Lapatinib-vista

INSTRUCTIONS for medical use of the medicinal product LAPATINIB-VISTA (LAPATINIB-VISTA)

Composition:

Active substance: lapatinib;

1 tablet contains 405 mg of lapatinib ditosylate, equivalent to 250 mg of lapatinib;

Excipients: microcrystalline cellulose (E 460), sodium starch glycolate (type A), povidone (E 1201), magnesium stearate (E 470b);

Coating: hypromellose (E 464), titanium dioxide (E 171), macrogol (E 1521), polysorbate 80 (E 433), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, almost white, film-coated tablets, embossed with "250" on one side and flat on the other.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Other antineoplastic agents. Protein kinase inhibitors. Lapatinib. ATC code L01XE07.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular domains of the tyrosine kinase receptors EGFR (ErbB1) and HER2 (ErbB2) (calculated Kiapp values of 3 nM and 13 nM, respectively) with slow dissociation from these receptors (half-life ≥ 300 hours). Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

The combination of lapatinib and trastuzumab may demonstrate complementary mechanisms of action, as well as potentially different resistance mechanisms. The ability of lapatinib to inhibit growth has been studied in cell lines exposed to trastuzumab. Lapatinib retained significant activity against HER2-amplified breast cancer cell lines selected for prolonged growth in trastuzumab-containing medium in vitro, and demonstrated an additive effect when combined with trastuzumab in these cell lines.

Pharmacokinetics

Absorption. After oral administration, lapatinib is incompletely and variably absorbed (AUC coefficient of variation approximately 70%). Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are reached approximately 4 hours after administration. Daily administration of a 1250 mg dose results in geometric mean Cmax values at steady state (coefficient of variation) of 2.43 (76%) µg/mL, and AUC values of 36.2 (79%) µg·h/mL.

Systemic exposure to lapatinib increases when administered with food. AUC values increase by 3- and 4-fold (Cmax by approximately 2.5- and 3-fold) when administered with a low-fat meal (5% fat [500 calories]) or a high-fat meal (50% fat [1000 calories]), respectively, compared to fasting. The timing of food intake also affects systemic exposure to lapatinib. Compared to administration 1 hour before a low-fat breakfast, mean AUC values increased approximately 2- and 3-fold when lapatinib was taken 1 hour after a low-fat or high-fat meal, respectively.

Distribution. Lapatinib is highly bound (>99%) to albumin and alpha-1-acid glycoprotein. In vitro studies have shown that lapatinib is a substrate for the efflux transporters BCRP (breast cancer resistance protein) and Pgp (ABCB1). Additionally, in vitro, lapatinib inhibits these efflux transporters as well as the hepatic uptake transporter OATP1B1 at clinically relevant concentrations (IC50 values of 2.3 µg/mL). The clinical significance of these effects on the pharmacokinetics of other drugs, as well as on the pharmacological activity of other anticancer agents, is unknown.

Biological transformation. Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, and to a lesser extent by CYP2C19 and CYP2C8, forming various oxidized metabolites, none of which exceeds 14% of the dose excreted in feces or 10% of lapatinib plasma concentrations.

Lapatinib inhibits CYP3A and CYP2C8 in vitro at clinically relevant concentrations. Lapatinib only weakly inhibits the following hepatic microsomal enzymes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6, or UGT enzymes (in vitro IC50 values ≥ 6.9 µg/mL).

Elimination. The elimination half-life increases in a dose-dependent manner following single doses. Steady state is achieved within 6–7 days of administration. The elimination half-life at steady state is 24 hours. Lapatinib is primarily eliminated via metabolism mediated by CYP3A4/5. Biliary excretion also contributes to elimination. Lapatinib and its metabolites are excreted predominantly in feces. Unchanged lapatinib accounts for a mean of 27% (range 3–67%) of the oral dose excreted in feces. Less than 2% of the administered oral dose (as lapatinib and metabolites) is excreted in urine.

