Xeloda - instructions for use, reviews, analogs and formulations (150 mg and 500 mg tablets) of the drug for the treatment of breast, rectal cancer in adults, children and pregnancy

In this article, you can read the instructions for using the drug Xeloda. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Xeloda in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Xeloda in the presence of existing structural analogues. Use for the treatment of breast cancer, rectum in adults, children, as well as in pregnancy and lactation.

Xeloda antitumor agent, antimetabolite. Capecitabine (Xeloda active ingredient) is a carbamate fluoropyrimidine derivative, an oral cytotoxic agent that activates in the tumor tissue and exerts a selective cytotoxic effect on it. Capecitabine has no cytotoxic effect, is converted to 5-fluorouracil (5-FU), which undergoes further metabolism. The formation of 5-FU occurs predominantly in the tumor tissue under the action of a tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of 5-FU on healthy body tissues.

Sequential enzymatic biotransformation of capecitabine in 5-FU creates higher drug concentrations in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients with colorectal cancer (n = 8), the concentration of 5-FU in the tumor tissue is 3.2 times greater than its concentration in the adjacent healthy tissues (range from 0.9 to 8.0).

The ratio of concentrations of 5-FU in tumor tissue and plasma is 21.4 (range from 3.9 to 59.9), the ratio of its concentration in healthy tissues and in plasma is 8.9 (range from 3 to 25.8).The activity of thymidine phosphorylase in the primary colorectal tumor is also 4 times higher than in the adjacent healthy tissues.

In tumor cells in patients with breast, stomach, colorectal cancer, cervical and ovarian cancer, there is a higher level of thymidine phosphorylase, capable of converting 5'-DFUR (5'-deoxy-5-fluorouridine) to 5-FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FUDF) and 5-fluorouridine triphosphate (FUTF). These metabolites damage the cells through two different mechanisms. First, FUUM and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TC) to form a covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is a necessary precursor of thymidine triphosphate, which in turn is extremely important for DNA synthesis, so the lack of this substance can lead to inhibition of cell division.

Secondly, in the process of RNA synthesis, the transcriptional enzymes of the nucleus can erroneously include FUTM in it instead of uridine-triphosphate (UTP).This metabolic "error" disrupts RNA processing and protein synthesis.

Composition

Capecitabine + excipients.

Pharmacokinetics

After oral administration, Xeloda is rapidly and completely absorbed, after which it transforms into metabolites - 5'-deoxy-5-fluorocytidine (5'-DFTST) and 5'-DFUR. The food reduces the absorption rate of capecitabine, but it does not significantly affect the AUC value of 5'-DFUR and the next metabolite of 5-FU.

Primarily metabolized in the liver under the influence of carboxyl esterase to the metabolite 5'-DFTST, which is then transformed into 5'-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite of 5-FU occurs predominantly in tumor tissue under the action of tumor angiogenic factor-thymidine phosphorylase (dTdPase).

Metabolites of capecitabine become cytotoxic only after conversion to 5-FU and metabolites of 5-FU. Further, 5-FU is catabolized with the formation of inactive metabolites - dihydro-5-fluorouracil (FUNH2), 5-fluoroureidopropionic acid (PUPF) and alpha-fluoro-beta-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

After taking Xeloda, its metabolites are excreted mainly in the urine. Most (95.5%) of the accepted dose of capecitabine is excreted in the urine. Excretion with feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose is excreted unchanged in the urine.

Combination Therapy

No effect of Xeloda on the pharmacokinetics of docetaxel or paclitaxel, as well as the effects of docetaxel or Paclitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine) was not detected.

Indications

Mammary cancer

combination therapy with docetaxel of locally advanced or metastatic breast cancer, with ineffective chemotherapy, including an anthracycline-based drug;
monotherapy of locally advanced or metastatic breast cancer, chemotherapy-resistant taxanes or anthracycline-based drugs, or if there are contraindications to them.

