Composition, form of production and packaging
The tablets covered with a film membrane of yellow color, oval in shape, biconvex, one side of the tablet smooth, the other is engraved with the inscription "GS XJG".
lapatinib ditosylate monohydrate 405 mg,
which corresponds to the content of lapatinib 250 mg
[PRING] microcrystalline cellulose - 387 mg, povidone K30 - 58.5 mg, sodium carboxymethyl starch (type A) - 40.5 mg, magnesium stearate - 9 mg, purified water - qs (it is removed in the manufacturing process).
The composition of the shell: opadrai В® yellow YS-1-12524-A - 27 mg (hypromellose - 17.23 mg, titanium dioxide - 7.13 mg, ferric oxide red oxide (E172) 0.005 mg, iron oxide yellow oxide (E172) 0.21 mg, Macrogol 400 - 2.16 mg, polysorbate 80 - 0.27 mg.
10 pieces. - blisters (7) - packs cardboard (2) - group packing.
140 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Lapatinib is a reversible selective inhibitor of intracellular tyrosine kinase that binds to EGFR (the receptor of epidermal growth factor, ErbB1) and HER2 (the receptor of epidermal growth factor of human, ErbB2) receptors. It differs from other rapidly reversible tyrosine kinase inhibitors by slower dissociation with ErbB1 and ErbB2 receptors (the dissociation period of 50% of the ligand from the ligand-receptor complex is approximately 300 min).
In addition to intrinsic in vitro activity, the additive activity of lapatinib and fluorouracil (active metabolite of capecitabine) was shown when used in combination on four lines of tumor cells. The inhibitory effect was evaluated on trastuzumab-treated cells. The combination of lapatinib and trastuzumab can 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 the lines of HER2-positive tumor cells in media containing trastuzumab, and in combination with trastuzumab showed a synergistic effect in these cell lines. These results demonstrate the absence of cross-resistance between the two HER2 receptor ligands (ErbB2).
Absorption after ingestion is incomplete and variable. The coefficient of variability of AUC is from 50% to 100%. It is defined in the systemic blood stream on average 0.25 h (range 0-1.5 h). With MAX is achieved approximately 4 hours after taking lapatinib.
C ss max in the equilibrium state with a daily intake of 1250 mg averages 2.43 (1.57-3.77) Ојg / ml, AUC - 36.2 (23.4-56.0) Ојg / h / ml.
Systemic exposure of lapatinib increases with taking the drug simultaneously with food. When taken with food low (5% fat or 500 calories) or high (50% fat or 1000 calories) the fat content of AUC increases by 3 and 4 times (C max - approximately 2.5 and 3 times), respectively.
Lapatinib has a high degree of binding (more than 99%) with albumin and alpha 1- acid glycoprotein of blood plasma.
In vitro studies have shown that lapatinib is a substrate for the carriers of 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 vector data. The clinical significance of these effects and the effect on other pharmacokinetics of drugs, as well as drugs that have antitumor activity, is still unknown. Lapatinib slightly inhibits the transport of organic anions (OAT) or an organic cation carrier (OCT).
Lapatinib is subjected to intensive metabolism, mainly by isoenzymes CYP3A4 and CYP3A5, to a lesser extent isoenzymes CYP2C19 and CYP2C8 with the formation of various oxidized metabolites.
In vitro lapatinib at clinically significant concentrations inhibits the isoenzymes CYP3A and CYP2C8.
Lapatinib slightly inhibits the following microsomal liver enzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6.
In healthy volunteers receiving ketoconazole (inhibitor of the isoenzyme CYP3A4) at a dose of 200 mg 2 times / day for 7 days, the systemic distribution of lapatinib increased approximately 3.6 times, T 1/2 - 1.7-fold.
In healthy volunteers receiving carbamazepine (inducer of isoenzyme CYP3A4) at a dose of 100 mg 2 times / day, for 3 days and 200 mg 2 times / day for 17 days, the systemic distribution of lapatinib decreased by 72%.
T 1/2 increases dose-dependently when taken in single doses.
The equilibrium state is achieved after 6-7 days of admission, T 1/2 in the equilibrium state is 24 h.
