Xeloda®

Active material: Capecitabine
When ATH: L01BC06
CCF: Anticancer drug. Antimetaʙolit
ICD-10 codes (testimony): C16, C18, C19, C20, C50
When CSF: 22.02.03
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)

Pharmaceutical form, composition and packaging

Pills, coated a light peach-colored, oblong, lenticular, Engraved “XELODA” on one side and “150” – on the other side of the tablet.

Excipients: lactose bezvodnaya, sodium croscarmellose, gipromelloza (3 mPa.s), microcrystalline cellulose, magnesium stearate.

The composition of the shell: Opadry Персик Ys-1-17255-A (gipromelloza 6 mPa.s), talc, Titanium dioxide, iron oxide yellow, iron oxide red.

10 PC. – blisters (6) – packs cardboard.
60 PC. – plastic bottles (1) – packs cardboard.

Pills, coated peach-colored, oblong, lenticular, Engraved “XELODA” on one side and “500” – on the other side of the tablet.

Excipients: lactose bezvodnaya, sodium croscarmellose, gipromelloza (3 mPa.s), microcrystalline cellulose, magnesium stearate.

The composition of the shell: Opadry Персик Ys-1-17255-A (gipromelloza 6 mPa.s), talc, Titanium dioxide, iron oxide yellow, iron oxide red.

10 PC. – blisters (12) – packs cardboard.
120 PC. – plastic bottles (1) – packs cardboard.

Pharmacological action

Anticancer drug, antimetaʙolit. Capecitabine – fluoropyrimidine carbamate derivative, cytostatic oral, activated in the tumor tissue and exerts a selective cytotoxic effect. In vitro capecitabine not obladaet tsitotoksicheskim эffektom. In vivo is converted to 5-fluorouracil (5-FU), which is subject to further metabolism. Formation of 5-FU occurs predominantly in tumor tissue by the action of the tumor angiogenic factor – timidinfosforilazы (dTdFazy), which minimizes the systemic exposure of 5-FU on healthy tissue. Posledovatelynaya fermentnaya biotransformation capecitabine in 5-FU sozdaet disease vыsokie concentrations in preparation tkanyah opuholi, than in the surrounding healthy tissues.

After oral administration of capecitabine to patients with colon cancer with 5-FU concentration in the tumor tissue was higher than its concentration in the adjacent healthy tissues 3.2 times. The ratio of concentrations of 5-FU in tumor tissue and plasma – 21.4, ratio of the concentration in healthy tissue and in plasma – 8.9. Thymidine phosphorylase activity in primary colorectal tumors as in 4 times higher, than in the surrounding healthy tissue.

In human tumors, such as breast cancer, stomach, colon, cervical and ovarian, contains more thymidine, capable of converting 5′-DFUR (5′-dezoksi-5-ftoruridin) 5-FU, than in the corresponding normal tissues.

How healthy, and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMF) and 5-triphosphate ftoruridina (FUTF). These metabolites damage cells via two different mechanisms. At first, ФдУМФ и фолатный кофактор N^5-10-metilentetragidrofolat svyazыvayutsya with timidilatsintazoy (TC) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate yavlyaetsya neobhodimыm predshestvennikom thymidine triphosphate, which, in turn, It is extremely important for DNA synthesis, so that the lack of this substance can cause inhibition of cell division. Secondly, in the synthesis of RNA transcription enzymes kernel can mistakenly incorporate the uridine triphosphate instead FUTF (UTF). This metabolic “error” gives RNA processing and protein synthesis.

Pharmacokinetics

Absorption

After oral administration, capecitabine is rapidly and completely absorbed from the gastrointestinal tract, this occurs after its transformation into metabolites – 5′-deoxy-5-ftortsitidin (5′-DFCR) and 5′-dezoksi-5-ftoruridin (5′-DFUR). Simultaneous food intake reduces the rate of absorption of capecitabine, but it has little effect on AUC 5′-DFUR and next metabolite 5-FU.

