Lapatinib

Lapatinib is a 4-anilinoquinazoline that inhibits the intracellular tyrosine kinase domains of the epidermal growth factor receptor (EGFR, ErbB1) and of HER2 (ErbB2). It dissociates slowly from both receptors.

Mechanism of Action

• Dual receptor inhibition: the estimated apparent Ki values are 3 nM for EGFR and 13 nM for HER2, with a slow off-rate (a dissociation half-life of 300 minutes or more).
• Antitumour effect: lapatinib inhibits ErbB-driven tumour cell growth in vitro and in several animal models.
• With trastuzumab: the two medicines may complement each other and have non-overlapping mechanisms of resistance. Lapatinib kept significant activity in HER2-amplified breast cancer cell lines selected for long-term growth in trastuzumab-containing medium, and was synergistic with trastuzumab in these lines.
• With capecitabine: an additive effect with 5-fluorouracil, the active metabolite of capecitabine, was shown in vitro in the four tumour cell lines tested.
• QT interval: a concentration-dependent increase in the QTc interval was shown in a dedicated placebo-controlled study (see Special Instructions).

Pharmacokinetics

• Absorption: absolute bioavailability is unknown; absorption is incomplete and variable (coefficient of variation about 70% for AUC). Plasma levels appear after a median lag time of 0.25 hours and peak about 4 hours after a dose. Food raises exposure sharply: AUC was about 3-fold higher after a low-fat meal and 4-fold higher after a high-fat meal than when fasting. Dosing 1 hour after a low-fat or high-fat meal gave about 2-fold and 3-fold higher AUC than dosing 1 hour before a low-fat breakfast.
• Distribution: more than 99% bound to albumin and alpha-1 acid glycoprotein. Lapatinib is a substrate of the transporters BCRP and P-glycoprotein; in vitro it also inhibits these and the hepatic uptake transporter OATP1B1 at clinically relevant concentrations.
• Metabolism: extensive, mainly by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8. No oxidised metabolite accounts for more than 14% of the dose recovered in faeces or more than 10% of the plasma lapatinib concentration. In vitro, lapatinib inhibits CYP3A and CYP2C8 at clinically relevant concentrations but did not significantly inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 or UGT enzymes.
• Elimination: the half-life after a single dose is about 14 hours; with repeated dosing the effective half-life is about 24 hours.
• Special populations: exposure is increased in moderate to severe hepatic impairment. Mild to moderate renal impairment needs no dose adjustment; there is no experience in severe renal impairment.

Lapatinib is indicated for adult patients with breast cancer whose tumours overexpress HER2 (ErbB2), in three combinations:

• With capecitabine: advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines, taxanes and trastuzumab in the metastatic setting.
• With trastuzumab: hormone receptor-negative metastatic disease that has progressed on earlier trastuzumab therapy given with chemotherapy.
• With an aromatase inhibitor: postmenopausal women with hormone receptor-positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study had not been treated before with trastuzumab or an aromatase inhibitor, and no data are available on the efficacy of this combination compared with trastuzumab plus an aromatase inhibitor in this patient group.

HER2 overexpression is defined by IHC 3+, or IHC 2+ with gene amplification, or gene amplification alone, and the HER2 status must be determined by accurate and validated methods.

• Hypersensitivity to lapatinib or to any of the excipients.

The most common reactions (in more than 25% of patients) are gastrointestinal events (diarrhoea, nausea, vomiting) and rash. Palmar-plantar erythrodysaesthesia was also common (more than 25%) with capecitabine, at a similar rate to capecitabine alone. Diarrhoea was the most common reaction leading to discontinuation with capecitabine or letrozole. With trastuzumab no additional reactions were reported, but cardiac toxicity was more frequent. The reactions below were reported with lapatinib alone or combined with capecitabine, trastuzumab or letrozole.