Basically excreted by the intestines - an average of 27% (from 3% to 67%) in unchanged form, less than 2% of the accepted dose is excreted by the kidneys in unchanged form and in the form of 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, the effect of renal dysfunction on the pharmacokinetics of lapatinib is unlikely, the kidneys produce less than 2% of the administered dose (in the form of lapatinib and its metabolites).
The pharmacokinetics of lapatinib has been studied with moderate (n = 8) and severe (n = 4) violations of the liver function . AUC lapatinib after taking a single dose of 100 mg orally increases by approximately 56% and 85% in patients with moderate and severe impairment of liver function, respectively. Prescribe lapatinib to patients with impaired liver function with caution. Patients with severe hepatic insufficiency in the history are recommended to reduce the dose of lapatinib. It is necessary to abolish therapy with lapatinib, without the subsequent resumption of its use, in patients with severe hepatotoxicity, developed against the background of its use.
Locally-distributed or metastatic breast cancer with overexpression of HER2:
- in combination with capecitabine in patients who had previously received anthracycline and taxane, who had progression with or after trastuzumab therapy for metastatic cancer.
Metastatic breast cancer with overexpression of HER2:
- in combination with trastuzumab in patients who have progressed to cancer with or after trastuzumab therapy for metastatic cancer.
Hormone-receptor-positive metastatic breast cancer with overexpression HER2:
- in combination with an aromatase inhibitor in postmenopausal patients.
The drug Tyverb should be taken 1 hour before meals or 1 hour after meals. The recommended daily dose can not be divided into receptions.
Missed doses of lapatinib are not replenished, i.e. Do not take missed doses, reducing the intervals between doses.
Locally advanced or metastatic breast cancer with overexpression of HER2
- in combination with capecitabine
The recommended dose of lapatinib is 1250 mg (5 tab.) Once daily, daily in combination with capecitabine.
The recommended dose of capecitabine is 2000 mg / m 2 / day, in 2 divided doses (every 12 hours) daily from 1 to 14 days of each 21-day therapy cycle. It is recommended to take capecitabine with food or within 30 minutes after eating.
- in combination with trastuzumab
The recommended dose of lapatinib is 1000 mg (4 tablets) once a day, daily in combination with trastuzumab.
The recommended dose of trastuzumab is 4 mg / kg, in the form of an IV loading dose, then 2 mg / kg IV once a week.
Hormone-receptor-positive metastatic breast cancer with overexpression of HER2
The recommended dose of lapatinib is 1500 mg (6 tablets) once a day, daily in combination with an aromatase inhibitor.
The recommended dose of letrozole (one of the possible drugs - aromatase inhibitors) when taken in combination with lapatinib is 2.5 mg once daily, daily. In the event that lapatinib is prescribed in combination with another aromatase inhibitor, it is necessary to study the dosage regimen of the corresponding drug in this group.
Suspension of lapatinib or dose reduction (all indications)
Disorders from the cardiovascular system
Treatment with lapatinib should be discontinued if symptoms of a reduction in the left ventricular ejection fraction (LVEF) up to grade 3 or greater (according to the general criteria for toxicity of the National Cancer Institute of the United States) or in the case of a decrease below the limit of the acceptable norm. Treatment with lapatinib can be resumed no earlier than 2 weeks at a lower dose (reduced from 1000 mg / day to 750 mg / day with the appointment of a combination with trastuzumab, from 1,250 mg / day to 1000 mg / day when a combination with capecitabine or with 1500 mg / day to 1,250 mg / day when administered with an aromatase inhibitor) if LVEF is within normal range and the patient has no symptoms of heart failure. According to reports, the majority of cases of LVEF decrease occur during the first 12 weeks of treatment, but there is insufficient data on the long-term effects of lapatinib.
Interstitial lung disease and / or pneumonitis
Treatment with lapatinib should be discontinued if pulmonary symptoms occur that indicate the development of interstitial lung disease and / or pneumonitis of grade 3 or higher (according to the general toxicity criteria of the National Cancer Institute of the United States).