Colorectal cancer

adjuvant therapy for colon cancer 3 stages after surgical treatment;
therapy of metastatic colorectal cancer.

Stomach cancer

first-line therapy of advanced stomach cancer.

Forms of release

Tablets coated with 150 mg and 500 mg.

Instructions for use and dosing regimen

The drug is taken orally, washed down with water, not later than 30 minutes after eating.

Standard dosing regimen

Monotherapy

Colorectal cancer, colon cancer and breast cancer

Xeloda is prescribed for 1250 mg / m2 twice a day, in the morning and in the evening (total daily dose of 2500 mg / m2) for two weeks, followed by a seven-day break.

Combination Therapy

Mammary cancer

The drug Xeloda is prescribed at 1250 mg / m2 twice a day for two weeks followed by a seven-day break, in combination with docetaxel at a dose of 75 mg / m2 every 3 weeks as an intravenous infusion for 1 hour.

Premedication is performed before docetaxel is administered in accordance with the instructions for its use.

Colorectal cancer and stomach cancer

As part of combination therapy, the dose of Xeloda should be reduced to 800-1000 mg / m2 twice a day for two weeks, followed by a seven-day break or up to 625 mg / m2 twice a day in continuous mode. The addition of immunobiological drugs to combination therapy does not affect the dose of Xeloda.

Antiemetics and premedication to ensure adequate hydration are prescribed before the introduction of Cisplatin and oxaliplatin according to the instructions for the use of cisplatin and oxaliplatin when used in combination with Xeloda.

In adjuvant therapy for colon cancer, stage 3, the recommended duration of therapy with Xeloda is 6 months, i.e. 8 courses.

In combination with cisplatin

Assign 1000 mg / m2 twice a day for two weeks, followed by a seven-day break in combination with cisplatin (80 mg / m2 every 3 weeks, intravenous infusion for 2 hours, the first infusion is assigned on the first day of the cycle). The first dose of Xeloda is prescribed in the evening on the first day of the therapy cycle, the last one on the morning of the 15th day.

In combination with oxaliplatin and / or bevacizumab

Assign 1000 mg / m2 2 times a day for two weeks followed by a seven-day break in combination with oxaliplatin and / or bevacizumab. The first dose of Xeloda is prescribed in the evening on the first day of the therapy cycle, the last one on the morning of the 15th day. Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the first day of the cycle.After bevacizumab, oxaliplatin is administered at a dose of 130 mg / m2, intravenous infusion for 2 hours.

In combination with epirubicin and a platinum-based drug

Assign 625 mg / m2 twice a day in a continuous mode in combination with epirubicin (50 mg / m2 every 3 weeks, intravenously bolus, starting from the first day of the cycle) and a preparation based on platinum. A platinum-based drug (cisplatin 60 mg / m2 or oxaliplatin at 130 mg / m2) should be administered on the first day of the cycle as an IV infusion for 2 hours, then 1 every 3 weeks.

In combination with irinotecan

Assign 1000 mg / m2 twice a day for two weeks, followed by a seven-day break in combination with irinotecan (250 mg / m2 every 3 weeks, intravenous infusion for 30 minutes, the first infusion is assigned on the first day of the cycle) .

In combination with irinotecan and bevacizumab

Assign 800 mg / m2 2 times a day for two weeks, followed by a seven-day break in combination with irinotecan and bevacizumab. Irinotecan is administered at a dose of 200 mg / m2 every 3 weeks, intravenous infusion for 30 minutes, the first infusion on the first day of the cycle. Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the first day of the cycle.

Correction of dose during treatment

General recommendations

Toxic effects of Xeloda can be eliminated by symptomatic therapy and / or dose adjustment (interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, you can not increase it later.

If, according to the attending physician, the toxic effect of Xeloda is not a serious or life-threatening patient, treatment can be continued at the initial dose without reducing it or interrupting therapy.