When administering the drug after ingestion dose 1250 mg / m² 14-day C_max capecitabine, 5′-DFCR, 5′-DFUR, 5-FU and FBAL (a-фтор-b-аланина) They were, respectively, 4.47, 3.05, 12.1, 0.95 and 5.46 ug / ml. The time to reach C_max was 1.50, 2.00, 2.00, 2.00 and 3.34 no, а AUC – 7.75, 7.24, 24.6, 2.03 and 36.3 mcg x h / ml, respectively.

Distribution

Capecitabine, 5′-DFCR, 5′-DFUR and 5-FU bound to proteins (mainly, albumin) respectively 54%, 10%, 62% and 10%.

Metabolism

It is metabolized in the liver under the influence of carboxyl metabolite to 5′-DFCR, which is then transformed into 5′-DFUR by cytidine deaminase action, located, primarily, in the liver and tumor tissues. Dalyneyshaya transformation to aktivnogo tsitotoksicheskogo metabolite 5-FU proishodit, predominantly, in tumor tissue by the action of the tumor angiogenic factor – timidinfosforilazы (dTdFazy). The concentrations of 5-FU and its active phosphorylated anabolitov tumor significantly higher than levels in healthy tissues, thereby providing a relatively selective cytotoxic effect.

AUC of 5-FU 6-22 half, than after / in the bolus of 5-FU in a dose of 600 mg / m². Capecitabine become cytotoxic metabolites only after conversion to 5-FU and 5-FU anabolity. Further, 5-FU is catabolized to inactive metabolites – dihydro-5-ftoruracila (FUN₂), 5-ftorureidopropionovoy acid (FUPK) и фтор-a-b-аланина (FBAL); This process is influenced by dihydropyrimidine dehydrogenase (DPD), Activity which limits the rate of reaction.

Deduction

T_1/2 capecitabine, 5′-DFCR, 5′-DFUR, 5-FU and FBAL is respectively 0.85, 1.11, 0.66, 0.76 and 3.23 no. Farmakokineticheskie options regimens, 5′-DFCR and 5′-DFUR on the 1st and 14th day of the same. AUC of 5-FU increases to the 14th day at 30-35%, and no longer increases (22 day). The therapeutic dose range pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU are dose-dependent.

Excreted in the urine – 95.5%, with feces – 2.6%. The primary metabolite in urine is FBAL, which accounts for 57% the dose. About 3% the dose is excreted in the urine as unchanged.

Pharmacokinetics in special clinical situations

Paul, the presence or absence of metastases in the liver before treatment, the index of general condition of the patient, the concentration of total bilirubin, serum albumin, ALT and AST in patients with colon cancer had no significant effect on the pharmacokinetics of 5′-DFUR, 5-FU and FBAL.

In patients with mild to moderate liver dysfunction, due to metastases, clinically significant changes in the pharmacokinetics of capecitabine occurs. Pharmacokinetic data in patients with severe hepatic impairment are absent.

With varying degrees of (from mild to severe) renal failure pharmacokinetics unchanged drug and 5-FU does not depend on QC. QC affects AUC value 5′-DFUR (увеличение AUC на 35% – with a decrease in QC 50%) and FBAL (увеличение AUC на 114% with a decrease in QC 50%). FBAL – metabolite, do not possess antiproliferative activity. 5′-DFUR – the immediate precursor of 5-FU.

Age did not affect the pharmacokinetics of 5′-DFUR and 5-FU. FBAL AUC increased in patients aged 65 and older (an increase in the age at 20% accompanied by an increase in the AUC FBAL 15%), what, probably, due to a change in renal function.

The pharmacokinetics in patients with blacks did not differ from that of patients with Caucasians.

Testimony

- Combination therapy with docetaxel for locally advanced or metastatic breast cancer, the ineffectiveness of chemotherapy, including drug anthracyclines;

- Monotherapy local-rasprostranennogo or metastaticheskogo cancer molochnoy zhelezы, the ineffectiveness of chemotherapy drugs taxanes or anthracyclines, or if there are contraindications to treatment with anthracyclines;

- Adjuvant therapy of colon cancer;

- First-line treatment of metastatic colorectal cancer;

- First-line treatment of advanced gastric cancer.

Dosage regimen

The drug is taken orally, drinking water, not later than, than 30 min after meal.