Treatment with lapatinib should be suspended in patients with grade 3 diarrhea, either grade 1 or grade 2 with complicated symptoms (according to the general criteria for toxicity of the National Cancer Institute of the USA) (spasmodic abdominal pain from mild to severe, nausea or vomiting 2 nd degree or higher (according to general toxicity criteria of the National Cancer Institute of the USA), decreased performance, fever, sepsis, neutropenia, severe bleeding or dehydration). Treatment with lapatinib can be resumed at a lower dose (reduction from 1000 mg / day to 750 mg / day, from 1,250 mg / day to 1,000 mg / day or from 1,500 mg / day to 1,250 mg / day) if the severity of diarrhea has decreased to 1 degree and below. Treatment with lapatinib should be completely discontinued in patients with grade 4 diarrhea (according to the general toxicity criteria of the National Cancer Institute of the United States).
Other manifestations of drug toxicity
The decision to discontinue treatment or discontinue treatment with the drug may be taken when the severity of the developing toxic effects is higher or equal to the 2nd degree (according to the general criteria of toxicity of the National Cancer Institute of the USA). Treatment can be resumed at a dose of 1000 mg / day when administered in combination with trastuzumab, 1250 mg / day when administered in combination with capecitabine or 1500 mg / day when given in combination with an aromatase inhibitor if the severity of toxic effects is reduced to grade 1 and below. In case of repeated toxic effects, the dose of lapatinib should be reduced from 1000 mg / day to 750 mg / day when administered in combination with trastuzumab, from 1,250 mg / day to 1,000 mg / day when administered in combination with capecitabine or 1,500 mg / day up to 1250 mg / day when administered in combination with an aromatase inhibitor.
Special patient groups
The experience of the drug in children is not.
There is insufficient data on the use of lapatinib in elderly patients (over 65 years of age).
There is no experience with lapatinib in patients with severe renal dysfunction , but it is unlikely that correction of the dosing regimen will be required due to the fact that less than 2% of the administered dose is excreted by the kidneys.
Lapatinib is metabolized in the liver. Moderate and severe violations of the liver are associated with an increase in systemic exposure by 56% and 85%, respectively. Caution should be used to administer lapatinib to patients with impaired liver function. In patients with severe impairment of liver function (class C on the Child-Pugh scale), it is necessary to reduce the dose of lapatinib. Reducing the dose from 1250 mg / day to 750 mg / day (when administered in combination with capecitabine) or from 1500 mg / day to 1000 mg / day (when used in combination with an aromatase inhibitor) in such patients results in AUC normalization. With the development of severe manifestations of hepatotoxicity during the use of lapatinib, drug withdrawal is necessary, reassignment is unacceptable.
The safety of lapatinib has been evaluated in clinical trials both in monotherapy and in combination with trastuzumab, capecitabine and letrozole.
Post-registration data correspond to data obtained during clinical trials.
The undesirable phenomena presented below are listed in accordance with the defeat of organs, organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10 000, < 1/1000), very rarely (<1/10 000, including individual cases).
Monotherapy with lapatinib
From the side of metabolism and nutrition: very often - anorexia.
From the cardiovascular system: often - a decrease in LVEF was observed in approximately 1% of patients receiving lapatinib, and was asymptomatic in more than 70% of cases. After abolition of lapatinib, normalization or improvement in LVEF was observed in more than 70% of cases. Symptomatic reduction in LVEF was observed in approximately 0.3% of patients receiving lapatinib. The undesirable phenomena observed in this case included shortness of breath, heart failure, palpitations .
From the respiratory system: infrequently - interstitial lung disease / pneumonitis.
On the part of the gastrointestinal tract: very often - diarrhea (which can lead to dehydration, but in most cases, grade 1 or 2 diarrhea did not lead to withdrawal of the drug), nausea, vomiting.
From the liver and biliary tract: infrequently - hyperbilirubinemia, hepatotoxicity. An increase in the concentration of bilirubin is possible due to inhibition of lactatinib conjugation in the liver OATP1B1 (a polypeptide carrying organic anions 1B1) or inhibition of bilirubin release with bile by P-glycoprotein or BCRP.
From the skin and subcutaneous tissues: very often - a rash (including acneiform dermatitis, in most cases passing, not requiring withdrawal of the drug); often - nail damage, including paronychia.
Allergic reactions: rarely - hypersensitivity reactions, including anaphylaxis.
On the part of the body as a whole: very often - weakness.