Renal impairment. Specific pharmacokinetic studies of lapatinib in patients with renal impairment or those undergoing hemodialysis have not been conducted. Available data indicate that patients with mild to moderate renal impairment do not require dose adjustment.

Hepatic impairment. The pharmacokinetics of lapatinib were studied in patients with moderate (n = 8) and severe (n = 4) hepatic impairment compared to healthy volunteers with normal liver function (n = 8). Systemic exposure (AUC) of lapatinib after a single 100 mg dose increased by 56% and 85% in patients with moderate and severe hepatic impairment, respectively. Lapatinib should be used with caution in patients with impaired liver function.

Clinical Characteristics

Indications

For use in the treatment of adult female patients with HER2-overexpressing (ErbB2) breast cancer:

• in combination with capecitabine, for patients with advanced or metastatic disease who have disease progression after prior therapy with trastuzumab in combination with an anthracycline and a taxane administered for metastatic disease;
• in combination with trastuzumab, for patients with metastatic hormone receptor-negative disease who have disease progression after chemotherapy regimens that included trastuzumab;
• in combination with an aromatase inhibitor, for postmenopausal women with metastatic hormone receptor-positive disease who have not received chemotherapy (in the registration trial, patients had not been previously treated with trastuzumab or aromatase inhibitors; there are no data on the efficacy of this combination compared to trastuzumab in combination with an aromatase inhibitor in this patient population).

Contraindications

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on lapatinib

Lapatinib is primarily metabolized by CYP3A (see section "Pharmacokinetics").

When coadministered with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 7 days) in healthy volunteers, systemic exposure to lapatinib (100 mg once daily) increased approximately 3.6-fold, and elimination half-life increased 1.7-fold. Concomitant use of lapatinib with strong CYP3A4 inhibitors (such as ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Caution should be exercised and careful monitoring for clinical status and possible adverse reactions is recommended when lapatinib is coadministered with moderate CYP3A4 inhibitors.

When coadministered with the CYP3A4 inducer carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days) in healthy volunteers, systemic exposure to lapatinib decreased by approximately 72%. Concomitant use of Lapatinib-Vista with known CYP3A4 inducers (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, or St. John’s wort) should be avoided.

Lapatinib is a substrate for the transporter proteins P-glycoprotein (Pgp) and BCRP (breast cancer resistance protein). Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin, St. John’s wort) of these proteins may alter the exposure and/or distribution of lapatinib (see section "Pharmacokinetics").

The solubility of lapatinib is pH-dependent. Concomitant use with agents that increase gastric pH should be avoided, as the solubility and absorption of lapatinib may be reduced. Prior treatment with a proton pump inhibitor (esomeprazole) reduces lapatinib exposure by an average of 27% (ranging from 6 to 49%). This effect diminishes with increasing age from 40 to 60 years.

Effect of lapatinib on other medicinal products

Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Coadministration of lapatinib with orally administered midazolam increases midazolam AUC by approximately 45%. When midazolam is administered intravenously, no clinically significant increase in midazolam AUC is observed. Concomitant use of lapatinib with orally administered medicinal products with a narrow therapeutic index that are CYP3A4 substrates (e.g., cisapride, pimozide, or quinidine) should be avoided (see sections "Special precautions for use" and "Pharmacokinetics").

Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Concomitant use of lapatinib with medicinal products with a narrow therapeutic index that are CYP2C8 substrates (e.g., repaglinide) should be avoided (see sections "Special precautions for use" and "Pharmacokinetics").

Coadministration of lapatinib with intravenous paclitaxel increases paclitaxel exposure by 23% due to lapatinib inhibition of CYP2C8 and/or P-glycoproteins (Pgp). Clinical studies have shown that this combination increases the frequency and severity of diarrhea and neutropenia. Lapatinib in combination with paclitaxel should be used with caution.

Coadministration of lapatinib with intravenous docetaxel does not significantly affect the AUC or Cmax of either active substance. However, the frequency of docetaxel-induced neutropenia increases.

