Most popular brand: Xeloda
Active ingredient: Capecitabine
Available dosage forms: 500 mg
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Capecitabine general information
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capecitabine (Capecitabine) – instructions for use, description of the pharmacological action, indications for use, dosage and mode of administration, contraindications, side effects
Code CAS: 154361 – 50 – 9
Characteristics: antimetabolite fluoropyrimidine carbamate derivative, the molecular weight of 359.35, the water solubility of ; 26 mg / ml at 20 ° C.
Mode of action
Pharmacology: Mode of action – an antineoplastic. Activated in the tumor tissue and exerts a selective cytotoxic effect; in vitro capecitabine cytotoxic effect is not. The body turns 5 – fluorouracil (5 – FU), which is further metabolized. Formation of 5 – FU of capecitabine in tumor tissue occurs (under the action of thymidine phosphorylase tumor angiogenic factor), which minimizes the systemic exposure of 5 – FU on healthy tissue. Both healthy and tumor cells metabolise 5 – FU cytotoxic active metabolites: 5 – fluoro – 2 ‘- deoxyuridine monophosphate (FdUMF) and 5 – fluorouridine triphosphate (FUTF). Metabolites of 5 – FU damage cells via two different mechanisms. In – First, folate cofactor FdUMF and N ^ 5 – 10 – methylenetetrahydrofolate covalently bind to thymidylate synthase to form a ternary complex that disrupts the formation of thymidylate from uracil ; thymidine precursor (thymidine triphosphate necessary for the synthesis of DNA and its deficiency leads to inhibition of cell division). In – the second, during the synthesis of RNA transcription kernel enzymes can mistakenly incorporate the FUTF instead uridine triphosphate (UTP), and this metabolic « error » violates RNA processing and protein synthesis.
The sequential enzymatic biotransformation of capecitabine to 5 – FU in the tumor cells creates a high concentration of the latter. Upon receiving capecitabine inside colon cancer patients concentration of 5 – FU in tumor tissue in concentrations greater than its surrounding healthy tissues by 3.2 times. The concentration ratio of 5 – FU in tumor tissue and plasma of 21.4, the ratio of the concentration in healthy tissue and plasma 8.9. thymidine phosphorylase activity in primary colorectal tumor 4 times higher than in the surrounding healthy tissues. The content of thymidine phosphorylase, involved in the conversion of a metabolite of capecitabine ; 5 ‘- deoxy – 5 – fluorouridine (5’ – DFUR) 5 – FU in tumor cells in patients with breast cancer, stomach, colon, cervix, and ovary is significantly higher than in the respective healthy tissues.
The possibility of the use of capecitabine as a drug of choice in metastatic colon cancer (colorectal) cancer. The overall objective remission rate was 25.7% in the treatment of capecitabine and 16.7% in the treatment scheme ; I / calcium folinate at a dose of 20 mg / m ^ 2, followed by I / spray administration of 5 – FU at a dose of 425 mg / m ^ 2, 1 – 5 days every 28 days (p <0.0002). The median time to progression and median survival were comparable.
confirmed the efficacy of capecitabine in combination with docetaxel for the treatment of locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. Capecitabine (1250 mg / m ^ 2, 2 times a day for 2 weeks followed by one week apart) in combination with docetaxel (intravenously infusion for 1 hour to 75 mg / m ^ 2 1 every 3 weeks) improves survival , increases the frequency of objective remission, time to disease progression or death.
Capecitabine has no mutagenic effect in vitro bacterial cells (Ames test) and mammalian cells (gene mutation test on cells of Chinese hamster V79 / HPRT). Displaying clastogenic effect in vitro in human peripheral blood lymphocytes. Capecitabine is teratogenic (anophthalmia, microphthalmia, oligodaktiliya, polydactyly, syndactyly, the expansion of the brain ventricles, etc.) And increased mortality of embryos in mice at a dose of 198 mg / kg / day. In monkeys at a dose of 90 mg / kg / day also showed an increase in the death of the embryos in the process of organogenesis. In female mice at a dose of 760 mg / kg / day caused decreased fertility in male ; degenerative changes in the testes (reduced sperm count).
After oral administration, capecitabine is rapidly and completely absorbed from the gastrointestinal tract, and then there is its transformation into metabolites, 5 ‘- deoxy – 5 – fluorocytidine (5’ – DFCR) and 5 ‘- DFUR. Simultaneous eating reduces the rate of absorption of capecitabine, but the value of AUC of 5 ‘- DFUR and the next metabolite ; 5 – FU ; effect is insignificant. In appointing the drug at a dose of 1250 mg / m ^ 2 after a meal S_max capecitabine, 5 ‘- DFCR, 5’ – DFUR, 5 – FU and inactive metabolite alpha – fluoro – beta-alanine (FBAL) 14 – day amounted to 4 47; 3.05; 12.1; 0.95 and 5.46 ug / ml. Time to reach S_max was 1.5; 2.0; 2.0; 2.0 and 3.34 hours, and AUC ; 7.75; 7.24; 24.6; 2.03 and 36.3 ug / hr / ml, respectively.