The use of lapatinib in combination with capecitabine
In addition to the adverse events observed with lapatinib monotherapy, the following adverse events were observed when lapatinib was used in combination with capecitabine at a frequency greater than 5% compared with capecitabine monotherapy.
From the digestive tract: very often - dyspepsia.
From the skin and subcutaneous tissues: very often - dry skin.
Adverse events observed with lapatinib in combination with capecitabine with the same incidence as with capecitabine monotherapy.
From the gastrointestinal tract: very often - stomatitis, constipation, pain in the abdomen.
From the skin and subcutaneous tissues: very often - palmar-plantar syndrome.
From the musculoskeletal system: very often - pain in the limbs, back pain.
From the nervous system: often - a headache.
From the side of the psyche: very often - insomnia.
On the part of the body as a whole: very often - inflammation of the mucous membrane of the mouth.
The use of lapatinib in combination with trastuzumab
When using lapatinib in combination with trastuzumab, there were no additional adverse events associated with lapatinib. There was an increased incidence of cardiotoxicity, but these phenomena by nature and severity were similar to those previously observed in the clinical studies program of lapatinib.
The use of lapatinib in combination with letrozole
In addition to the adverse events observed with lapatinib monotherapy, the following adverse events were observed with lapatinib in combination with letrozole at a frequency greater than 5% compared with letrozole monotherapy.
From the respiratory system: very often - nosebleeds.
From the skin and subcutaneous tissues: very often - alopecia, dry skin.
- lactation period (breastfeeding);
- Children's age (lack of experience of application).
- hypersensitivity to lapatinib or any other component of the drug.
Caution should be given to the drug in conditions that can lead to left ventricular failure, moderate or severe liver dysfunction (7 or more Child-Pugh score), severe renal failure, in patients older than 65 years, concomitant with moderate inhibitors isoenzyme CYP3A4.
It should avoid simultaneous reception with inductors or potent inhibitors of the isoenzyme CYP3A4, grapefruit juice; with drugs that are substrates of CYP3A4 isoenzymes for CYP2C8 with a narrow therapeutic range; with drugs that increase the pH of gastric juice (reduced solubility and absorption of lapatinib).
PREGNANCY AND LACTATION
There are no known cases of lapatinib in pregnancy.
Women of childbearing age should be warned about using adequate contraception, as well as the ensuing interruption of pregnancy during treatment with lapatinib.
When used in doses toxic to the mother, lapatinib did not have teratogenic in studies on pregnant mice and rabbits, but at the same time was the cause of some of the variations in development.
It is not known whether lapatinib is excreted in breast milk. During therapy, lapatinib is recommended to stop breast-feeding because of the possible occurrence of adverse events typical of an infant.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with mild and moderate renal impairment is required dosing regime correction. No experience with lapatinib in patients with severely impaired renal function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with impaired hepatic function of the drug should be used with caution. In severe hepatic dysfunction (class C Child-Pugh) necessary to reduce the dose of lapatinib. Dose reduction from 1250 mg / day to 750 mg / day or 1500 mg / day to 1000 mg / day in these patients leads to normalization of AUC. With the development of severe manifestations of hepatotoxicity requires removal of the drug, re-appointment is inadmissible.
APPLICATION FOR CHILDREN
Contraindicated: children's age (lack of application experience).
APPLICATION IN ELDERLY PATIENTS
Insufficient data on the use of lapatinib in patients of advanced age (over 65 years).
Lapatinib treatment should be performed only under the supervision of a specialist who is experienced in the use of anticancer drugs.
Before treatment, it is imperative to determine the left ventricular ejection fraction, to ensure that LVEF is within acceptable limits. During treatment with lapatinib control LVEF should continue not to miss its reduction of range.
It is impossible to completely eliminate the effect of lapatinib on the QT interval, as there are reports of a slight increase in the QT interval in patients with advanced cancer. Care must be taken when assigning lapatinib patients with concomitant factors affecting the increase in QT interval (such as hypokalemia, hypomagnesemia, congenital long QT interval syndrome or while the use of drugs affecting the increase in QT interval). The concentration of potassium in the blood and magnesium must be brought back to normal before application lapatinib. ECG QT interval control should be carried out before the beginning and throughout treatment lapatinib.
