Tyverb^® (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Glaxo Wellcome Operations (United Kingdom)

Or

S.C. Sandoz, S.r.L. (Romania)

Packaging and Quality Control Release

GLAXO WELLCOME OPERATIONS (United Kingdom)

Or

Glaxo Wellcome, S.A. (Spain)

Or

S.C. SANDOZ, S.r.L. (Romania)

ATC Code

L01EH01 (Lapatinib)

Active Substance

Lapatinib (Rec.INN registered by WHO)

Dosage Form

Tyverb®

Film-coated tablets, 250 mg: 70 or 140 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, oval, biconvex, with one side being smooth and the other engraved with “GS XJG”.

Excipients: microcrystalline cellulose – 387 mg, povidone K30 – 58.5 mg, sodium starch glycolate (type A) – 40.5 mg, magnesium stearate – 9 mg, purified water – q.s. (removed during the manufacturing process).

Coating composition opadry^® yellow YS-1-12524-A – 27 mg (hypromellose – 17.23 mg, titanium dioxide – 7.13 mg, iron oxide red (E172) – 0.005 mg, iron oxide yellow (E172) – 0.21 mg, macrogol 400 – 2.16 mg, polysorbate 80 – 0.27 mg.

10 pcs. – blisters (7) – cardboard packs (2) – group packaging.
140 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein tyrosine kinase inhibitor

Pharmacological Action

Lapatinib is a reversible selective inhibitor of intracellular tyrosine kinase, binding to EGFR (Epidermal Growth Factor Receptor, ErbB1) and HER2 (Human Epidermal Growth Factor Receptor 2, ErbB2) receptors. It differs from other rapidly reversible tyrosine kinase inhibitors by slower dissociation from ErbB1 and ErbB2 receptors (the half-life for dissociation of 50% of the ligand from the ligand-receptor complex is approximately 300 minutes).

In addition to its own in vitro activity, additive activity of lapatinib and fluorouracil (the active metabolite of capecitabine) was demonstrated when used in combination on four tumor cell lines. The inhibitory effect was assessed on trastuzumab-treated cells. The combination of lapatinib and trastuzumab may provide an additive mechanism of action, as well as possible non-parallel mechanisms for overcoming resistance to anti-HER2 therapy.

Lapatinib demonstrated significant activity on HER2-positive tumor cell lines in media containing trastuzumab, and in combination with trastuzumab exhibited a synergistic effect in these cell lines. These results demonstrate a lack of cross-resistance between the two HER2 (ErbB2) receptor ligands.

Pharmacokinetics

Absorption

Absorption after oral administration is incomplete and variable. The variability coefficient for AUC ranges from 50% to 100%. It is detected in the systemic circulation on average after 0.25 hours (range 0-1.5 hours). C_max is reached approximately 4 hours after taking lapatinib.

C_ss^max at steady state with daily administration of a 1250 mg dose averages 2.43 (1.57-3.77) µg/ml, AUC – 36.2 (23.4-56.0) µg×h/ml.

Systemic exposure of lapatinib increases when the drug is taken with food. When taken with low-fat (5% fat or 500 calories) or high-fat (50% fat or 1000 calories) meals, AUC increases by 3 and 4 times (C_max— approximately 2.5 and 3 times), respectively.

Distribution

Lapatinib is highly bound (more than 99%) to albumin and alpha₁-acid glycoprotein in blood plasma.

In vitro studies have shown that Lapatinib is a substrate for the transporters BCRP (Breast Cancer Resistance Protein, ABCG2 – ATP-binding cassette transporter G2) and P-glycoprotein (ABCB1 ATP-binding cassette transporter B1). Also in vitro, Lapatinib had an inhibitory effect on these transporters. The clinical significance of these effects and the impact on the pharmacokinetics of other drugs, including those with antitumor activity, is not yet known. Lapatinib weakly inhibits the organic anion transporter (OAT) or the organic cation transporter (OCT).

Metabolism

Lapatinib undergoes extensive metabolism, primarily by the CYP3A4 and CYP3A5 isoenzymes, and to a lesser extent by the CYP2C19 and CYP2C8 isoenzymes, forming various oxidized metabolites.

In vitro, Lapatinib at clinically significant concentrations inhibits the CYP3A and CYP2C8 isoenzymes.

Lapatinib weakly inhibits the following hepatic microsomal enzymes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6.