Very common (≥1/10): anorexia, diarrhoea (which can lead to dehydration), nausea, vomiting, rash (including acneiform dermatitis) and fatigue. With capecitabine: insomnia, dyspepsia, stomatitis, constipation, abdominal pain, palmar-plantar erythrodysaesthesia and mucosal inflammation. With letrozole: headache, hot flush, epistaxis, cough, dyspnoea, alopecia, pruritus, arthralgia and asthenia. With either: dry skin, pain in an extremity and back pain.

Common (≥1/100 to <1/10): decreased left ventricular ejection fraction, hyperbilirubinaemia, hepatotoxicity, nail disorders (including paronychia) and skin fissures; headache with capecitabine; constipation with letrozole.

Uncommon (≥1/1,000 to <1/100): interstitial lung disease or pneumonitis.

Rare (≥1/10,000 to <1/1,000): hypersensitivity reactions including anaphylaxis.

Not known: ventricular arrhythmias or torsades de pointes with QT prolongation, pulmonary arterial hypertension, and severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (these come from spontaneous reports and published cases).

The important serious reactions are decreased left ventricular ejection fraction (fatal cases reported, causality uncertain), interstitial lung disease or pneumonitis, hepatotoxicity (rarely fatal), severe diarrhoea and serious skin reactions.

Lapatinib is cleared mainly by CYP3A and is a substrate of P-glycoprotein (Pgp) and BCRP. It also inhibits CYP3A4, CYP2C8 and Pgp in vitro, so it can raise levels of other medicines.

Effects of other medicines and food on lapatinib

• Strong CYP3A4 inhibitors (ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone): avoid. Ketoconazole raised lapatinib exposure about 3.6-fold and its half-life 1.7-fold in healthy volunteers. With moderate CYP3A4 inhibitors, proceed with caution and monitor for adverse reactions.
• CYP3A4 inducers (rifampicin, rifabutin, carbamazepine, phenytoin, St John’s wort): avoid. Carbamazepine lowered lapatinib exposure by about 72%.
• Pgp and BCRP modulators: inhibitors (ketoconazole, itraconazole, quinidine, verapamil, ciclosporin, erythromycin) and inducers (rifampicin, St John’s wort) of these transporters may change lapatinib exposure and distribution.
• Medicines that raise gastric pH: avoid, because lapatinib solubility depends on pH. Pre-treatment with a proton pump inhibitor (esomeprazole) lowered exposure by an average of 27% (range 6–49%), an effect that fades with increasing age from about 40 to 60 years.
• Food and grapefruit: food raises bioavailability up to about 4-fold, and exposure is about 2 to 3 times higher when taken 1 hour after food than 1 hour before the first meal of the day. Grapefruit juice may inhibit CYP3A4 in the gut wall and raise lapatinib levels, so it should be avoided.

Effects of lapatinib on other medicines

• CYP3A4 substrates: an oral CYP3A4 probe substrate showed about 45% higher exposure (no meaningful change when it was given intravenously). Avoid orally administered CYP3A4 substrates with a narrow therapeutic window, such as cisapride, pimozide and quinidine.
• CYP2C8 substrates: avoid those with a narrow therapeutic window, such as repaglinide.
• Paclitaxel (intravenous): exposure rose by 23%, with more frequent and severe diarrhoea and neutropenia. Use with caution.
• Docetaxel (intravenous): no significant change in the AUC or Cmax of either medicine, but docetaxel-induced neutropenia was more frequent.
• Irinotecan (in the FOLFIRI regimen): exposure to the active metabolite SN-38 rose about 40%. Monitor adverse reactions and consider reducing the irinotecan dose.
• Pgp substrates: oral digoxin exposure rose by about 80%. Use caution with narrow-therapeutic-window Pgp substrates and consider a lower dose of the substrate.
• BCRP and OATP1B1 substrates (topotecan, rosuvastatin): the clinical relevance has not been evaluated, but an effect cannot be excluded.
• Capecitabine, letrozole and trastuzumab: no meaningful change in their pharmacokinetics or in those of lapatinib.