At a toxicity of 1 degree do not change the dose. With toxicity levels 2 and 3, Xeloda should be discontinued.

With the disappearance of signs of toxicity or a decrease in the latter to 1 degree, the treatment with Xeloda can be resumed in full dosage.

With the development of signs of toxicity of the 4th degree, treatment should be discontinued or temporarily interrupted until the symptoms are reduced or reduced to 1 degree, after which the drug can be used at a dose of 50% of the initial dose.

The patient should immediately inform the doctor about the unwanted events that develop in him. It should immediately stop taking Xeloda if severe or moderate toxicity occurs.

If due to toxic effects several Xeloda medications were missed, these doses are not replenished.

Hematological toxicity

Therapy with Xeloda should be discontinued if signs of grade 3 or 4 hematologic toxicity are found.

Correction of the dose in special cases

Patients with metastases to the liver and mild or moderate impairment of liver function do not require a change in the initial dose. However, these patients should be carefully monitored. The use of the drug in patients with severe hepatic insufficiency has not been studied.

It is recommended to reduce the initial dose to 75% of 1250 mg / m2 in patients with initial moderate renal failure (CK 30-50 ml / min, according to Cockcroft's formula).

In patients with mild renal insufficiency (KK 51-80 ml / min) correction of the initial dose is not required.

Patients of elderly and senile age. Correction of the initial dose with monotherapy with Xeloda is not required. However, severe adverse events of grade 3 and 4 associated with ongoing therapy developed in patients older than 80 years more often than in younger patients.

Side effect

anorexia;
dehydration;
decreased appetite;
headache;
dizziness (except vertigo);
paresthesia;
dysgeusia (perversion of taste);
increased tear;
conjunctivitis;
diarrhea;
vomiting, nausea;
stomatitis (including ulcerative);
stomach ache;
constipation;
pain in epigastrium;
dyspepsia;
palmar-plantar syndrome (paresthesia, edema, hyperemia, skin peeling, blistering);
dermatitis;
rash;
alopecia;
erythema;
dry skin;
hyperbilirubinemia;
fatigue;
drowsiness;
fever;
weakness;
asthenia;
dry mouth;
flatulence;
esophagitis;
gastritis;
duodenitis;
colitis;
gastrointestinal bleeding;
swelling of the lower extremities;
cardiomyopathy;
myocardial ischemia;
myocardial infarction;
heart failure;
sudden death;
tachycardia;
supraventricular arrhythmias, including atrial fibrillation;
ventricular extrasystoles;
a taste disorder;
insomnia;
confusion of consciousness;
encephalopathy;
symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination);
depression;
infectious complications associated with myelosuppression, weakened immunity, and / or impaired mucosal integrity,such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis;
anemia, myelosuppression, pancytopenia;
focal skin peeling;
photosensitivity reaction;
eye irritation;
dyspnea;
cough;
backache;
asthenia;
pain in the limbs;
increased drowsiness;
candidiasis of the oral cavity;
decreased body weight;
peripheral neuropathy;
thrombosis / embolism;
increased blood pressure;
a sore throat;
nose bleed;
dysphonia;
rhinorrhea;
pain in the jaw;
fever;
stenosis of the tear duct.

Contraindications

established deficiency of DPD (dihydropyrimidine dehydrogenase), as for other fluoropyrimidines;
simultaneous administration of sorivudine and its structural analogues of brivudine type;
renal failure of severe degree (CC below 30 ml / min);
the initial content of neutrophils <1.5 × 109 / l and / or platelets <100 × 109 / l;
if there are contraindications to one of the combination therapy preparations, Xeloda should not be prescribed;
pregnancy;
the period of breastfeeding;
children's age (efficacy and safety of use not established);
increased sensitivity to capecitabine or any other components of the drug;
hypersensitivity to fluorouracil, or when there are reported cases of unexpected or severe adverse reactions to fluoropyrimidine derivatives in a history.