In healthy volunteers receiving ketoconazole (a CYP3A4 isoenzyme inhibitor) at a dose of 200 mg twice daily for 7 days, the systemic exposure of lapatinib increased approximately 3.6-fold, and T_1/2 increased 1.7-fold.

In healthy volunteers receiving carbamazepine (a CYP3A4 isoenzyme inducer) at a dose of 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, the systemic exposure of lapatinib decreased by 72%.

Excretion

T_1/2 increases dose-dependently when administered in single doses.

Steady state is reached after 6-7 days of administration, T_1/2 at steady state is 24 hours.

It is primarily excreted via the intestine – on average 27% (from 3% to 67%) unchanged, less than 2% of the administered dose is excreted by the kidneys unchanged and as metabolites.

Pharmacokinetics in special clinical cases

The pharmacokinetics of lapatinib in patients with impaired renal function or patients on hemodialysis has not been specifically studied. However, impaired renal function is unlikely to affect the pharmacokinetics of lapatinib, as less than 2% of the administered dose is excreted by the kidneys (as lapatinib and its metabolites).

The pharmacokinetics of lapatinib was studied in moderate (n=8) and severe (n=4) hepatic impairment. The AUC of lapatinib after a single 100 mg oral dose increased by approximately 56% and 85% in patients with moderate and severe hepatic impairment, respectively. Lapatinib should be prescribed with caution to patients with impaired liver function. A dose reduction of lapatinib is recommended for patients with a history of severe hepatic impairment. Lapatinib therapy must be discontinued, without subsequent resumption, in patients who develop severe hepatotoxicity during its use.

Indications

Locally advanced or metastatic breast cancer with HER2 overexpression

• In combination with capecitabine in patients previously treated with anthracycline and taxane, who have progressed during or after trastuzumab therapy prescribed for metastatic cancer.

Metastatic breast cancer with HER2 overexpression

• In combination with trastuzumab in patients who have progressed during or after trastuzumab therapy prescribed for metastatic cancer.

Hormone receptor-positive metastatic breast cancer with HER2 overexpression

• In combination with an aromatase inhibitor in postmenopausal women.

ICD codes

Dosage Regimen

Tyverb^® should be taken 1 hour before or 1 hour after a meal. The recommended daily dose should not be divided into multiple doses.

Missed doses of lapatinib should not be made up, i.e., missed doses should not be taken by shortening the intervals between doses.

Locally advanced or metastatic breast cancer with HER2 overexpression

• in combination with capecitabine

The recommended dose of lapatinib is 1250 mg (5 tablets) once daily, daily in combination with capecitabine.

The recommended dose of capecitabine is 2000 mg/m²/day, in 2 divided doses (every 12 hours) daily from day 1 to day 14 of each 21-day therapy cycle. Capecitabine is recommended to be taken with food or within 30 minutes after a meal.

• in combination with trastuzumab

The recommended dose of lapatinib is 1000 mg (4 tablets) once daily, daily in combination with trastuzumab.

The recommended dose of trastuzumab is 4 mg/kg, as an intravenous loading dose, then 2 mg/kg intravenously once a week.

Hormone receptor-positive metastatic breast cancer with HER2 overexpression

The recommended dose of lapatinib is 1500 mg (6 tablets) once daily, daily in combination with an aromatase inhibitor.

The recommended dose of letrozole (one of the possible aromatase inhibitor drugs) when taken in combination with lapatinib is 2.5 mg once daily, daily. If Lapatinib is prescribed in combination with another aromatase inhibitor, the dosing regimen of the respective drug in this group should be reviewed.

Interruption of lapatinib administration or dose reduction (all indications)

Cardiovascular disorders

Lapatinib treatment should be discontinued if symptoms of left ventricular ejection fraction (LVEF) decrease to Grade 3 or higher (according to the National Cancer Institute Common Terminology Criteria for Adverse Events) or if it falls below the lower limit of normal. Lapatinib treatment may be resumed no earlier than 2 weeks later at a reduced dose (reduced from 1000 mg/day to 750 mg/day when prescribed in combination with trastuzumab, from 1250 mg/day to 1000 mg/day when prescribed in combination with capecitabine, or from 1500 mg/day to 1250 mg/day when prescribed with an aromatase inhibitor), if the LVEF is within normal limits and the patient is asymptomatic for heart failure. Available data indicate that most cases of LVEF decrease occur within the first 12 weeks of treatment, but there is insufficient data on the long-term effects of lapatinib.