Coadministration of lapatinib with irinotecan (administered as part of the FOLFIRI regimen) increases the AUC of SN-38, the active metabolite of irinotecan, by approximately 40%. The exact mechanism of this interaction is not fully understood, but it is presumed to involve inhibition of one or more transporter proteins by lapatinib. Lapatinib-Vista in combination with irinotecan should be used with caution, with close monitoring for adverse reactions and consideration of the need to reduce the dose of irinotecan.

Lapatinib inhibits P-glycoprotein (Pgp) in vitro at clinically relevant concentrations. Coadministration of lapatinib with oral digoxin increases digoxin AUC by approximately 80%. Lapatinib-Vista should be used with caution when coadministered with medicinal products with a narrow therapeutic index that are substrates of Pgp transporter proteins.

Lapatinib inhibits BCRP and OATP1B1 transporter proteins in vitro. The clinical significance of these effects has not been studied. It cannot be excluded that lapatinib may affect the pharmacokinetics of BCRP substrates (e.g., topotecan) and OATP1B1 substrates (e.g., rosuvastatin) (see section "Pharmacokinetics").

Coadministration of lapatinib with capecitabine, letrozole, or trastuzumab does not significantly affect the pharmacokinetic parameters of these agents (or metabolites of capecitabine) or of lapatinib.

Interactions with food and beverages

The bioavailability of lapatinib increases nearly 4-fold when administered with food, depending on the fat content of the meal. Furthermore, depending on the type of food, the bioavailability of lapatinib is approximately 2–3 times higher when the drug is taken 1 hour after a meal compared to taking it 1 hour before the first meal of the day (see sections "Dosage and administration" and "Pharmacokinetics").

Grapefruit juice may inhibit CYP3A4 in the intestinal wall and increase lapatinib bioavailability; therefore, grapefruit juice should be avoided during treatment with Lapatinib-Vista.

Special precautions for use

Clinical data indicate that the combination of lapatinib with chemotherapy is less effective than the combination of trastuzumab with chemotherapy.

Cardiotoxicity

Left ventricular ejection fraction (LVEF) reduction has been reported during treatment with lapatinib (see section "Adverse reactions"). Lapatinib has not been evaluated in patients with symptomatic heart failure. Lapatinib should be used with caution in patients with left ventricular dysfunction (including concomitant use with potentially cardiotoxic medicinal products). Prior to initiating treatment, LVEF should be assessed in all patients to confirm that baseline values are within institutional normal limits. LVEF should be monitored periodically during treatment with lapatinib to avoid a decline below acceptable limits (see section "Dosage and administration"). In some cases, LVEF reduction may be severe and lead to heart failure. Fatal cases have been reported, although the causal relationship remains unclear. In the lapatinib clinical trial program, cardiac adverse reactions, including LVEF reduction, occurred in approximately 1% of patients receiving lapatinib. Symptomatic LVEF reduction was observed in approximately 0.3% of patients receiving lapatinib. However, in a pilot clinical study evaluating lapatinib in combination with trastuzumab in patients with metastatic disease, the incidence of cardiac adverse reactions, including LVEF reduction, was higher (7%) compared to lapatinib monotherapy (2%). The nature and severity of cardiac adverse reactions in this study were similar to those previously observed with lapatinib.

Concentration-dependent QTc interval prolongation has been demonstrated in a dedicated placebo-controlled crossover study in patients with advanced solid tumors.

Therefore, lapatinib should be used with caution in patients who may be at risk for QT prolongation (such as those with hypokalemia, hypomagnesemia, or congenital long QT syndrome), and when co-administered with other medicinal products that may prolong the QT interval or increase lapatinib exposure, such as strong CYP3A4 inhibitors. Hypokalemia or hypomagnesemia should be corrected prior to starting treatment. Electrocardiography (ECG) with QT interval measurement should be performed before starting treatment and again 1–2 weeks after initiation of therapy. Additional ECGs should be performed as clinically indicated, for example, after starting concomitant medications that may affect the QT interval or interact with lapatinib.