Interstitial lung disease and pneumonitis
There are reported cases of interstitial lung disease and pneumonitis due to taking lapatinib. Patients should be monitored in order to avoid the occurrence of pulmonary symptoms indicative of interstitial lung disease development and / or pneumonitis.
There have been reports of cases of diarrhea, including severe diarrhea, for the treatment of lapatinib. Diarrhea typically occurs early in treatment lapatinib, with nearly half of these patients, diarrhea occurred during the first 6 days. Diarrhea usually lasts 4-5 days. Lapatinib-induced diarrhea is shown, generally at mild; diarrhea 3rd and 4th degree (according to Common Toxicity Criteria of the National Cancer Institute of the United States) is observed in less than 10% and less than 1% of patients, respectively. Early detection and prompt treatment are important for the optimal control of diarrhea. Patients should be instructed that they must immediately report any changes in the nature of a chair. Recommended therapy immediately assign diarrhea antidiarrheals (e.g.,loperamide) after the first case of unformed stool. When diarrhea severe may require the assignment of electrolytes and fluid to prevent dehydration (orally or /), the use of antibiotics such as fluoroquinolones (especially if diarrhea lasts more than 24 hours; the patient has a fever, or neutropenia 3rd or 4th degree), suspending reception or removal of the drug.
During lapatinib therapy and for at least 3 months after the end of the need to use reliable methods of contraception.
Manifestations hepatotoxicity (ALT or AST exceeding 3 times ULN, total bilirubin content exceeding the upper limit of normal 1.5-fold) were observed in clinical studies (less than 1% of patients) and in the post-registration period. Hepatotoxicity may be severe. Cases with fatal outcome have been reported, although a causal relationship with the reception of lapatinib has not been established. Hepatotoxicity may develop over a period of several days to several months after initiation of therapy. Necessary to control liver function laboratory parameters (transaminases, bilirubin, and alkaline phosphatase) prior to initiation of therapy, then every 4-6 weeks during the course of treatment and clinical indications. In the event of severe liver dysfunction require cancellation lapatinib,repeated use of the drug is not allowed.
Patients carrying the allele HLA DQA1 * 02: 01 and DRB1 * 07: 01 have an increased risk of liver toxicity associated with lapatinib. In patients treated with lapatinib monotherapy, the overall risk of severe liver injury (ALT more than 5 times higher than the normal range, 3rd degree (according to the Common Toxicity Criteria of the US National Cancer Institute)) was higher (about 8%) of the carrier DQA1 * 02: 01 and DRB1 * 07: 01 than non-carriers (0.5%). Carriage HLA alleles characteristic (from 15% to 25%) Caucasian, Asian, African, and Hispanic populations, but lower (1%) in the Japanese population.
When assigning lapatinib patients with severe hepatic impairment history recommended dose reduction lapatinib.
The simultaneous use of CYP3A4 inhibitors or inducers
must be used with caution lapatinib together with inhibitors or inducers of CYP3A4 isoenzyme because of risk increase or decrease (respectively) in systemic exposure lapatinib.
Impact on the ability to drive vehicles and manage mechanisms
Effects on ability to drive vehicles and other activities that require high concentration and psychomotor speed reactions, has not been studied. Based on the mechanism of action of lapatinib, it can not be assumed adverse effect of the drug on such activities. However, one should take into account the patient's general condition and the profile of the side effects of lapatinib, caution should be exercised when driving and busy with other potentially hazardous activities that require high concentration and psychomotor speed reactions.
The maximum daily dose in the studies was 1800 mg.
More frequent taking the drug can lead to increased concentrations of lapatinib in serum, however should not be taken missed doses, reducing intervals between doses.
Symptoms: The effects associated with side effects, in some cases - the skin ulceration, sinus tachycardia (however, with normal ECG) and / or mucous membrane damage. Cases of overdose have also been observed without clinical symptoms.
Treatment: symptomatic therapy. Hemodialysis is not effective. Treatment should be prescribed by a doctor.