The standard dosing regimen

During the monotherapy Xeloda^® administered at a dose of 2500 mg / m²/d (by 1250 mg / m² 2 times / day, in the morning and in the evening) during 2 weeks followed by a seven-day break.

At combination therapy with docetaxel Xeloda^® appoint 1250 mg / m² 2 times / day for 2 weeks followed by one week apart in combination with docetaxel at a dose 75 mg / m² 1 once every 3 of the week. Premedication is conducted before the introduction of docetaxel in accordance with the instructions for use of docetaxel.

At combination therapy with cisplatin Xeloda^® appoint 1000 mg / m² 2 times / day for 2 weeks followed by one week apart plus cisplatin (80 mg / m² 1 once every 3 of the week, / in infusion for 2 no). The first dose of Xeloda^® appointed by the evening of the 1st day of the cycle of therapy, latest – in the morning on the 15th day.

Premedication with antiemetics and to ensure adequate hydration prior to administration of cisplatin are appointed in accordance with the instructions for its use.

Calculation of the total daily dose of capecitabine is performed, depending on the body surface area (table 1).

Table 1. Calculation of the dose of capecitabine (the standard starting dose)

Dosage adjustments during treatment

General recommendations

The phenomena of toxicity in the treatment of Xeloda^® symptomatic treatment can be eliminated and / or changing the dose of Xeloda^® (interrupting treatment or reducing the dose).

When toxicity 1 extent to adjust the dose should not be.

When toxicity 2 and 3 degree Xeloda^® discontinue. After, as the severity of adverse events is reduced to 1 degrees, receiving Xeloda^® be resumed at full dose or adjusted in accordance with the recommendations, are shown in Table 2.

With the development of signs of toxicity 4 degree of treatment should be stopped or temporarily interrupted until the relief of symptoms or reduce to 1 degrees, whereupon the use of the drug is resumed at a dose, component 50% from the previous.

Stop taking Xeloda^® in the event of severe toxicity or moderate.

If, due to the toxic effects were omitted several capecitabine, these doses did not fill, but simply continue the planned cycles of therapy. If the dose was reduced, can not subsequently increase it.

In the table 2 with recommendations to change the dose in the case of toxic effects (in accordance with the criteria of toxicity, developed by the National Cancer Institute of Canada, NCIC CTC, version 1; December 1994 g).

Table 2. Changing the dose of capecitabine in monotherapy

In combination with dotsetakselom

When capecitabine is used in combination with docetaxel, should follow the recommendations for dose adjustment in case of toxicity according to the criteria of the National Cancer Institute of Canada, NCIC CTC, version 1.0; December 1994 g.

Table 3. Changing doses during combination therapy with capecitabine (K) and dotsetakselom (D)

Dose adjustment in special cases, combination therapy of capecitabine and docetaxel

Correction of the dose of Xeloda^® and / or docetaxel should be on the general principles, shown above, Unless otherwise indicated cases dose adjustment. If any toxic effects are not serious or life-threatening (eg, alopecia, change in taste, nail changes), Treatment can be continued at the same dose without its reduction or discontinuation of therapy. At the beginning of each cycle of therapy, if the expected delay in the introduction of either docetaxel, Libo regimens, you need to postpone the introduction until, until you can resume therapy with both drugs. If you have to cancel docetaxel, capecitabine treatment can be continued with the compliance to the resumption of capecitabine (tab. 3).

Hematologic toxicity. Treatment with Xeloda^® You can continue with the development of neutropenia, including 3 severity. However, the patient should be carefully monitored and treatment should be discontinued upon accession of other adverse events 2 severity (eg, diarrhea, stomatitis, fever). Therapy should be discontinued in the event of neutropenia 4 its degree of toxicity up to a resolution 0-1 severity. The treatment can be resumed only after, as the neutrophil count exceeds 1.5 x 10⁹/l (0-1 severity). The dose of docetaxel should be reduced 75 to 55 mg / m² in patients with neutropenic < 5 x 10⁹/l (4 severity) of more than 1 weeks or febrile neutropenia (>38° C). If neutropenia 4 degree or febrile neutropenia developed in the treatment of docetaxel dose 55 mg / m², it should be canceled. Patients with baseline neutrophil count <1.5 x 10⁹/l or platelets <100 x 10⁹/l can not be treated with combination therapy with capecitabine and docetaxel.