Interstitial lung disease and/or pneumonitis

Lapatinib treatment should be discontinued if pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis of Grade 3 or higher (according to the National Cancer Institute Common Terminology Criteria for Adverse Events) occur.

Diarrhea

Lapatinib treatment should be interrupted in patients with Grade 3 diarrhea, or Grade 1 or 2 diarrhea with complicated symptoms (according to the National Cancer Institute Common Terminology Criteria for Adverse Events) (moderate to severe abdominal cramping, nausea or vomiting of Grade 2 or higher (according to the National Cancer Institute Common Terminology Criteria for Adverse Events), decreased performance status, fever, sepsis, neutropenia, significant bleeding, or dehydration). Lapatinib treatment may be resumed at a lower dose (reduction 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) if the severity of diarrhea has decreased to Grade 1 or lower. Lapatinib treatment should be permanently discontinued in patients with Grade 4 diarrhea (according to the National Cancer Institute Common Terminology Criteria for Adverse Events).

Other drug toxicities

The decision to discontinue treatment or take a break from treatment with the drug may be made when the severity of developing toxic effects is Grade 2 or higher (according to the National Cancer Institute Common Terminology Criteria for Adverse Events). Treatment may be resumed at a dose of 1000 mg/day when prescribed in combination with trastuzumab, 1250 mg/day when prescribed in combination with capecitabine, or 1500 mg/day when prescribed in combination with an aromatase inhibitor, if the severity of toxic effects has decreased to Grade 1 or lower. In case of recurrence of toxic effects, the dose of lapatinib should be reduced from 1000 mg/day to 750 mg/day when prescribed in combination with trastuzumab, from 1250 mg/day to 1000 mg/day when prescribed in combination with capecitabine, or from 1500 mg/day to 1250 mg/day when prescribed in combination with an aromatase inhibitor.

Special patient groups

There is no experience with the use of the drug in children.

There is insufficient data on the use of lapatinib in elderly patients (over 65 years old).

There is no experience with the use of lapatinib in patients with severe renal impairment, but it is unlikely that dose adjustment will be required because less than 2% of the administered dose is excreted by the kidneys.

Lapatinib is metabolized in the liver. Moderate and severe hepatic impairment are associated with an increase in systemic exposure by 56% and 85%, respectively. Lapatinib should be prescribed with caution to patients with impaired liver function. In patients with severe hepatic impairment (Child-Pugh class C), a dose reduction of lapatinib is necessary. Reducing the dose from 1250 mg/day to 750 mg/day (when prescribed in combination with capecitabine) or from 1500 mg/day to 1000 mg/day (when used in combination with an aromatase inhibitor) in such patients leads to normalization of AUC. If severe hepatotoxicity develops during the use of lapatinib, the drug must be discontinued; re-administration is not permissible.

Adverse Reactions

The safety of lapatinib has been evaluated in clinical trials both as monotherapy and when used in combination with trastuzumab, capecitabine, and letrozole.

Post-marketing data are consistent with data obtained during clinical trials.

The adverse events presented below are listed according to the affected organ, organ system, and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated cases).

Lapatinib monotherapy

Metabolism and nutrition disorders: very common – anorexia.

Cardiac disorders common – decreased LVEF was observed in approximately 1% of patients receiving Lapatinib and was asymptomatic in more than 70% of cases. After discontinuation of lapatinib, normalization or improvement in LVEF was observed in more than 70% of cases. Symptomatic decreased LVEF was observed in approximately 0.3% of patients receiving Lapatinib. Adverse events observed in this case included dyspnea, heart failure, palpitations.

Respiratory, thoracic and mediastinal disorders uncommon – interstitial lung disease/pneumonitis.

Gastrointestinal disorders very common – diarrhea (which may lead to dehydration, however, in most cases, Grade 1 or 2 diarrhea did not lead to drug discontinuation), nausea, vomiting.

Hepatobiliary disorders uncommon – hyperbilirubinemia, hepatotoxicity. Increased bilirubin concentration may be due to inhibition by lapatinib of hepatic conjugation via OATP1B1 (Organic Anion Transporting Polypeptide 1B1) or inhibition of bilirubin excretion into bile via P-glycoprotein or BCRP.

Skin and subcutaneous tissue disorders: very common – rash (including acneiform dermatitis, mostly transient, not requiring drug discontinuation); common – nail disorders, including paronychia.