Inhibitors, or inducers of CYP3A isoenzyme can affect the pharmacokinetics of lapatinib. With simultaneous use of certain inhibitors lapatinib and isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole, grapefruit juice), be careful and carefully watch the clinical condition of the patient and possible adverse reactions. If necessary, concomitant administration of a strong CYP3A4 isoenzyme inhibitor lapatinib should reduce the dose to 500 mg / day, calculated so as to adjust to lapatinib AUC value corresponding to the application without lapatinib inhibitors. However, there is currently no clinical data on the use of lapatinib in such a dose adjustment in patients receiving potent inhibitor of CYP3A4 isoenzyme. After canceling a potent inhibitor only after its removal from the body,After approximately 1 week should again increase to the recommended dose of lapatinib.
With simultaneous application of lapatinib and known isoenzyme inducers of CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, St. John's wort) and care must be taken and carefully watch the clinical condition of the patient and possible adverse reactions.
If necessary, co-administration to a patient potent inducer of CYP3A4 isoenzyme lapatinib dose should be selected based on tolerance, gradually increasing it to 1,250 mg / day to 4500 mg / day or 1500 mg / day to 5500 mg / day. This dose is calculated so as to adjust to lapatinib AUC value corresponding to the application without lapatinib isoenzyme inducers of CYP3A4. However, there is currently no clinical data on the use of lapatinib in patients receiving potent inducer of CYP3A4 isoenzyme. After canceling a potent inducer isoenzyme CYP3A4, only about 2 weeks later again be reduced to the recommended dose of lapatinib.
Lapatinib solubility is pH dependent. Avoid concomitant use of substances that increase the pH of gastric juice, as lapatinib solubility and absorption may decrease. Prior therapy a proton pump inhibitor (such as esomeprazole) lapatinib activity decreased by an average of 27% (ranging from 6% to 49%). This effect decreases with increasing age from 40 years to 60 years. It should therefore be used with caution in Lapatinib patients receiving proton pump inhibitors.
Lapatinib inhibits in vitro CYP3A4 isoenzyme in clinically relevant concentrations. The simultaneous use of lapatinib with midazolam for ingestion leads to increased midazolam AUC by about 45%. The on / in the introduction of midazolam revealed no clinically significant increase in AUC. Care should be taken while appointing lapatinib and preparations for oral administration with a narrow therapeutic range that are substrates isoenzyme CYP3A4.
Lapatinib inhibits isozyme CYP2C8 in vitro to clinically relevant concentrations. It should be used with caution lapatinib concurrently with medications with a narrow therapeutic index that are substrates of CYP2C8 isoenzyme.
The simultaneous use of lapatinib with paclitaxel / paclitaxel in effect increases by 23% due to the inhibition of CYP2C8 isozyme lapatinib and / or P-glycoprotein. Increasing the frequency of occurrence and severity of diarrhea and neutropenia was observed with the combination of lapatinib and paclitaxel in clinical trials. Recommended with caution lapatinib concurrently with paclitaxel.
The simultaneous use of lapatinib with docetaxel / v had no significant effect on AUC and C max any active substances. However, there was an increase in the incidence of docetaxel-induced neutropenia.
The simultaneous use of lapatinib with irinotecan (when administered within the FOLFIRI regimen) resulted in higher AUC SN-38, the active metabolite of irinotecan, approximately 40%. The exact mechanism of this interaction is not known. Recommended with caution lapatinib concurrently with irinotecan.
Lapatinib is a substrate for transport protein P-glycoprotein, and BCRP. Inhibitors and inducers of these proteins can alter the activity and / or distribution of lapatinib.
Lapatinib inhibits transport protein is P-glycoprotein in vitro to clinically relevant concentrations. The simultaneous use of lapatinib with digoxin when administered leads to an increase in AUC of digoxin by approximately 98%. It should be used with caution lapatinib while the use of drugs with a narrow therapeutic range that are substrates of P-glycoprotein.
Lapatinib inhibits BCRP transport proteins and OATR1V1 in vitro. The clinical significance of these effects has not been studied, but it is not excluded that lapatinib can affect the pharmacokinetics of substrates BCRP (e.g., topotecan) and OATR1V1 (e.g. rosuvastatin).
Combined application of lapatinib with capecitabine, trastuzumab letrozole or no effect on the pharmacokinetic parameters of these drugs.
Bioavailability lapatinib independent of food intake.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 2 years.