Application in pregnancy and lactation

The drug is contraindicated for use in pregnancy and lactation.

During the treatment with Xeloda and at least 3 months after the end, reliable methods of contraception should be used. If the pregnancy occurred during the period of therapy, the patient should be aware of the potential threat to the fetus.

Use in children

Contraindicated in children and adolescents under the age of 18 years (efficacy and safety of use not established).

special instructions

It is necessary to carefully monitor the manifestations of toxicity in patients receiving Xeloda.

Most of the undesirable phenomena are reversible and do not require complete discontinuation of the drug, although there may be a need for dose adjustment or temporary withdrawal of the drug.

Diarrhea

Treatment with Xeloda can cause diarrhea, sometimes severe.Patients with severe diarrhea should be carefully monitored, and with the development of dehydration it is necessary to rehydrate and compensate for the loss of electrolytes. Standard antidiarrhoeal drugs (eg, loperamide) should be prescribed as soon as possible for medical reasons. If necessary, reduce the dose of Xeloda.

Dehydration

Dehydration should be prevented or eliminated at the outset of the occurrence. Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

With the development of dehydration of 2 degrees or higher, treatment with Xeloda should be immediately interrupted and rehydrated. Treatment can not be resumed until the completion of rehydration and elimination or correction of the factors that caused it. The dose of the drug should be modified in accordance with the recommendations for adverse events leading to dehydration.

Toxicity

The spectrum of cardiotoxicity in the treatment with capecitabine is similar to that of other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure, and ECG changes.These undesirable phenomena are more typical for patients suffering from coronary artery disease in the anamnesis.

In rare cases, unexpected severe toxic effects (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-FU are due to inadequate dihydropyrimidine dehydrogenase (DPD) activity. Thus, the relationship between reduced activity of DPD and a more pronounced, potentially lethal toxicity of 5-FU can not be ruled out.

The manifestation of skin toxicity of Xeloda is the development of the palmar-plantar syndrome (synonyms - palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). The median time to development of toxicity in patients receiving Xeloda with monotherapy is 79 days (range 11 to 360 days), and the severity varies from grade 1 to grade 3. Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia / paresthesia, pricking or redness of the palms and / or soles, discomfort. Palmar-plantar syndrome of the 2nd degree is characterized by painful reddening and swelling of the hands and / or feet, and the discomfort caused by these symptoms disrupts the daily activity of the patient.Palmar-plantar syndrome of the third degree is defined as wet desquamation, ulceration, blistering and sharp pains in hands and / or feet, as well as severe discomfort, making it impossible for the patient to any kinds of daily activities. If a palmar-plantar syndrome occurs in the 2nd or 3rd degree, therapy with Xeloda should be discontinued until the symptoms disappear or decrease to 1 st degree. If there is a syndrome of the 3rd degree, subsequent doses of Xeloda should be reduced.

Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of the palmar-plantar syndrome in the administration of Xeloda in combination with cisplatin, as it may reduce the effectiveness of cisplatin.

Hyperbilirubinemia

The drug Xeloda can cause hyperbilirubinemia. If in connection with treatment with Xeloda, hyperbilirubinemia> 3 × VGN or an increase in the activity of hepatic aminotransferases (ALT, ACT)> 2.5 × UGN, treatment should be discontinued.

The therapy can be resumed with a decrease in the level of bilirubin and the activity of hepatic aminotransferases below these limits.

Simultaneous reception with coumarin anticoagulants

In patients taking Xeloda and oral anticoagulants, coumarin derivatives, coagulation factors (prothrombin time or MHO) should be monitored and, accordingly, a dose of anticoagulant should be selected.