Hypersensitivity reactions. With the development of severe allergic reactions (reduction in blood pressure ≥ 20 mmHg., bronchospasm, generalized rash, swelling) use of these drugs should be stopped immediately and appoint appropriate therapy. It is impossible to resume the use of drugs, which have caused hypersensitivity reaction.

Perifericheskaya neuropathy. The first appearance of toxicity 2 degree docetaxel dose reduced to 55 mg / m². When toxicity 3 degree docetaxel cancel. In both cases it is necessary to adhere the above correction scheme doses of capecitabine.

Fluid retention. It is necessary to carefully monitor such heavy (3 or 4 degrees) toxicity effects, possibly related to docetaxel, as the pleural or pericardial effusion or ascites. When they appear docetaxel should be abolished. Capecitabine treatment can be continued without dose modification.

Gepatotoksichnostь. Usually, Docetaxel should not be prescribed to patients with serum bilirubin, exceeds the upper limit of normal (VGN). An increase in ALT activity, AST or ALP must adhere to the following rules of correction dose of docetaxel (table 4).

Table 4. Correction of the dose of docetaxel

After, in the specific cycle reduced dose of docetaxel, in subsequent cycles further reducing its dose is not recommended, unless there is a further deterioration of. If after a dose reduction of docetaxel indicators of functional liver samples recovered, docetaxel dose can be increased again to the same.

Degidratatsiya. Dehydration should be prevented or eliminate the very beginning of occurrence. Dehydration can quickly develop in patients with anorexia, asthenia, toshnotoy, vomiting or diarrhea. With the development of dehydration 2 degree or above capecitabine treatment should be immediately interrupted and rehydration hold. Treatment can not reopen until the completion of rehydration and removal or correction factors to cause it. The dose should be modified in accordance with recommendations for adverse events, leading to dehydration, according to the above instructions.

Reducing the dose of capecitabine to 75% and 50% starting from

When Xeloda monotherapy^® or combination therapy Xeloda^® and docetaxel dose can be applied 75% and 50% the standard initial, calculated according to body surface area (tables 5 and 6).

Table 5. Raschetnaya dose regimens, component 75% the standard starting dose

Table 6. Raschetnaya dose regimens, component 50% the standard starting dose

Combinations tsisplatinom

If in the opinion of the attending physician or non-serious toxic effects are not life threatening, eg, alopecia, taste disturbance, nail changes, treatment may be continued without dose reduction or interruption of therapy. For more information about cisplatin should look to the instructions for its use.

Dose adjustment during haematological toxicity

Patients can start a new three-week treatment cycle, if they are at the beginning of the cycle an absolute neutrophil count (AREC) more than 1 x 10⁹/l and platelet count greater 100 x 10⁹/l. Otherwise treatment should be postponed until recovery of hematological parameters. Detailed dose correction circuit in the case of hematologic toxicity is shown in Table 7.

Table 7. Driving correction dose of Xeloda^® (K) in combination with tsisplatinom (C) while hematologic toxicity in the planned day of treatment.

If during the treatment cycle results of the survey on the dose-limiting toxicity suggest, receiving Xeloda^® to interrupt, and subsequent treatment cycles dose Xeloda^® and cisplatin must be reduced according to the recommendations in the table 8.

Table 8. Driving correction dose of Xeloda^® (K) in combination with tsisplatinom (C) while hematologic toxicity during the treatment cycle

Correction of the dose of Xeloda^® while hematological toxicity

Recommendations for corrective doses of Xeloda^® are signs of toxicity, associated with taking Xeloda^®, and does not relate to the manifestation of toxicity with cisplatin or combinations of these drugs. For Example, Neurotoxicity / ototoxicity not require dose reduction of Xeloda^®. In the event of hematological toxicity 2, 3 or 4 degree receiving Xeloda^® immediately suspend or terminate, as indicated in the table 2. Missed dose of Xeloda^® during a break in taking the drug should not be to fill. The planned treatment regimen should be maintained. If the calculated CC decreases during treatment below 30 ml / min, the receiving Xeloda^® discontinue. In the table 9 shows a diagram of the correction dose of Xeloda^® and cisplatin depending on resort.