Immune system disorders rare – hypersensitivity reactions, including anaphylaxis.

General disorders and administration site conditions: very common – asthenia.

Administration of lapatinib in combination with capecitabine

In addition to the adverse events observed during lapatinib monotherapy, the following adverse events were observed during the use of lapatinib in combination with capecitabine with a frequency higher than 5% compared to capecitabine monotherapy.

Gastrointestinal disorders: very common – dyspepsia.

Skin and subcutaneous tissue disorders: very common – dry skin.

Adverse events observed with the use of lapatinib in combination with capecitabine with the same frequency as with capecitabine monotherapy.

Gastrointestinal disorders: very common – stomatitis, constipation, abdominal pain.

Skin and subcutaneous tissue disorders: very common – palmar-plantar erythrodysesthesia syndrome.

Musculoskeletal and connective tissue disorders very common – pain in extremity, back pain.

Nervous system disorders common – headache.

Psychiatric disorders very common – insomnia.

General disorders and administration site conditions very common – mucosal inflammation.

Administration of lapatinib in combination with trastuzumab

When lapatinib was used in combination with trastuzumab, no additional lapatinib-related adverse events were noted. An increased incidence of cardiotoxicity was observed, but these events were similar in nature and severity to those previously observed in the lapatinib clinical trial program.

Administration of lapatinib in combination with letrozole

In addition to the adverse events observed during lapatinib monotherapy, the following adverse events were observed during the use of lapatinib in combination with letrozole with a frequency higher than 5% compared to letrozole monotherapy.

Respiratory, thoracic and mediastinal disorders very common – epistaxis.

Skin and subcutaneous tissue disorders: very common – alopecia, dry skin.

Contraindications

• Pregnancy;
• Lactation period (breastfeeding);
• Childhood (no experience with use).
• Hypersensitivity to lapatinib or any other component of the drug.

With caution the drug should be prescribed for conditions that may lead to left ventricular failure, moderate or severe hepatic impairment (7 points or more on the Child-Pugh scale), severe renal failure, in patients over 65 years of age, concurrently with moderate inhibitors of the CYP3A4 isoenzyme.

Concomitant use with inducers or potent inhibitors of the CYP3A4 isoenzyme, grapefruit juice; with drugs that are substrates of the CYP3A4 and CYP2C8 isoenzymes with a narrow therapeutic range; with drugs that increase gastric pH (reduces solubility and absorption of lapatinib) should be avoided.

Use in Pregnancy and Lactation

No cases of lapatinib use during pregnancy are known.

Women of childbearing potential should be warned about the use of adequate contraception, as well as the termination of an occurred pregnancy during treatment with lapatinib.

When used in doses toxic to the mother, Lapatinib did not possess teratogenic properties in studies on pregnant mice and rabbits, but at the same time was the cause of some developmental abnormalities.

It is not known whether Lapatinib is excreted in breast milk. Breastfeeding should be discontinued during lapatinib therapy due to the possible occurrence of characteristic adverse events in the breastfed infant.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with impaired liver function. In severe liver impairment (Child-Pugh class C), the dose of lapatinib should be reduced. Reducing the dose from 1250 mg/day to 750 mg/day or from 1500 mg/day to 1000 mg/day in such patients leads to normalization of AUC. If severe manifestations of hepatotoxicity develop, the drug should be discontinued; re-administration is not permissible.

Use in Renal Impairment

No dose regimen adjustment is required for patients with mild to moderate renal impairment. There is no experience with the use of lapatinib in patients with severe renal impairment.

Pediatric Use

Contraindicated: pediatric age (lack of use experience).

Geriatric Use

Insufficient data on the use of lapatinib in elderly patients (over 65 years of age).

Special Precautions

Treatment with lapatinib should be carried out only under the supervision of a specialist experienced in the use of anticancer drugs.

Cardiotoxicity

Before starting treatment, it is necessary to determine LVEF to ensure that LVEF is within acceptable limits. During treatment with lapatinib, monitoring of LVEF should be continued to detect its decrease beyond acceptable values.

The influence of lapatinib on the QT interval cannot be completely excluded, as there are reports of cases of slight QT interval prolongation in patients with advanced cancer. Caution should be exercised when prescribing lapatinib to patients with concomitant factors affecting QT interval prolongation (such as hypokalemia, hypomagnesemia, congenital long QT syndrome, or concurrent use of drugs that affect QT interval prolongation). Blood potassium and magnesium concentrations should be normalized before starting lapatinib. ECG with QT interval monitoring should be performed before starting and throughout lapatinib treatment.

