Pharmacological properties of the drug Lapatinib
Lapatinib is a novel, reversible, selective, orally active intracellular tyrosine kinase inhibitor that inhibits ErbB2 (ErbB1) and HER2+/neu (ErbB2+) tyrosine kinases and epidermal growth factor receptor (EGFR) type I. Thus, lapatinib is the first dual tyrosine kinase inhibitor. The drug differs from other rapidly reversible tyrosine kinase inhibitors by its slower dissociation from the ErbB1 and ErbB2 receptors (the dissociation period of 50% of lapatinib from the ligand-receptor complex is about 300 minutes). Lapatinib is a drug for targeted therapy of advanced and metastatic breast cancer. In preclinical studies, the antitumor efficacy of lapatinib was demonstrated in both trastuzumab-sensitive and trastuzumab-resistant cell lines. The bioavailability of lapatinib is dependent on food intake.
Use of the drug Lapatinib
Orally 1 hour before or 1 hour after meals. A course of treatment with lapatinib should only be administered by a specialist experienced in the use of anticancer drugs. Lapatinib is taken in combination with capecitabine. The recommended dose of lapatinib is 1250 mg (5 tablets) once a day, daily. A missed dose of lapatinib is not made up, that is, you should not take the missed dose by reducing the interval between doses. The recommended dose of capecitabine is 2000 mg/m2/day in 2 divided doses (every 12 hours) daily from days 1 to 14, every 21-day cycle. It is recommended to take capecitabine with food or within 30 minutes after a meal. Suspension of lapatinib or dose reduction is carried out for: disorders of the cardiovascular system. Treatment with lapatinib should be discontinued if symptoms occur when left ventricular ejection fraction decreases to National Cancer Institute grade III or greater, or if it decreases below the acceptable limit. Treatment with lapatinib can be resumed no earlier than 2 weeks later at a lower dose (1000 mg/day) and only if the level of left ventricular ejection fraction is within acceptable normal limits. Interstitial pulmonary process/pneumonitis. Treatment with lapatinib should be discontinued if pulmonary symptoms suggestive of National Cancer Institute grade 3 or greater interstitial pulmonary disease/pneumonitis develop. Other manifestations of drug toxicity. A decision to discontinue use or change the dosage of the drug may be made when the level of toxic effects that develop is greater than or equal to grade 2 according to the National Cancer Institute's classification of adverse events. Treatment can be started again with a dose of 1250 mg/day if the level of toxic effects has decreased to grade I or less. If toxic effects reoccur, the dose of lapatinib should be reduced to 1000 mg/day. Children. There is no experience of use in children. Elderly patients. There were no differences in the efficacy, tolerability, or safety of lapatinib depending on age. Patients with impaired renal function. No dosage adjustment is required in patients with impaired renal function. Patients with impaired liver function. There is insufficient data to formulate specific recommendations for adjusting the dosage regimen in patients with impaired liver function.
Tyverb
When using lapatinib and CYP3A inhibitors (ketoconazole, itraconazole, grapefruit juice) simultaneously, it is necessary to monitor the patient's clinical condition and possible adverse reactions.
The use of ketoconazole (CYP3A4 inhibitor) at a dose of 200 mg 2 times a day for 7 days increases the AUC of lapatinib by 3.6 times, T1/2 by 1.7 times. If it is necessary to co-administer a strong CYP3A4 inhibitor to a patient, reduce the dose of lapatinib to 500 mg/day, calculated in such a way as to adjust the AUC of lapatinib to a value corresponding to the use of lapatinib without inhibitors.
After discontinuation of a strong inhibitor, the dose of lapatinib is increased to the recommended dose only after 1 week (there are currently no clinical data on the use of lapatinib with such a dose adjustment in patients receiving a strong CYP3A4 inhibitor).
When using lapatinib concomitantly with CYP3A4 inducers (rifampicin, carbamazepine, phenytoin), it is necessary to monitor the patient's clinical condition and possible adverse reactions. The use of carbamazepine (CYP3A4 inducer) at a dose of 100 mg 2 times / day for 3 days and 200 mg 2 times / day for 17 days reduces the AUC of lapatinib by 72%.
When coadministering a strong CYP3A4 inducer, the dose of lapatinib is adjusted based on tolerability, gradually increasing it from 1250 mg/day to 4500 mg/day. The dose is calculated to adjust the AUC of lapatinib to a value consistent with the use of lapatinib without inducers. After discontinuation of a strong inducer, the dose of lapatinib is reduced to the recommended dose only after 2 weeks (there are currently no clinical data on the use of lapatinib in patients receiving a strong CYP3A4 inducer).