Correction dose cisplatin in hematological toxicity

Cisplatin dose adjustment is carried out when the signs of toxicity, associated with cisplatin therapy and non-reception Xeloda^® or combinations thereof, in accordance with the recommendations in the instructions for its use.

Renal toxicity

Before treatment, QC must be greater 60 ml / min, and it must be determined prior to each treatment cycle, using the Cockcroft.

If after the first treatment cycle QC < 60 ml / min, it must be re-calculated after 24 h hydration.

If the kidney function of cisplatin dose should be adjusted according to the instructions for use of cisplatin.

When you assign a combination of Xeloda^® cisplatin and cisplatin dose change, as indicated in the table 9.

Table 9. Driving correction dose of cisplatin and Xeloda^® depending on QC

* if CC less than 40 ml / min, Xeloda monotherapy^® may continue until, KK is still > 30 ml / min.

Nausea or vomiting

In case of nausea and vomiting 3/4 degrees, despite adequate prophylaxis, in subsequent cycles should be reduced to the dose of cisplatin 60 mg / m².

Ototoxicity

Patients with functional hearing impaired, with the advent of sound in the ears or at a significant loss for the first time the perception of high frequency sounds on the audiogram should discontinue treatment with cisplatin, but continue therapy Xeloda^®.

Neurotoxicity

Patients with neurotoxicity 2 the degree of NCI-CTC criteria should discontinue treatment with cisplatin, but continue therapy Xeloda^®.

Dose adjustment in special cases

In patients with liver metastases and mild to moderate impaired liver function change the starting dose is not required. However, these patients should be carefully monitored. In patients with severe hepatic impairment has not been studied drug.

In patients with an initial renal failure moderate (CC 30-50 ml / min) it is recommended to reduce the initial dose 75% by standard. Patients with renal insufficiency, mild (CC 51-80 ml / min) correction of the initial dose is required. If subsequent dose adjustments in the above table are marked adverse events 2, 3 or 4 severity, needed temporary withdrawal of the drug and close monitoring of the patient's condition. If during treatment is determined by creatinine clearance less than 30 ml / min, Xeloda therapy^® discontinue. Recommendations for dose adjustment in moderate renal impairment apply both to monotherapy, and to a combination therapy of capecitabine (table 5).

Correction at the initial dose elderly patients not required. However, in patients older 80 years of adverse events 3 and 4 severity were more frequent, than in younger. It is recommended that careful monitoring of elderly patients. In lechenii kapetsitabinom in combination with at dotsetakselom older patients 60 years marked increase in the frequency of adverse events 3 and 4 severity and serious adverse events, associated with therapy. Patients older 60 years, who will receive a combination of capecitabine plus docetaxel, It is recommended to reduce the starting dose of capecitabine to 75% (950 mg / m² 2 times / day). Calculation of the dose is presented in Table 5.

The safety and efficacy of capecitabine at children I have not been studied.

Side effect

Frequently (≥10%): diarrhea, stomatitis, nausea, vomiting, hand-foot syndrome, fatigue, weakness, lethargy, hypersomnia.

From the digestive system: diarrhea, vomiting, stomatitis (incl. ulcerative), anorexia, decreased appetite, abdominal pain, epigastric pain, constipation, dry mouth, dyspepsia, oral candidiasis; less than 5% cases – flatulence, esophagitis, gastritis, duodenitis, colitis, Ikotech, gastrointestinal bleeding; in a few cases – hepatic failure and cholestatic hepatitis; their causal relationship to the use of capecitabine is not installed.

Dermatological reactions: hand-foot syndrome (paresthesia, edema, hyperemia, peeling of the skin, bullation), dermatitis, xerosis, erythematous rash, эritema, alopecia, itch, patchy peeling, dermatomelasma, violation of the structure and discoloration of nails, onixolizis; less than 5% cases – photosensitivity reactions, syndrome, reminiscent of radiation dermatitis, cracked skin.

From the central and peripheral nervous system: headache, sleep disturbance (severe drowsiness, insomnia), paresthesia, dizziness, perifericheskaya neuropathy; less than 5% cases – confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, impaired balance and coordination), depression.

