TAJVERB

Active material: Lapatinib
When ATH: L01XE07
CCF: Anticancer drug. An inhibitor of protein tyrosine kinase
ICD-10 codes (testimony): C50
When CSF: 22.06
Manufacturer: GlaxoSmithKline Trading Company (Russia)

Pharmaceutical form, composition and packaging

Pills, Film-coated yellow color, oval, lenticular, one side of the Tablet is smooth, on another inscription “GS XJG”.

Excipients: microcrystalline cellulose, povidone K30, sodium carboxymethyl starch (Type A), magnesium stearate.

The composition of the coating film: É dye yellow (gipromelloza, Titanium dioxide, iron oxide red (E172), iron oxide yellow (E172), macrogol 400, polysorbate 80).

10 PC. – blisters (7) – packs cardboard (2) – packaging.

Pharmacological action

Anticancer drug. Reversible, selective inhibitor of the intracellular tyrosine kinase, communicates with epidermal growth factor receptor (epidermal growth factor receptor – EGFR/ErbB1 и human epidermal growth factor receptor – HER2 /neu/ЕrbВ2 ). It differs from other tyrosine kinase inhibitors bystroobratimyh slower dissociation with ErbB1- and ErbV2 receptors (period of dissociation 50% ligand from the ligand-receptor complex is approximately 300 m).

In addition to its own in vitro activity has been demonstrated additive activity of lapatinib and 5-fluorouracil (the active metabolite of capecitabine) when used in combination for four tumor cell lines. The inhibitory effect was evaluated for trastuzumab-treated cells. Lapatinib demonstrated significant activity on tumor cell lines immortalized in media, containing trastuzumab, that shows no cross-resistance between the two ligands HER2 / neu / ErbB2 .

Studies in vitro have shown, that lapatinib is a substrate for the BCRP vectors (breast cancer resistance protein, breast cancer resistance protein) – ABCGI (АТР-binding cassette subfamily G1, АТФ-связывающий кассетный транспортер G1), гликопротеина P и АВСВ1 (ATP-binding cassette subfamily B1, АТФ-связывающий кассетный транспортер B1). Also, in vitro lapatinib provided ingibiruty effect on the data carriers. The clinical significance of these effects and influence on other drugs farmakokinetiku, as well as preparations, having antitumor activity, still unknown.

Clinical effectiveness and safety

According to the research lapatinib is an active drug, when administered as monotherapy in patients with metastatic breast cancer. The results showed, that the combined use of lapatinib with capecitabine for the treatment of patients with erbB2-positive advanced breast cancer increases the time to progression, and significantly, and significantly reduces the risk of disease progression.

It was identified a trend towards improved survival, and reduced the risk of death.

Pharmacokinetics

Absorption

Absorption after oral administration is incomplete and variable. The coefficient of variability of AUC is from about 50 to 100%. Defined in the systemic circulation at a mean 0.25 no (range 0-1.5 no). FROM_makh It reached approximately 4 h after administration of lapatinib.

C_ss^max in equilibrium with a daily dose of 1250 mg averages 2.43 (1.57-3.77) ug / ml, AUC – 36.2 (23.4-56) g × h / ml.

The bioavailability of lapatinib is dependent on food intake. Systemic exposure of lapatinib is increased when taking the drug at the same time food. AUC increases 3 and 4 times, C_max about 2.5 and 3 times higher when taken with food low or high fat, respectively.

Distribution

Lapatinib has a high degree of binding (more than 99%) with albumin and Alpha-1 acid glikoproteinom blood plasma.

Metabolism

Lapatinib undergoes extensive metabolism, mainly via CYP3A4 and CYP3A5, to a lesser extent CYP2C19 and CYP2C8 to form various oxygenated metabolites.

In vitro lapatinib at clinically relevant concentrations inhibits CYP2C8 CYP3Ai. Lapatinib inhibits slightly following microsomal liver enzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6.

In healthy volunteers, receiving ketokonazol (CYP3A4 inhibitor) dose 200 mg 2 times / day, during 7 days, system distribution lapatiniba increased approximately 3.6 times, T_1/2 – in 1.7 times.

In healthy volunteers, receiving carbamazepine (CYP3A4 inducer) dose 100 mg 2 times / day, during 3 days and 200 mg 2 times / day for 17 days, system distribution decreased lapatiniba 72%.

Deduction

T_1/2 dozozawisimo increases when taking one-time doses. The equilibrium state is achieved after 6-7 day reception, T_1/2 equilibrium is 24 no.

The main conclusions intestine – average 27% in unchanged form, less 2% the dose is excreted by the kidneys unchanged and as metabolites.

Pharmacokinetics in special clinical situations

It is unlikely the effect of renal impairment on the pharmacokinetics of lapatinib.