Lapatinib inhibits CYP3A4 and CYP2C8 at clinically relevant concentrations (in vitro). Caution is required during the simultaneous use of lapatinib and drugs with a narrow therapeutic index that are substrates of these enzymes. Slightly inhibits microsomal liver enzymes CYP1A2, CYP2C9, CYP2C19 and CYP2D6.
Lapatinib is a substrate for transport proteins (p-glycoprotein and BCRP - breast cancer resistance protein). Inhibitors and inducers of these proteins may alter the action and/or distribution of lapatinib.
Lapatinib inhibits the transport proteins p-glycoprotein, BCRP and OATP1B1 (organic anion transport polypeptide) in vitro and may therefore affect the pharmacokinetics of the substrates p-glycoprotein (digoxin), BCRP (topotecan) and OATP1B1 (rosuvastatin).
Side effects of Lapatinib
The safety of lapatinib was assessed both in monotherapy and in combination with capecitabine. The incidence of side effects was classified as follows: very often - ≥1/10; often - ≥1/100, but ≤1/10; sometimes - ≥1/1000, but ≤1/100; rarely - ≥1/10,000, but ≤1/1000), very rarely - ≤1/10,000), including isolated cases. Monotherapy with lapatinib Metabolic: very often - anorexia. From the cardiovascular system: often - decreased left ventricular ejection fraction (90% - asymptomatic). It recovered spontaneously in 60% of patients after discontinuation of the drug. In 0.1% of patients, a decrease in left ventricular ejection fraction was manifested by symptoms: dyspnea, heart failure, palpitations. From the respiratory system : sometimes - interstitial pulmonary process/pneumonitis. From the gastrointestinal tract: very often - diarrhea (which can lead to dehydration), nausea, vomiting. From the liver and biliary tract: sometimes - hyperbilirubinemia. On the part of the skin and its appendages: very often - rash (including acne). From the body as a whole: very often - weakness. Lapatinib in combination with capecitabine. In addition to those described above, the following adverse reactions were observed with the combined use of lapatinib and capecitabine with a frequency of more than 5%, compared with capecitabine monotherapy. From the gastrointestinal tract: very often - dyspepsia. On the part of the skin and its appendages: very often - dry skin. Identified with equal frequency in the lapatinib + capecitabine group and in the capecitabine group. From the gastrointestinal tract: very often - stomatitis, constipation, pain in the abdominal area. From the skin and its appendages: very often - palmar-plantar erythrodysesthesia. From the liver and biliary tract: very often - hyperbilirubinemia. From the body as a whole: very often - inflammation of the mucous membrane (mucositis). From the musculoskeletal system: very often pain in the back and limbs. From the side of the central nervous system: very often - insomnia; often - headache.
Special instructions for the use of Lapatinib
Treatment with lapatinib should only be carried out under the supervision of a specialist experienced in chemotherapy. Before starting treatment, it is imperative to determine the level of left ventricular ejection fraction. Monitoring of left ventricular ejection fraction levels should be continued during treatment with lapatinib to ensure that they do not fall below acceptable limits. Treatment with lapatinib should be discontinued if the ejection fraction decreases to grade III or greater, or if it decreases below the acceptable limit. Treatment with lapatinib can be resumed no earlier than 2 weeks later at a lower dose (1000 mg/day) and only if the level of left ventricular ejection fraction is within acceptable normal limits. A persistent decrease in left ventricular ejection fraction over 9 weeks of treatment usually limits the duration of therapy. There are reports of cases of interstitial pulmonary process and pneumonitis associated with lapatinib. Patients should be under medical supervision for the possibility of pulmonary symptoms indicating the development of interstitial pulmonary process/pneumonitis. It is recommended to prescribe antidiarrheal drugs when symptoms of diarrhea first develop. Severe diarrhea may require administration of electrolytes and fluids to prevent dehydration (oral or IV), interruption of lapatinib, or discontinuation of the drug. Women and men of reproductive age should use reliable methods of contraception during lapatinib therapy and for at least 3 months after its completion. Use during pregnancy and lactation. Women of childbearing age should be warned about the need to terminate pregnancy during treatment with lapatinib. Lapatinib was not teratogenic in studies in pregnant mice and rabbits, but was associated with some developmental abnormalities at maternally toxic doses. It is not known whether lapatinib is excreted into breast milk. It is recommended that breastfeeding be discontinued during lapatinib therapy due to the potential risk of characteristic adverse events in the nursing infant. Impact on the ability to drive vehicles and machinery. The mechanism of action of lapatinib suggests no effect on the ability to concentrate. However, the general clinical condition of the patient and the possibility of side effects should be taken into account when assessing the ability to drive vehicles and operate mechanisms that require quick reactions.