Interstitial lung disease and pneumonitis

Lapatinib administration has been associated with pulmonary toxicity, including interstitial lung disease and pneumonitis (see section "Adverse reactions"). Patients should be monitored for signs and symptoms of pulmonary toxicity (dyspnea, cough, fever), and treatment should be discontinued in patients who develop grade 3 or higher symptoms (according to the National Cancer Institute Adverse Event Classification, USA). Pulmonary toxicity may be severe and may lead to respiratory failure. Fatal cases have been reported, although the causes remain unclear.

Hepatotoxicity

Hepatotoxicity has been reported during treatment with lapatinib, which in rare cases may lead to fatal outcomes. Hepatotoxicity may occur several days or months after initiation of therapy. Patients should be informed about the potential for hepatotoxicity prior to starting treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be assessed before starting treatment, monthly during therapy, and as clinically indicated. If liver function abnormalities are severe, lapatinib treatment should be discontinued and not restarted. Patients carrying the HLA alleles DQA1*02:01 and DRB1*07:01 have an increased risk of lapatinib-associated hepatotoxicity. In a large randomized clinical trial of lapatinib monotherapy (1194 patients), the overall risk of severe hepatic injury (alanine aminotransferase levels ≥5 times the upper limit of normal, grade 3 severity according to the National Cancer Institute Adverse Event Classification, USA) was 2.8% after 1 year of treatment. The risk among carriers of DQA1*02:01 and DRB1*07:01 alleles was 10.3%, compared to 0.5% in patients without these alleles. HLA allele carriage is common (15–25%) among Europeans, Asians, African Americans, and Latin Americans, but less frequent (1%) in Japanese.

Lapatinib-Vista should be used with caution in patients with moderate or severe hepatic impairment and in patients with severe renal impairment (see sections "Dosage and administration" and "Pharmacokinetics").

Diarrhea

Diarrhea, including severe cases, has been reported during treatment with lapatinib (see section "Adverse reactions"). Diarrhea may be potentially life-threatening if associated with dehydration, renal failure, neutropenia, and/or electrolyte imbalance. Fatal cases have been reported. Diarrhea typically occurs early during lapatinib treatment, with nearly half of affected patients experiencing onset within 6 days. Diarrhea usually lasts 4–5 days. Lapatinib-associated diarrhea is generally mild in severity, with grade 3 and grade 4 diarrhea (according to the National Cancer Institute Adverse Event Classification, USA) occurring in <10% and <1% of patients, respectively. Prior to initiating treatment, baseline bowel habits should be established and other symptoms (fever, cramping abdominal pain, nausea, vomiting, dizziness, and thirst) assessed to allow monitoring for changes during therapy and identification of patients at increased risk of diarrhea. Patients should be advised to promptly report any changes in bowel habits. In potentially severe cases of diarrhea, neutrophil count and body temperature should be assessed. Prompt management of diarrhea with antidiarrheal agents is essential. In severe cases, oral or intravenous electrolyte and fluid replacement, antibiotics (such as fluoroquinolones, especially if diarrhea persists beyond 24 hours, fever is present, or grade 3–4 neutropenia occurs), and interruption or discontinuation of lapatinib may be required (see section "Dosage and administration" – "Discontinuation or dose reduction" – "Diarrhea").

Severe skin reactions

There have been reports of severe skin reactions with lapatinib use. If Stevens-Johnson syndrome, toxic epidermal necrolysis (e.g., progressive skin rash, often with blistering or mucosal involvement), or other life-threatening skin reactions or erythema multiforme are suspected, lapatinib treatment should be discontinued.

Concomitant use with CYP3A4 inhibitors and inducers

Concomitant administration of lapatinib with CYP3A4 inhibitors or inducers should be done with caution due to increased or decreased lapatinib concentrations, respectively (see section "Interaction with other medicinal products and other forms of interaction").