The use of the drug in elderly and senile patients

The incidence of toxic effects on the part of the gastrointestinal tract in patients with colorectal cancer at the age of 60-79 years who received monotherapy with Xeloda did not differ from that in the general population of patients. In patients 80 years and older, reversible adverse events from the third and fourth degree gastrointestinal tract, such as diarrhea, nausea and vomiting, developed more often. In patients older than 65 years who received combined therapy with capecitabine and other antitumor drugs, there was an increase in the incidence of adverse reactions of the 3rd and 4th degree of severity and adverse events that led to discontinuation of therapy compared with patients younger than 65 years of age.

When analyzing safety data in patients older than 60 years who received combination therapy with Xeloda and docetaxel,an increase in the incidence of third-and fourth-degree adverse events, serious adverse events and early withdrawal of therapy due to adverse events compared with those in patients younger than 60 years of age.

Renal insufficiency

Care should be taken when prescribing Xeloda to patients with moderate renal insufficiency. As with treatment with fluorouracil, the incidence of adverse events of the 3rd and 4th degree of severity associated with the therapy was higher in patients with moderate renal insufficiency (CK 30-50 ml / min).

Liver failure

Patients with hepatic insufficiency during therapy with Xeloda should be under close medical supervision. The effect of a violation of liver function, not due to metastatic liver damage or severe hepatic insufficiency, is not known for distribution of Xeloda.

Handling of an unused product and an expired product

The ingestion of the medicinal product together with the waste in the environment must be minimized.Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

Impact on the ability to drive vehicles and manage mechanisms

The drug Xeloda has little or moderate influence on the ability to drive vehicles, mechanisms. Patients who experience such undesirable effects as dizziness, weakness, or nausea should refrain from controlling vehicles and mechanisms.

Drug Interactions

Coumarin anticoagulants

In patients taking Xeloda along with coumarin anticoagulants (warfarin and fenprokumone), violations of coagulation and / or bleeding disorders were reported in a few days or months after initiation of capecitabine therapy, and in several cases within one month after completion.

In patients taking Xeloda and anticoagulants of the coumarin series concomitantly, coagulation factors (prothrombin time or MHO) should be carefully monitored, and the anticoagulant dose should be selected in accordance with these indices.

Phenytoin

With the simultaneous administration of Xeloda and phenytoin, an increase in plasma concentration in plasma was reported. Special studies of the inter-drug interaction between Xeloda and phenytoin have not been carried out, but it is assumed that the mechanism of interaction is based on the suppression of the CYP2C9 isoenzyme under the influence of capecitabine. In patients receiving both phenytoin and Xeloda, the concentration of phenytoin in the plasma should be monitored regularly.

Antacids

When assessing pharmacokinetic parameters of Xeloda with simultaneous administration with antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in the concentration of capecitabine and one of the metabolites (5'-DFTST) in blood plasma was noted. The three major metabolites of capecitabine (5'-DFUR, 5-FU and FBAL) did not exert any influence on the agents studied.

Calcium folinate (Leucovorin)

Calcium folinate does not affect the pharmacokinetics of capecitabine and its metabolites. However, it is possible to increase the toxic effect of capecitabine due to the influence of calcium folinate on the pharmacodynamics of Xeloda.

Sorivudine and its analogs

Literary sources describe the clinically significant drug interaction between sorivudine and 5-FU, which is based on the inhibitory effect of sorivudine on DPD. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines. Therefore, Xeloda should not be given concurrently with sorivudine or its structural analogues such as brivudine. Observe at least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and the start of treatment with Xeloda.

Oxaliplatin

There was no clinically significant difference in the exposure of capecitabine or metabolites of oxaliplatin (free platinum or total platinum) with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab

Clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was not observed.

Analogues of the drug Xeloda

Structural analogs for the active substance:

Capecitabine;
Tutabin.

If there are no analogues of the medication for the active substance, you can go to the links below for diseases, from which the corresponding drug helps,and see the available analogues for therapeutic effects.

Used for the treatment of diseases: cancer, tumor, mammary cancer, rectal cancer, stomach cancer, colon cancer