From the senses: increased lacrimation, conjunctivitis, taste disturbance; rarely – stenosis of the nasolacrimal duct.

The respiratory system: sore throat, breathlessness, cough, nose bleed, disfonija.

On the part of the musculoskeletal system: artralgii, mialgii.

Cardio-vascular system: edema of the lower extremities; less than 5% cases – kardialgii, angina, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, PVCs.

From the hematopoietic system: anemia, neutropenia, granulocytopenia, Lymphocytopenia, thrombocytopenia; less than 5% cases – pancytopenia.

From the laboratory parameters: (regardless of their connection with capecitabine) – giperʙiliruʙinemija, increased ALT / AST, giperkreatininemiя, increased activity of alkaline phosphatase, giperglikemiâ, hypo / hypercalcemia, hypoalbuminemia, giponatriemiya, kaliopenia.

Co side of the body as a whole: fatigue, fever, weakness, degidratatsiya, weight loss, lethargy, back pain; less than 5% cases – infectious complications against the backdrop of myelosuppression, weakening of the immune system and compromising the integrity of the mucous membranes, local and systemic (Bacterial, viral and fungal), possibly fatal, sepsis.

Contraindications

- Set dihydropyrimidine dehydrogenase deficiency;

- Simultaneous reception sorivudina and its structural analogs (eg, brivudin);

- Severe renal insufficiency (QC below 30 ml / min);

- Pregnancy;

- Lactation (breast-feeding);

- Up to 18 years (efficacy and safety have not been established);

- Contraindications to the other components of the combination therapy;

- Hypersensitivity to capecitabine and other fluoropyrimidine derivative, or any components of the preparation.

FROM caution should be prescribed the drug for IBS, kidney or liver failure, simultaneously with oral anticoagulants coumarin, and patients over the age of 60 years.

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

Cautions

Capecitabine is performed under careful supervision. Most adverse events are reversible and do not require the complete abolition of the drug, although you may need dose adjustment or temporary drug discontinuation.

The spectrum of cardiotoxicity in the treatment of capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, stenokardiю, Arrhythmia, cardiac arrest, cardiac insufficiency and ECG changes. These adverse events were more common in patients with coronary artery disease.

In rare cases, there are severe toxicity effects, associated with 5-FU, as stomatitis, diarrhea, neutropenia and neurotoxicity, due to insufficient activity of dihydropyrimidine dehydrogenase (DPD). We can not exclude a link between decreased activity of DPD and more pronounced potentially lethal toxicity of 5-FU.

Caution should be exercised in the appointment of capecitabine to patients with renal insufficiency. In patients with renal insufficiency moderately (CC 30-50 ml / min), as well as in the treatment of 5-FU, the frequency of adverse events 3 and 4 the severity of the above.

In patients with baseline renal insufficiency moderately (CC 30-50 ml / min) recommended starting dose reduction of up to 75% by standard. Recommendations for correction of the initial dose relate to patients with moderate renal insufficiency as in the single-agent capecitabine, and combination therapy. If a subsequent dose adjustment in accordance with the table, shown in section “Dosage regimen”, observed adverse events 2, 3 or 4 severity, needed temporary withdrawal of the drug and close monitoring of the state of.

Capecitabine can cause diarrhea, sometimes heavy. When capecitabine monotherapy diarrhea 2-4 severity appears over 31 day of therapy and lasts, average, 4-5 days. Patients with severe diarrhea should be carefully monitored, spending their rehydration and compensation for the loss of electrolytes in the case of dehydration. Diarrhea 2 severity is defined as increased stool up 4-6 once a day or at night chair, diarrhea 3 degrees – how frequent stools up 7-9 once a day or incontinence and malabsorption, diarrhea 4 degrees – how frequent stools up 10 or more times per day, the appearance of visible blood in the stool or the need for parenteral maintenance therapy. When diarrhea 2, 3 and 4 degree capecitabine therapy should be interrupted until the disappearance of diarrhea or reduce its intensity to the extent 1. When diarrhea 3 and 4 degree of capecitabine should be resumed at a lower dose (table 2). According to the testimony as early as possible it is recommended to assign the standard antidiarrheal drugs (eg, loperamide).