Lapatinib
Treatment with lapatinib should only be carried out under the supervision of a specialist experienced in chemotherapy.
Use with caution in conditions that can lead to left ventricular failure, moderate or severe liver dysfunction (Child-Pugh score of 7 or more).
Information on available contraindications and the safety of capecitabine when used in combination with lapatinib should be taken into account.
Before starting treatment, it is necessary to assess the level of left ventricular ejection fraction. During treatment, the level of left ventricular ejection fraction should be monitored to prevent this indicator from falling below acceptable values. Treatment with lapatinib should be discontinued if the ejection fraction decreases to grade 3 or more, or if it decreases below the acceptable limit. Treatment with lapatinib can be resumed no earlier than 2 weeks later at a lower dose (1000 mg/day and only if the level of left ventricular ejection fraction is within acceptable normal limits). A persistent decrease in left ventricular ejection fraction over 9 weeks of treatment usually limits the duration of therapy.
During treatment, patients should be monitored for pulmonary symptoms indicating the development of interstitial pulmonary process/pneumonitis.
At the first symptoms of diarrhea, it is recommended to prescribe antidiarrheal drugs. Severe diarrhea may require administration of electrolytes and fluids to prevent dehydration (orally or IV) and interruption or discontinuation of lapatinib.
Before starting treatment, then monthly, or as clinically indicated, liver function indicators (transaminase activity, alkaline phosphatase, bilirubin content) should be monitored. In case of severe liver dysfunction, treatment with lapatinib should be discontinued and re-treatment should not be performed. There are known cases of hepatotoxicity when prescribed tyrosine kinase inhibitors. In patients with impaired liver function, there is insufficient data to formulate specific recommendations for adjusting the dosage regimen.
Use in pediatrics
There is no experience using the drug in children.
Impact on the ability to drive vehicles and operate machinery
The mechanism of action of lapatinib suggests no effect on concentration abilities. However, the general clinical condition of the patient and the possible development of adverse events should be taken into account when assessing the ability to drive a car and operate mechanisms that require quick reactions.
Drug interactions Lapatinib
CYP3A inhibitors or inducers may affect the pharmacokinetics of lapatinib. When using lapatinib concomitantly with known CYP3A inhibitors (e.g. ketoconazole, itraconazole, grapefruit juice), caution should be exercised and the patient's clinical condition and the likelihood of adverse reactions should be carefully monitored. If it is necessary to co-administer a strong CYP 3A4 inhibitor to a patient, reduce the dose of lapatinib 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 adjustments in patients receiving a strong CYP3A4 inhibitor. After discontinuation of the potent inhibitor and its removal from the body, approximately 1 week later, the dose of lapatinib should be increased again to the recommended dose. When using lapatinib and known inducers of CYP 3A4 (for example, rifampicin, carbamazepine, phenytoin) together, caution should be exercised and the patient's clinical condition and the likelihood of adverse reactions should be carefully monitored. If it is necessary to simultaneously prescribe a strong CYP 3A4 inducer to a patient, the dose of lapatinib should be adjusted based on tolerability, gradually increasing it from 1250 to 4500 mg/day. This dose is calculated to adjust the AUC of lapatinib to a value consistent with the use of lapatinib without inducers. However, there are currently no clinical data on the use of lapatinib in patients receiving a strong CYP 3A4 inducer. After discontinuation of the powerful inducer, the dose of lapatinib should be reduced again to the recommended dose only after 2 weeks. Lapatinib inhibits in vitro at clinically relevant concentrations. Caution is required when coadministering lapatinib and drugs with a narrow therapeutic index that are substrates of these enzymes. Lapatinib is a substrate for the transport proteins glycoprotein II and BCRP. Inhibitors and inducers of these proteins may alter the action and/or distribution of lapatinib. Lapatinib inhibits the transport proteins glycoprotein II, BCRP and OATP1B1 in vitro . The clinical significance of these effects has not been studied, but it is possible that lapatinib may affect the pharmacokinetics of glycoprotein II substrates (eg digoxin), BCRP (eg topotecan) and OATP1B1 (eg rosuvastatin). The combined use of lapatinib with capecitabine or trastuzumab does not affect the pharmacokinetic parameters of these drugs.