The pharmacokinetics of lapatinib has been studied at moderate (7-9 points on the Child-Pugh classification, n=8) and heavy (>9 points on the Child-Pugh classification, n=4) hepatic dysfunction. AUC lapatinib after a single dose 100 mg incremented by 56% and 85% respectively.

Testimony

is a common and/or metastatic tumor of mammary gland with human tissular kallikrein ErbB2 +(HER2 )-receptors, as part of combination therapy with capecitabine, patients, previously treated with, which included trastuzumab.

Dosage regimen

The course of treatment lapatinibom may only be carried out by a specialist, with experience in the use of anticancer drugs. Lapatinib is taken in combination with kapecitabinom.

The recommended dose is lapatiniba 1250 mg (5 tab.)/d, single, daily. Lapatinib is taken as 1 hours before or after 1 h postprandial.

Missed dose of lapatinib is not replenished, ie. take the missed dose, reducing intervals between doses, should not.

The recommended dose of involving Capecitabine – 2000 mg / m² body surface per day, in 2 admission (every 12 no), daily from 1-14 days, every 21 day. It is recommended to take Capecitabine during delivery or during 30 min after meal.

Experience with the drug in children no

There was no difference in the effectiveness of, tolerability and safety of lapatinib depending on the age (elderly patients).

Patients with impaired renal function It does not require correction dosing regimen.

In patients with impaired liver function insufficient data to generate concrete recommendations on correction mode.

Suspension of receiving lapatiniba or dose reduction

Violations on the part of the cardiovascular system

Treatment of lapatinib should be discontinued if symptoms decrease left ventricular ejection fraction to 3 degree or more (classification of adverse events of the National Cancer Institute), or in the case of reduction below the admissible norm. Lapatinib treatment can be resumed not earlier than 2 weeks at a lower dose (1000 mg / day) and only if the level of left ventricular ejection fraction is within the acceptable normal limits.

Interstitial Pneumonitis/pulmonary

Treatment of lapatinib should be discontinued in the event of pulmonary symptoms indicative of interstitial lung development process / pneumonitis 3 degree or more (classification of adverse events of the National Cancer Institute).

Other manifestations of drug toxicity

The decision to terminate the use or change the dosage of the drug can be taken, When the level of developing toxic effects is greater than or equal to 2 degree classification of adverse events National Cancer Institute. Treatment can be started again with doses 1250 mg / day, If the level of toxic effects decreased to 1 degree and less. In the case of a re-emergence of toxic effects lapatiniba dose should be reduced to 1000 mg / day.

Side effect

Security lapatiniba to be evaluated when alone, and when combined with the application of kapecitabinom.

The incidence of adverse events was classified as follows:: Often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10 000, <1/1000), rarely (<1/10 000), including individual cases.

Monotherapy lapatinibom

From the digestive system: Often – anorexia, diarrhea (which can lead to dehydration), nausea, vomiting; sometimes – giperʙiliruʙinemija, increased ALT, IS, Alkaline phosphatase.

Cardio-vascular system: often – decrease in left ventricular ejection fraction (90% – symptomatic). It resolves spontaneously in 60% patients after drug withdrawal. Symptomatic decrease in left ventricular ejection fraction was observed in 0.1% patients (dyspnoea, heart failure, palpitations).

The respiratory system: sometimes – interstitial pulmonary process / pneumonitis.

Dermatological reactions: Often – rash (including acne).

From the body as a whole: Often – weakness.

Lapatinib in combination with capecitabine

In addition to the above described, the following unwanted reactions were observed on the background of the combined use of lapatiniba and involving Capecitabine above 5%, compared to kapecitabinom alone.

From the digestive system: Often – dyspepsia.

Dermatological reactions: Often – xerosis.

Occurred with the same frequency in the lapatinib group + capecitabine and capecitabine gruppe

From the digestive system: Often – stomatitis, constipation, abdominal pain, giperʙiliruʙinemija.

Dermatological reactions: Often – palmar-plantar eritrodizesteziya.

From the body as a whole: Often – mukozit.

On the part of the musculoskeletal system: Often – pain in the back and limbs.

CNS: Often – insomnia; often – headache.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

-hypersensitivity to lapatinibu or any other component of the drug.

Should take into account information about the existing contraindications and safety of drugs Capecitabine, If he is appointed in combination with lapatinibom.

FROM caution should be prescribed for conditions, which can lead to left ventricular failure, hepatic dysfunction moderate or severe (7 and more points on the Child-Pugh).

Pregnancy and lactation

No known cases of lapatiniba during pregnancy.

Women of childbearing age should be warned about the use of adequate contraception, and, interruption of pregnancy during treatment lapatinibom. When used in doses, toxic to the mother, Lapatinib was not teratogenic properties in studies in pregnant mice and rabbits but, in the same time, was the cause of some developmental disorders.

Women and men during lapatinibom therapy and for at least 3 months after the need to use reliable methods of contraception.