During treatment with Lapatinib-Vista, consumption of grapefruit juice should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of lapatinib with other medicinal products that have a narrow therapeutic index and are substrates of CYP3A4 and/or CYP2C8 is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with agents that increase gastric pH should be avoided, as the solubility and absorption of lapatinib may be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Important information about excipients

Each tablet of Lapatinib-Vista contains 40 mg of sodium. This should be taken into account if the patient is on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment with Lapatinib-Vista and for at least 5 days after the last dose.

Pregnancy

There are no data on lapatinib use in pregnant women. Reproductive toxicity was observed in animal studies (see section "Pharmacological properties"). The potential risk in humans is unknown.

Lapatinib should be used during pregnancy only if clearly needed.

Lactation

The safety of lapatinib during lactation has not been established. It is unknown whether lapatinib is excreted in human breast milk. In rats, impaired growth of offspring was observed when exposed to lapatinib via breast milk. Women receiving lapatinib should discontinue breastfeeding during treatment and for at least 5 days after the last dose.

Fertility

There are no data on the use of lapatinib in women of reproductive age.

Ability to influence the ability to drive and use machines

Lapatinib has no influence on the ability to drive or operate machinery. Given the pharmacological properties of lapatinib, a detrimental effect on such activities is unlikely. However, when assessing a patient's ability to perform tasks requiring high attention concentration and rapid psychomotor responses, the patient's clinical condition and the nature of adverse reactions should be taken into account.

Method of Administration and Dosage

The treatment course with Lapatinib-Vista must be prescribed only by a physician experienced in the use of anticancer agents.

The HER2 (ErbB2) overexpression status must be established by the presence of IHC 3+ or IHC 2+ with gene amplification, or by gene amplification alone. The HER2 status must be determined using validated and accurate methods.

Dosage

Lapatinib-Vista in combination with capecitabine

The recommended dose of Lapatinib-Vista is 1250 mg (5 tablets) once daily.

The recommended dose of capecitabine is 2000 mg/m²/day administered in two divided doses (every 12 hours) daily on days 1 to 14 of a 21-day treatment cycle. Capecitabine should be taken with food or within 30 minutes after a meal (see the capecitabine medical instructions for use).

Lapatinib-Vista in combination with trastuzumab

The recommended dose of Lapatinib-Vista is 1000 mg (4 tablets) once daily.

The recommended dose of trastuzumab is 4 mg/kg body weight as an intravenous loading dose, followed by 2 mg/kg body weight intravenously once weekly (see the trastuzumab medical instructions for use).

Lapatinib-Vista in combination with an aromatase inhibitor

The recommended dose of Lapatinib-Vista is 1500 mg (6 tablets) once daily.

When Lapatinib-Vista is used in combination with an alternative aromatase inhibitor, refer to the medical instructions for use of that specific product.

Discontinuation or dose reduction

Cardiovascular disorders

Treatment with Lapatinib-Vista should be discontinued in the event of symptoms associated with left ventricular ejection fraction (LVEF) decline of grade 3 or higher (according to the National Cancer Institute, USA classification) or if LVEF falls below the lower limit of normal (see section "Special precautions"). Reinitiation of Lapatinib-Vista may be considered at a reduced dose (1000 mg/day when used with capecitabine, 750 mg/day when used with trastuzumab, or 1250 mg/day when used with an aromatase inhibitor) no sooner than 2 weeks after discontinuation and only if LVEF has returned to normal limits and the patient is asymptomatic.

Interstitial lung disease / pneumonitis

Treatment with Lapatinib-Vista should be discontinued in the event of pulmonary symptoms indicative of interstitial lung disease or pneumonitis of grade 3 or higher (according to the National Cancer Institute, USA adverse reaction classification) (see section "Special precautions").

Diarrhea

Treatment with Lapatinib-Vista should be interrupted in the event of grade 3 diarrhea or grade 1–2 diarrhea (according to the National Cancer Institute, USA adverse reaction classification) with signs of complications (moderate to severe abdominal cramping, nausea or vomiting of grade 2 or higher, reduced performance status, fever, sepsis, neutropenia, overt bleeding, or dehydration) (see sections "Special precautions" and "Adverse reactions"). Treatment with Lapatinib-Vista may be resumed at a reduced dose (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) once diarrhea resolves to grade 1 or lower. Permanent discontinuation of Lapatinib-Vista is recommended in the case of grade 4 diarrhea (according to the National Cancer Institute, USA adverse reaction classification).