Interstitial lung disease and pneumonitis

There are reports of cases of interstitial lung disease and pneumonitis associated with lapatinib intake. Patients should be monitored to exclude the occurrence of pulmonary symptoms indicative of the development of interstitial lung disease and/or pneumonitis.

Diarrhea

There are reports of cases of diarrhea, including severe diarrhea, during treatment with lapatinib. Diarrhea usually occurred early in lapatinib treatment, with almost half of such patients experiencing diarrhea within the first 6 days. Diarrhea typically lasts 4-5 days. Lapatinib-induced diarrhea is generally mild; grade 3 and grade 4 diarrhea (according to the National Cancer Institute Common Terminology Criteria for Adverse Events) is observed in less than 10% and less than 1% of patients, respectively. Early detection and timely treatment are crucial for optimal diarrhea control. Patients should be instructed to immediately report any changes in bowel habits. It is recommended to initiate anti-diarrheal therapy (e.g., loperamide) immediately after the first occurrence of unformed stool. In cases of severe diarrhea, administration of electrolytes and fluids to prevent dehydration (orally or intravenously), use of antibiotics such as fluoroquinolones (especially if diarrhea lasts more than 24 hours; the patient has fever or grade 3 or 4 neutropenia), and interruption or discontinuation of the drug may be required.

Contraception

Reliable methods of contraception must be used during lapatinib therapy and for at least 3 months after its completion.

Hepatotoxicity

Manifestations of hepatotoxicity (ALT or AST activity exceeding 3 times the ULN; total bilirubin content exceeding 1.5 times the upper limit of normal) were observed in clinical studies (less than 1% of patients) and in the post-marketing period. Hepatotoxicity can be severe. Fatal cases have been reported, although a causal relationship with lapatinib intake has not been established. Hepatotoxicity can develop from several days to several months after the start of therapy. Laboratory parameters of liver function (aminotransferases, bilirubin, and alkaline phosphatase) should be monitored before starting therapy, then every 4-6 weeks during the course of treatment and as clinically indicated. If severe liver dysfunction occurs, lapatinib should be discontinued; re-administration of the drug is not permissible.

Patients carrying HLA DQA1*02:01 and DRB1*07:01 alleles have an increased risk of hepatotoxicity associated with the use of lapatinib. In patients using Lapatinib as monotherapy, the overall risk of severe liver injury (ALT more than 5 times the upper limit of normal, grade 3 (according to the National Cancer Institute Common Terminology Criteria for Adverse Events)) was higher (about 8%) in carriers of DQA1*02:01 and DRB1*07:01 than in non-carriers (0.5%). Carriage of the HLA allele is characteristic (from 15% to 25%) of the Caucasian, Asian, African, and Latin American populations but is lower (1%) in the Japanese population.

When prescribing lapatinib to patients with a history of severe liver impairment, a reduction in the lapatinib dose is recommended.

Concomitant use of CYP3A4 inhibitors or inducers

Lapatinib should be co-administered with caution with inhibitors or inducers of the CYP3A4 isoenzyme due to the risk of increased or decreased (respectively) systemic exposure to lapatinib.

Effect on ability to drive and operate machinery

The effect on the ability to drive vehicles and engage in other activities requiring increased concentration and speed of psychomotor reactions has not been studied. Based on the mechanism of action of lapatinib, an adverse effect of the drug on such activities cannot be assumed. However, the general condition of the patient and the side effect profile of lapatinib should be taken into account; caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

The maximum daily dose in studies was 1800 mg.

More frequent administration of the drug may lead to increased serum concentrations of lapatinib; therefore, missed doses should not be taken by reducing the intervals between doses.

Symptoms: consequences associated with side effects, in some cases – skin ulceration, sinus tachycardia (nevertheless, with normal ECG) and/or mucosal lesions. Cases of overdose without clinical symptoms have also been observed.

Treatment: symptomatic therapy. Hemodialysis is not effective. Treatment should be carried out as prescribed by a physician.

