting, dyspepsia*, stomatitis*, constipation*, abdominal pain*.
Common: Constipation†
Common: Hyperbilirubinaemia, hepatotoxicity.
Very common: Rash (including dermatitis acneiform), dry skin*†, palmar-plantar erythrodysaesthesia*, alopecia†, pruritus†.
Common: Nail disorders including paronychia.
Not known: Serious cutaneous reactions, including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)**
Very common: Pain in extremity*†, back pain*†, arthralgia†.
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
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.
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. However, a few cases of acute renal failure have been reported secondary to severe dehydration due to diarrhoea.
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.
The risk of lapatinib-induced hepatotoxicity was associated with carriage of the HLA alleles DQA1*02:01 and DRB1*07:01.
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