Treatment must be started only by a physician experienced in the use of anti-cancer medicinal products. The tablets are taken once daily, continuously, and the daily dose must not be divided. They are taken at least one hour before or at least one hour after food, and the timing in relation to meals should be standardised (for example, always one hour before a meal) to limit variability between doses. The prescribing information of the combination partner should be consulted for its dosing, dose reductions, contraindications and safety information.

Recommended Dose

• With capecitabine: lapatinib 1,250 mg (five tablets) once daily, continuously. Capecitabine 2,000 mg/m² per day in two doses 12 hours apart on days 1–14 of a 21-day cycle, taken with food or within 30 minutes after food.
• With trastuzumab: lapatinib 1,000 mg (four tablets) once daily, continuously. Trastuzumab 4 mg/kg as an intravenous loading dose, then 2 mg/kg intravenously every week.
• With an aromatase inhibitor: lapatinib 1,500 mg (six tablets) once daily, continuously. The aromatase inhibitor is dosed according to its own SmPC.

Dose Delay and Reduction

• Cardiac events: stop lapatinib for symptoms associated with a decreased left ventricular ejection fraction (LVEF) of NCI CTCAE grade 3 or higher, or if the LVEF falls below the institution’s lower limit of normal. After at least 2 weeks, once the LVEF has recovered to normal and the patient has no symptoms, it may be restarted at a reduced dose: 750 mg/day with trastuzumab, 1,000 mg/day with capecitabine or 1,250 mg/day with an aromatase inhibitor.
• Interstitial lung disease or pneumonitis: stop for pulmonary symptoms of grade 3 or higher.
• Diarrhoea: interrupt dosing for grade 3 diarrhoea, or grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting of grade 2 or higher, decreased performance status, fever, sepsis, neutropenia, frank bleeding or dehydration). When it settles to grade 1 or less, restart at a lower dose (1,000 to 750 mg/day, 1,250 to 1,000 mg/day, or 1,500 to 1,250 mg/day). Stop permanently for grade 4 diarrhoea.
• Other toxicities: interruption or discontinuation may be considered for toxicity of grade 2 or higher. Once it improves to grade 1 or less, restart at 1,000 mg/day with trastuzumab, 1,250 mg/day with capecitabine or 1,500 mg/day with an aromatase inhibitor. If the toxicity recurs, restart at a lower dose: 750 mg/day with trastuzumab, 1,000 mg/day with capecitabine or 1,250 mg/day with an aromatase inhibitor.
• Severe liver changes: stop lapatinib and do not retreat.

Special Populations

• Renal impairment: no adjustment in mild to moderate impairment; caution in severe impairment, where there is no experience.
• Hepatic impairment: use with caution in moderate to severe impairment because exposure is increased; the data are insufficient to recommend a dose adjustment.
• Elderly: data are limited for the capecitabine and trastuzumab combinations in patients aged 65 or over. In the phase III study with letrozole (642 patients), 44% were 65 or older, with no overall differences in efficacy or safety.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed Dose

Missed doses are not replaced. Dosing resumes with the next scheduled daily dose.

Place in Therapy

Data have shown that lapatinib combined with chemotherapy is less effective than trastuzumab combined with chemotherapy.

Cardiac Toxicity

Lapatinib has been associated with decreases in LVEF, which may be severe and lead to cardiac failure; fatal cases were reported, with the cause of death uncertain. It has not been evaluated in patients with symptomatic cardiac failure, and caution is needed in conditions that could impair left ventricular function, including treatment with potentially cardiotoxic medicines. Cardiac function, including LVEF, must be assessed before treatment to confirm a baseline within the institution’s normal limits, and monitored during treatment. Across the development programme, cardiac events including LVEF decreases occurred in about 1% of patients (symptomatic decreases in about 0.3%); with trastuzumab in the metastatic setting the rate was higher (7%, against 2% with lapatinib alone).