Other toxicities

A decision to discontinue or interrupt treatment with Lapatinib-Vista may be made if the patient experiences toxicities of grade 2 or higher (according to the National Cancer Institute, USA adverse reaction classification). Treatment may be resumed at the standard dose of 1250 mg/day when used with capecitabine, 1000 mg/day when used with trastuzumab, or 1500 mg/day when used with an aromatase inhibitor, once toxicities have resolved to grade 1 or lower. In case of recurrent toxicities, the dose of Lapatinib-Vista may be reduced to 1000 mg/day (with capecitabine), 750 mg/day (with trastuzumab), or 1250 mg/day (with an aromatase inhibitor).

Renal impairment

Patients with mild to moderate renal impairment do not require dose adjustment. Lapatinib-Vista should be used with caution in patients with severe renal impairment due to lack of experience with the drug in this patient population.

Hepatic impairment

Treatment with Lapatinib-Vista should be discontinued and never reinitiated in patients with severe hepatic impairment (see section "Special precautions").

Due to increased drug exposure, Lapatinib-Vista should be used with caution in patients with moderate or severe hepatic impairment. There are currently insufficient data to provide dose adjustment recommendations for patients with hepatic impairment.

Elderly patients

Data on the use of lapatinib in combination with capecitabine or trastuzumab in patients aged 65 years and older are limited.

In a phase III clinical trial evaluating lapatinib in combination with letrozole in patients with hormone receptor-positive metastatic breast cancer (the all-randomized population as treated, N=642), 44% of participants were aged 65 years or older. No overall differences in efficacy or safety were observed between these patients and those younger than 65 years.

Method of administration

Lapatinib-Vista is intended for oral administration.

The daily dose should not be split. Lapatinib-Vista should be taken at least one hour before or at least one hour after a meal. To minimize variability in each individual patient, administration of Lapatinib-Vista should be standardized relative to food intake, e.g., always taken one hour before meals (see section "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics" regarding absorption).

Missed doses should not be taken as double doses; the next dose should be taken according to the prescribed schedule (see section "Overdose").

When co-administering with other medicinal products, refer to their respective medical instructions for use regarding dosage, including dose reductions, contraindications, and safety.

Pediatric population

The safety and efficacy of lapatinib in children (under 18 years of age) have not been established. Data are lacking.

Overdose

There is no specific antidote for inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine phosphorylation. The maximum daily dose used in clinical studies was 1800 mg.

Cases of lapatinib overdose, both asymptomatic and symptomatic, have been reported during patient treatment. In patients who received up to 5000 mg of lapatinib, symptoms included known adverse reactions associated with lapatinib use (see section "Adverse reactions"), and in some cases, scalp hair disorders and/or mucositis, sinus tachycardia (with normal ECG), and/or mucosal inflammation were observed. In one case, a patient who ingested 9000 mg of lapatinib also developed sinus tachycardia (with normal ECG).

Renal excretion is not a major route of elimination for lapatinib, and the drug is highly protein-bound; therefore, hemodialysis is unlikely to be an effective method for lapatinib removal. Supportive treatment should be administered according to the patient's clinical condition or in accordance with national guidelines for the management of poisoning.

Adverse Reactions

The safety of lapatinib has been evaluated both as monotherapy and in combination with other chemotherapeutic agents for the treatment of various types of cancer 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 section "Pharmacological Properties").

The most commonly observed adverse reactions (> 25%) during treatment with lapatinib were gastrointestinal disorders (such as diarrhea, nausea, and vomiting) and rash. When lapatinib was used in combination with capecitabine, palmar-plantar erythrodysesthesia [PPE] was also frequently observed (> 25%). The incidence of PPE was similar in the groups receiving lapatinib with capecitabine and capecitabine as monotherapy. Diarrhea was the most common adverse reaction leading to treatment discontinuation when lapatinib was used in combination with capecitabine or with letrozole.