Drug Interactions

Inhibitors or inducers of the CYP3A isoenzyme can affect the pharmacokinetics of lapatinib. When lapatinib is used concomitantly with certain CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, itraconazole, grapefruit juice), caution should be exercised and the patient’s clinical condition and possible adverse reactions should be carefully monitored. If concomitant administration of a potent CYP3A4 isoenzyme inhibitor is necessary, the dose of lapatinib should be reduced to 500 mg/day, calculated to adjust the AUC of lapatinib to a value corresponding to the use of lapatinib without inhibitors. However, there are currently no clinical data on the use of lapatinib with such dose adjustment in patients receiving a potent CYP3A4 isoenzyme inhibitor. After discontinuation of a potent inhibitor, only after it has been eliminated from the body, approximately 1 week later, the lapatinib dose should be increased again to the recommended one.

When lapatinib is used concomitantly with known CYP3A4 isoenzyme inducers (e.g., rifampicin, carbamazepine, phenytoin, St. John’s wort), caution should be exercised and the patient’s clinical condition and possible adverse reactions should be carefully monitored.

If concomitant administration of a potent CYP3A4 isoenzyme inducer to a patient is necessary, the dose of lapatinib should be selected based on tolerance, gradually increasing it from 1250 mg/day to 4500 mg/day or from 1500 mg/day to 5500 mg/day. This dose is calculated to adjust the AUC of lapatinib to a value corresponding to the use of lapatinib without CYP3A4 isoenzyme inducers. However, there are currently no clinical data on the use of lapatinib in patients receiving a potent CYP3A4 isoenzyme inducer. After discontinuation of a potent CYP3A4 isoenzyme inducer, only after approximately 2 weeks should the lapatinib dose be reduced again to the recommended one.

The solubility of lapatinib is pH-dependent. Concomitant use of substances that increase gastric pH should be avoided, as the solubility and absorption of lapatinib may decrease. Prior treatment with a proton pump inhibitor (e.g., esomeprazole) reduced the activity of lapatinib by an average of 27% (range from 6% to 49%). This effect decreases with increasing age from approximately 40 years to 60 years. Therefore, Lapatinib should be prescribed with caution to patients who have taken proton pump inhibitors.

Lapatinib inhibits the CYP3A4 isoenzyme in vitro at clinically significant concentrations. Concomitant use of lapatinib with oral midazolam leads to an approximately 45% increase in the AUC of midazolam. With intravenous administration of midazolam, no clinically significant increase in AUC was detected. Caution is required when co-administering lapatinib and orally administered drugs with a narrow therapeutic range that are substrates of the CYP3A4 isoenzyme.

Lapatinib inhibits the CYP2C8 isoenzyme in vitro at clinically significant concentrations. Lapatinib should be prescribed with caution concomitantly with drugs with a narrow therapeutic range that are substrates of the CYP2C8 isoenzyme.

Concomitant use of lapatinib with intravenous paclitaxel increases exposure to paclitaxel by 23% due to inhibition of the CYP2C8 isoenzyme and/or P-glycoprotein by lapatinib. An increase in the incidence and severity of diarrhea and neutropenia was observed with the combination of lapatinib and paclitaxel in clinical studies. Lapatinib should be prescribed with caution concomitantly with paclitaxel.

Concomitant use of lapatinib with intravenous docetaxel did not significantly affect the AUC or C_max of any active substances. However, an increase in the incidence of docetaxel-induced neutropenia was noted.

Concomitant use of lapatinib with irinotecan (administered as part of the FOLFIRI regimen) led to an approximately 40% increase in the AUC of SN-38, the active metabolite of irinotecan. The exact mechanism of this interaction is unknown. Lapatinib should be prescribed with caution concomitantly with irinotecan.

Lapatinib is a substrate for the transport proteins P-glycoprotein and BCRP. Inhibitors and inducers of these proteins may alter the activity and/or distribution of lapatinib.

Lapatinib inhibits the P-glycoprotein transport protein in vitro at clinically significant concentrations. Concomitant use of lapatinib with oral digoxin leads to an approximately 98% increase in the AUC of digoxin. Lapatinib should be prescribed with caution when used concomitantly with drugs with a narrow therapeutic range that are substrates of P-glycoprotein.

Lapatinib inhibits the BCRP and OATP1B1 transport proteins in vitro. The clinical significance of these effects has not been studied, but it is possible that Lapatinib may affect the pharmacokinetics of BCRP substrates (e.g., topotecan) and OATP1B1 substrates (e.g., rosuvastatin).

Concomitant use of lapatinib with capecitabine, letrozole, or trastuzumab does not affect the pharmacokinetic parameters of these drugs.

The bioavailability of lapatinib is dependent on food intake.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.