QT Prolongation

Caution is needed in patients with hypokalaemia, hypomagnesaemia or congenital long QT syndrome, with other medicines known to prolong the QT interval, and when lapatinib exposure is raised, for example by strong CYP3A4 inhibitors. Correct hypokalaemia or hypomagnesaemia before treatment. An ECG with QT measurement should be recorded before treatment and one to two weeks after starting, and again when clinically indicated, for example after starting a medicine that may affect the QT interval or interact with lapatinib.

Interstitial Lung Disease and Pneumonitis

Monitor for pulmonary symptoms (dyspnoea, cough, fever) and stop treatment at grade 3 or higher. Pulmonary toxicity may be severe and lead to respiratory failure; fatal cases have been reported, with the cause of death uncertain.

Hepatotoxicity

Hepatotoxicity may occur days to several months after starting and may rarely be fatal. Patients should be told of this risk at the start. Liver function (transaminases, bilirubin and alkaline phosphatase) should be checked before treatment and monthly thereafter, or as clinically indicated. If liver changes are severe, stop lapatinib and do not retreat. Carriers of the HLA alleles DQA1*02:01 and DRB1*07:01 have a higher risk: in a large monotherapy trial (1,194 patients), severe liver injury (ALT above 5 times the upper limit of normal) after one year occurred in 2.8% overall, 10.3% of carriers and 0.5% of non-carriers. Carriage is common (15 to 25%) in Caucasian, Asian, African and Hispanic populations but lower (1%) in Japanese populations. Caution is warranted in moderate or severe hepatic impairment and in severe renal impairment.

Diarrhoea

Diarrhoea, including severe diarrhoea, can be life-threatening if accompanied by dehydration, renal insufficiency, neutropenia or electrolyte imbalance, and fatal cases have been reported. It usually starts early (almost half of affected patients first had it within 6 days) and lasts 4 to 5 days. It is usually low grade; grade 3 and grade 4 diarrhoea occurred in under 10% and under 1% of patients. At the start of treatment the patient’s bowel pattern and other symptoms (fever, cramping pain, nausea, vomiting, dizziness, thirst) should be recorded, and patients should report any change promptly. In potentially severe cases, consider measuring neutrophil counts and body temperature. Proactive treatment with an antidiarrhoeal medicine is important. Severe cases may need oral or intravenous fluids and electrolytes, antibiotics such as fluoroquinolones (especially if diarrhoea lasts beyond 24 hours, with fever, or with grade 3 or 4 neutropenia), and interruption or discontinuation of lapatinib.

Serious Skin Reactions

Serious skin reactions have been reported. Stop lapatinib if erythema multiforme or a life-threatening reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis (for example, a progressive rash often with blisters or mucosal lesions) is suspected.

Interacting Medicines and Food

Avoid CYP3A4 inducers and strong CYP3A4 inhibitors, grapefruit juice, medicines that raise gastric pH, and orally administered CYP3A4 or CYP2C8 substrates with a narrow therapeutic window.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use adequate contraception and avoid becoming pregnant during treatment and for at least 5 days after the last dose.
• Pregnancy: there are no adequate data in pregnant women. Animal studies showed reproductive toxicity, and the risk to humans is not known. Lapatinib should not be used in pregnancy unless clearly necessary.
• Breastfeeding: safe use has not been established, and it is not known whether lapatinib passes into human milk. Growth retardation was seen in rat pups exposed through milk. Breastfeeding must be stopped during treatment and for at least 5 days after the last dose.
• Fertility: there are no adequate data in women of childbearing potential.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Lapatinib has no influence on the ability to drive and use machines, and a harmful effect cannot be predicted from its pharmacology. The patient’s clinical status and the safety profile should be kept in mind for tasks that need judgement, motor or cognitive skills.

Do not store above 30 °C. The tablets are not refrigerated and need no cold chain. Tyverb is supplied in blister packs or bottles; keep it out of the sight and reach of children.

Blister packs: 2 years. Bottles: 3 years. Do not use after the expiry date on the pack.

Prescription only (Rx): a medicinal product subject to restricted medical prescription (Annex II B), started by a physician experienced in the use of anti-cancer medicinal products. Lapatinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.