During the use of lapatinib in combination with trastuzumab, no additional adverse reactions were recorded. An increased frequency of cardiac toxicity was observed; however, these events were similar in nature and severity to those observed in the lapatinib clinical trial program (see section "Special Warnings and Precautions for Use. Cardiotoxicity"). These data are based on the effects of this combination in 149 patients from the main clinical trial.

List of Adverse Reactions

The following adverse reactions have been causally linked to the use of lapatinib either as monotherapy or in combination with capecitabine, trastuzumab, or letrozole.

The following classification is used for the frequency of adverse reactions: 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); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

* These adverse reactions were observed during the use of lapatinib in combination with capecitabine.

† These adverse reactions were observed during the use of lapatinib in combination with letrozole.

** Adverse reactions identified from spontaneous reports and published literature.

Description of selected adverse reactions

Decreased left ventricular ejection fraction and QT interval prolongation

Decreased left ventricular ejection fraction (LVEF) was observed in approximately 1% of patients receiving lapatinib, with more than 70% of cases being asymptomatic. Condition improved or recovered in more than 70% of cases, of which nearly 60% continued receiving lapatinib, and in approximately 40% of cases, lapatinib treatment was continued. Symptomatic reduction in LVEF occurred in 0.3% of patients receiving lapatinib as monotherapy or in combination with other anticancer medicinal products. Symptoms included dyspnea, heart failure, and palpitations. Overall, 58% of patients who remained asymptomatic recovered. Reduction in LVEF was observed in 2.5% of patients receiving lapatinib in combination with capecitabine, compared to 1.0% of patients receiving capecitabine as monotherapy. Reduction in LVEF occurred in 3.1% of patients receiving lapatinib in combination with letrozole, compared to 1.3% of patients receiving letrozole plus placebo. Reduction in LVEF occurred in 6.7% of patients receiving lapatinib in combination with trastuzumab, compared to 2.1% of patients receiving lapatinib as monotherapy.

QT interval prolongation (maximum mean ΔΔQTcF 8.75 sec; 90% CI 4.08, 13.42), concentration-dependent, was observed in a dedicated study in patients with advanced solid tumors (see section "Special precautions for use").

Diarrhea

Diarrhea was observed in approximately 65% of patients receiving lapatinib in combination with capecitabine, in 64% of patients receiving lapatinib in combination with letrozole, and in 62% of patients receiving lapatinib in combination with trastuzumab. Most cases of diarrhea were of Grade 1 or 2 severity and did not lead to discontinuation of lapatinib treatment. Diarrhea is amenable to prophylactic management (see section "Special precautions for use"). However, there have been reports of several cases of acute renal failure secondary to severe dehydration due to diarrhea.

Rash

Rash was observed in approximately 28% of patients receiving lapatinib in combination with capecitabine, in 45% of patients receiving lapatinib in combination with letrozole, and in 23% of patients receiving lapatinib in combination with trastuzumab. Rash was usually mild in severity and did not lead to discontinuation of lapatinib treatment. Prescribers are advised to examine the patient's skin before treatment and regularly during treatment. Patients experiencing skin reactions should be advised to avoid exposure to sunlight and to use sunscreen with SPF ≥ 30. In the event of a skin reaction, a full-body examination should be performed at each visit until one month after resolution.

Patients with severe or persistent skin reactions should be referred to a dermatologist.

Hepatotoxicity

The risk of lapatinib-induced hepatotoxicity is associated with carriage of HLA alleles DQA1*02:01 and DRB1*07:01 (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 7 tablets in a blister; 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

REMEDIKA LTD

or

PHAROS MT Limited

Manufacturer's address and location of their business operations.

Acharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus

or

Hf62x, Hal Far Industrial Estate, Hal Far, Birzebbuga, BBG 3000, Malta