Unknown, whether lapatinib in breast milk. During therapy lapatinibom to stop breast-feeding because of the possible occurrence of specific adverse events u baby.

Cautions

Treatment of lapatinib should be carried out only under the supervision of a specialist, with experience of chemotherapy.

Before treatment, it is necessary to determine the level of ejection fraction of the left ventricle. Monitoring of left ventricular ejection fraction should be continued during treatment lapatinibom, to prevent its decline below the limits of acceptable values. Lapatinibom treatment should be discontinued in case of ejection fraction reduction to 3 degree or more, or in the case of reduction below the admissible norm. Lapatinib treatment can be resumed not earlier than 2 weeks at a lower dose (1000 mg/day and only if the level of ejection fraction of the left ventricle is within the acceptable boundaries of rules). A permanent decline in left ventricular ejection fraction for 9 weeks of treatment, usually, It limits the duration of therapy.

There have been reports of cases of pulmonary interstitial pnevmonita and process in connection with the acquisition of lapatiniba. Patients should be monitored for the occurrence of pulmonary symptoms, indicating the development of interstitial pulmonary process / pneumonitis.

Recommended the appointment protivodiarejnyh drugs when you first develop symptoms. If severe diarrhea may require the appointment of electrolytes and fluids to prevent dehydration (PO / in), suspension or cancellation products lapatiniba reception.

Application of lapatiniba accompanied by gepatotoksičnost′û, which rarely can be severe. The function of the liver (aminotransferase levels, bilirubin and AP) should be controlled before starting treatment, then monthly, either on clinical indications. Lapatinibom treatment should be discontinued if severe liver; such patients Tajverbom re-treatment is not assigned. There are cases of hepatotoxicity in the appointment of tyrosine kinase inhibitors.

Effects on ability to drive vehicles and management mechanisms

The mechanism of action of lapatinib suggest no effect on the ability to concentrate. Nonetheless, It should take into account the overall clinical condition of the patient and the possible development of adverse events when assessing the ability to drive a car and operate machinery, requiring quick response.

Overdose

The maximum daily dose of studies was 1800 mg.

More frequent reception drug can lead to increased concentrations of serum lapatiniba, Therefore, you should not take missed dose, reducing intervals between doses.

Symptoms: registered one message for admission 3000 mg lapatiniba for 10 days and developed diarrhea 3 extent and vomit on the 10th day. Symptoms were resolved after the on/in the rehydration and therapy.

Treatment: simptomaticheskaya therapy. Hemodialysis is not effective. A specific antidote to lapatinibu does not exist.

Drug Interactions

CYP3A inducers or inhibitors can affect the pharmacokinetics of lapatinib. With simultaneous use of lapatinib and known inhibitors of CYP3A (eg, ketoconazole, itraconazole, grapefruit juice) you must be careful and closely monitor the patient's clinical condition and possible adverse reactions. If necessary, the patient co-administration of strong CYP3A4 inhibitor necessary to reduce the dose of lapatinib 500 mg / day, calculated as, to adjust the lapatinib AUC to the value, appropriate use of lapatinib without inhibitors. But, no clinical data lapatinib at a dose adjustment for patients, receiving a potent inhibitor of CYP3A4. After canceling a strong inhibitor, Only after removing it from the body, after about 1 week should again increase the dose to the recommended lapatinib.

With simultaneous use of lapatinib and known inducers of CYP3A4 (eg, rifampicin, Carbamazepine, phenytoin) and you must be careful and closely monitor the patient's clinical condition and possible adverse reactions.

If you need simultaneous appointment the patient a strong inducer of CYP3A4 dose lapatiniba should pick up, based on portability, gradually increasing it with 1250 mg / day to 4500 mg / day. This dose is calculated as, to adjust the lapatinib AUC to the value, appropriate use of lapatinib without inductors. However, no clinical data in patients lapatinib, receiving strong CYP3A4 inducer. After the abolition of the strong inducer, Only after about 2 week should again be reduced to the recommended dose of lapatinib.

Lapatinib inhibits the in vitro CYP3A4 and CYP2C8 at clinically relevant concentrations. Care should be taken while the appointment of lapatinib and drugs with a narrow therapeutic range, are substrates of these enzymes. Lapatinib is a substrate for the transport proteins P glycoprotein and BCRP. Inhibitors and inducers of these proteins may alter the action and / or distribution of lapatinib.

Lapatinib inhibits the transport proteins glycoprotein P, BCRP and OATR1V1 in vitro. The clinical significance of these effects was not investigated, but it is not excluded, that lapatinib can affect the farmakokinetiku glycoprotein substrates (P) (eg, digoksina), BCRP (eg, Topotecan) and OATR1V1 (eg, rosuvastatin).

Combined use of lapatiniba with kapecitabinom or trastuzumabom does not affect the pharmacokinetic parameters of drugs.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 2 year.