Tyverb, 250 mg, film-coated tablets, 140 pcs.
Inhibitors or inducers of the CYP3A isoenzyme may affect the pharmacokinetics of lapatinib. When using lapatinib and some inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole, grapefruit juice), caution should be exercised and the patient's clinical condition and possible adverse reactions should be carefully monitored. If it is necessary to simultaneously prescribe a potent inhibitor of the CYP3A4 isoenzyme to a patient, it is necessary to reduce the dose of lapatinib to 500 mg / day, calculated so as 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 adjustments in patients receiving a strong CYP3A4 inhibitor. After discontinuation of a powerful inhibitor and its removal from the body, approximately 1 week later, the dose of lapatinib should be increased again to the recommended dose.
When using lapatinib and known inducers of the CYP3A4 isoenzyme (for example, rifampicin, carbamazepine, phenytoin) simultaneously, caution should be exercised and the patient's clinical condition and possible adverse reactions should be carefully monitored.
If it is necessary to simultaneously prescribe a potent inducer of the CYP3A4 isoenzyme to a patient, the dose of lapatinib should be selected based on tolerability, gradually increasing it from 1250 to 4500 mg/day or from 1500 to 5500 mg/day. This dose is calculated to adjust the AUC of lapatinib to a value consistent with the use of lapatinib without inducers of the CYP3A4 isoenzyme. However, there are currently no clinical data on the use of lapatinib in patients receiving a strong CYP3A4 inducer. After discontinuation of a powerful isoenzyme inducer, only after approximately 2 weeks, the dose of lapatinib should be reduced again to the recommended dose.
Lapatinib inhibits in vitro
isoenzyme CYP3A4 in clinically significant concentrations. Concomitant use of lapatinib with orally administered midazolam resulted in an approximately 45% increase in midazolam AUC. With intravenous administration of midazolam, no clinically significant increase in AUC was detected. Caution is warranted when coadministering lapatinib with orally administered drugs with a narrow therapeutic index that are substrates of the CYP3A4 isoenzyme.
Lapatinib inhibits CYP2C8 in vitro
in clinically significant concentrations. Caution should be used when administering lapatinib concomitantly with drugs with a narrow therapeutic index that are CYP2C8 substrates.
Concomitant use of lapatinib with IV paclitaxel increased paclitaxel exposure by 23% due to lapatinib inhibition of CYP2C8 and/or P-gp. An increased incidence and severity of diarrhea and neutropenia was observed when using the combination of lapatinib and paclitaxel in clinical trials. Caution is recommended when administering lapatinib concomitantly with paclitaxel.
Co-administration of lapatinib with IV docetaxel did not significantly affect the AUC or Cmax of either active substance. However, there was an increased incidence of docetaxel-induced neutropenia.
Concomitant use of lapatinib with irinotecan (when administered as part of the FOLFIRI regimen) resulted in an approximately 40% increase in the AUC of SN-38, the active metabolite of irinotecan. The exact mechanism of this interaction is unknown. Caution is recommended when lapatinib is administered concomitantly with irinotecan.
Lapatinib is a substrate for the transport proteins P-gp and BCRP. Inhibitors and inducers of these proteins may alter the activity and/or distribution of lapatinib.
Lapatinib inhibits the transport protein P-gp in vitro
in clinically significant concentrations. Concomitant use of lapatinib with orally administered digoxin resulted in an approximately 98% increase in digoxin AUC. Caution should be used when administering lapatinib concomitantly with drugs with a narrow therapeutic index that are P-gp substrates.
Lapatinib inhibits transport proteins BCRP and OATP1B1 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 (eg topotecan) and OATP1B1 (eg rosuvastatin).
The combined use of lapatinib with capecitabine, letrozole or trastuzumab does not affect the pharmacokinetic parameters of the drugs.
The bioavailability of lapatinib is dependent on food intake.
Lapatinib overdose, symptoms and treatment
The maximum daily dose in studies was 1800 mg. More frequent use of the drug may lead to increased concentrations of lapatinib in the blood serum, so you should not take missed doses, reducing the interval between doses. Symptoms: There has been one report of taking 3000 mg lapatinib for 10 days and developing grade 3 diarrhea and vomiting on the 10th day. Symptoms disappeared after IV rehydration and discontinuation of therapy. Treatment: symptomatic therapy. Hemodialysis is ineffective. There is no specific antidote to lapatinib.
List of pharmacies where you can buy Lapatinib:
- Moscow
- Saint Petersburg