The frequency of toxic effects on the gastrointestinal tract in patients with colorectal cancer at the age of 60-79 years, poluchavshih monoterapiyu kapetsitabinom, I did not differ from that of the general population of patients. Patients 80 and older reversible gastrointestinal disorders 3 and 4 degrees, such as diarrhea, nausea and stomatitis, were more frequent. Patients older 60 years, treated with combination therapy with capecitabine and docetaxel, It noted an increase in the frequency of treatment-related adverse events 3 and 4 severity, serious adverse events and early discontinuation due to adverse events, compared with those in patients younger 60 years.

Dermal toxicity manifestation is the development of hand-foot syndrome 1-3 severity (synonyms – palmar-plantar erythema, acral or eritrodizesteziya, caused by chemotherapy). The time to monotherapy is from 11 to 360 days, average, 79 days.

Hand-foot syndrome 1 degree does not violate the patient's activities of daily living and is manifested by numbness, dizesteziyami and paresteziyami, tingling, or redness of the palms and / or soles, discomfort.

Hand-foot syndrome 2 degree manifested painful redness and swelling of the hands and / or feet, and the discomfort caused by these symptoms violates the daily activities of the patient.

Hand-foot syndrome 3 degree is defined as moist desquamation, izayazvlenie, blistering and sharp pains in the hands and / or feet, as well as severe discomfort, making it impossible for the patient any kind of daily activity.

In the event of hand-foot syndrome 2 or 3 degree of use of capecitabine should be interrupted until the symptoms disappear or reduce to 1 degrees; the next occurrence of the syndrome 3 extent necessary to reduce the dose of capecitabine (table 2). Vitamin B₆ (pyridoxine) not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in the appointment of Xeloda^® in combination with tsisplatinom, because it can reduce the effectiveness of cisplatin.

If, in connection with the treatment of capecitabine marked hyperbilirubinemia, more than 3 times the ULN, or elevated liver aminotransferases (GOLD, IS) more, than 2.5 times the ULN, the use of capecitabine should be interrupted. It can be resumed when the level of bilirubin and liver transaminases below these limits. In diseases of the liver nonmetastatic nature therapy is performed under close supervision. Pharmacokinetics in liver disease, not due to liver metastases, as well as severe hepatic insufficiency has not been studied.

Patients, while receiving capecitabine and oral anticoagulants (coumarin derivatives), should be carefully monitored indicators clotting (prothrombin time) and adjust the dose of anticoagulant.

Overdose

Symptoms: nausea, vomiting, diarrhea, mukozit, gastrointestinal irritation and bleeding, as well as the suppression of bone marrow function.

Treatment: symptomatic therapy.

Drug Interactions

Capecitabine enhances the effects of indirect anticoagulants, which may lead to a violation of indicators of coagulation and bleeding after a few days or months after initiation of therapy with capecitabine, in one case, – a month after its completion. Increases in AUC of warfarin 57% and INR 91%.

Research on the interaction of capecitabine and other drugs, метаболизирующихся изоферментом CYP2С9, not carried out. Caution should be exercised in the appointment of capecitabine with these drugs.

Capecitabine increases the concentration of phenytoin plasma. Expected, that it is based on the suppression of CYP2C9 isoenzymes influenced capecitabine. Patients, prinimayushtih capecitabine odnovremenno with fenitoinom, to regularly monitor the concentration of phenytoin plasma.

Antacids, containing aluminum and magnesium hydroxide, slightly increases the concentration of capecitabine and one metabolite (5′-DFCR) plasma; three osnovnыh metabolite (5′-DFUR, 5-FU and FBAL) capecitabine they do not affect.

Calcium folinate (leucovorin) It did not affect the pharmacokinetics of capecitabine and its metabolites, may enhance the toxic effect of capecitabine.

With simultaneous use of capecitabine with sorivudinom and its analogues could potentially happen fatal gain fluoropyrimidine toxicity due to suppression of dihydropyrimidine dehydrogenase sorivudinom.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored at a temperature no higher than 30 ° C, out of reach of children. Shelf life – 2 year (bottles), 3 year (blisters). The drug should not be used beyond the expiration date.