Capecitabine initially hydrolysed by liver carboxylesterase 5 ‘- DFCR, which is converted to 5’ – DFUR by cytidine deaminase effect the liver and tumor tissues, and is further metabolized to 5 – FU under the action of thymidine phosphorylase. 5 – FU is metabolized to active metabolites FdUMF FUTF and less toxic and 5 – fluoro – 5,6 – dihydro – fluorouracil (under the action of dihydropyrimidine dehydrogenase). Last metabolized (as a result of cleavage of the pyrimidine ring) to inactive metabolites ; 5 – ftorureidopropionovoy acid and FBAL.
binding proteins (mainly albumin), capecitabine, 5 ‘- DFCR, 5’ – DFUR and 5 – FU are respectively 54, 10, 62 and 10%. T_1 / 2 capecitabine, 5 ‘- DFCR, 5’ – DFUR, 5 – FU and FBAL is 0.85; 1.11; 0.66; 0.76 and 3.23 hours, respectively.
The pharmacokinetic parameters capecitabine, 5 ‘- DFCR and 5’ – DFUR 1 – and 14 – on days do not differ, in a range of therapeutic doses are dose-dependent, with the exception of 5 – FU. AUC 5 – FU day 14 increased by 30 – 35% and no further increase.
Write mainly with urine ; 95.5%; with faeces ; 2.6%. The main metabolite in urine is FBAL (57% of the dose), about 3% of the dose is excreted in the urine in unchanged form. In patients with mild to moderate hepatic impairment, caused by metastases, in elderly patients the pharmacokinetic parameters and the processes bioactivation of capecitabine clinically not significantly changed. FBAL AUC increased in patients aged 65 years and older (age increase of 20% accompanied by an increase in AUC FBAL 15%), which is probably due to a change in renal function.
The results of the pharmacokinetic study conducted in patients with cancer with varying degrees (from mild to severe) renal failure have shown that the pharmacokinetics of unchanged drug and 5 – FU is independent of creatinine clearance. Creatinine clearance affects the AUC value 5 ‘- DFUR (increased AUC by 35% ; Cl creatinine in reducing by 50%) and FBAL (increased AUC 114% ; Cl creatinine in reducing by 50%). In severe renal insufficiency (Cl creatinine less than 30 mL / min) changes in the pharmacokinetic properties have not been studied.
Indications for use
Application: Breast cancer (locally advanced or metastatic). Monotherapy ; the ineffectiveness of chemotherapy drugs from the group of taxanes (paclitaxel) or anthracyclines, or with contraindications to anthracycline chemotherapy. Combination therapy with docetaxel ; the ineffectiveness of chemotherapy drugs including anthracyclines. Colon cancer (metastatic).
Contraindications:: Hypersensitivity (including to fluorouracil or other fluoropyrimidines in history), severe renal impairment (Cl creatinine less than 30 mL / min), dihydropyrimidine dehydrogenase deficiency; when combined with docetaxel treatment should be considered a contraindication to the use of docetaxel.
Restrictions on the use of CAD, hyperbilirubinemia, metastatic liver disease with infringement of its function, the elderly or children’s age (18).
Pregnancy and lactation: Contraindicated in pregnancy. At the time of treatment should stop breastfeeding.
Side effects: From the nervous system and sensory organs: more than 2% of patients ; fatigue, headache, paresthesia, weakness, fatigue, dizziness, taste disturbance, peripheral neuropathy, insomnia, somnolence, increased lacrimation, conjunctivitis, eye irritation; less than 2% ; confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, impaired balance and coordination).
On the part of cardio – vascular system (blood, hemostasis): more than 2% of patients ; anemia; less than 2% of patients ; false angina, cardiomyopathy, angina, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias (including atrial fibrillation), ventricular premature beats, hypo – or hypertension, thrombosis, phlebitis; bone marrow suppression, pancytopenia.
From the respiratory system: more than 2% of patients ; shortness of breath, cough, sore throat; rare ; bronchospasm, dyspnea, respiratory distress – syndrome, embolism pulmonary vessels.
From the digestive tract: more than 2% of patients ; diarrhea, nausea, vomiting, stomatitis, abdominal pain, epigastric, constipation, anorexia, decreased appetite, dyspepsia, dry mouth, flatulence, violation of stool consistency (soft stool), oral candidiasis, hyperbilirubinemia; less than 2% of patients ; ulcer – inflammation of the mucous membranes (esophagitis, gastritis, duodenitis, colitis, gastro – intestinal bleeding). Cases of hepatic failure and cholestatic hepatitis (their causal relationship to the use of capecitabine is not installed).
From the musculo – skeletal system: more than 2% of patients in monotherapy and more than 5% of patients treated with docetaxel in combination with ; pain in the extremities, myalgia, arthralgia, back pain, lower limb swelling.
For the skin: more than 2% of patients ; palmar – plantar syndrome (numbness, paresthesia, tingling, swelling, redness, peeling, blistering, and a sharp pain syndrome), dermatitis, dry skin, rash erythematous, alopecia, pruritus, patchy scaling, hyperpigmentation, nail infections; less than 2% of patients ; cracked skin, photosensitivity, a syndrome resembling radiation dermatitis, onycholysis, brittleness, discoloration and nail dystrophy.
Others: less than 2% of patients ; infection on the background of myelosuppression, weakened immunity disorders and mucosal integrity (bacterial, viral and fungal, local and systemic, fatal) sepsis; chest pain, changes in the level of ALT, AST, hyperglycemia; more than 5% of patients treated with docetaxel in combination with ; dehydration, weight loss; very rare ; stenosis tearfully – nasal canal, nosebleeds.
Interaction: In combination with cyclophosphamide may enhance cytotoxicity (thymidine phosphorylase activity is increased in tumor tissue). When concomitantly with coumarin anticoagulants (warfarin and phenprocoumon) possible violations of indicators of coagulation and bleeding (occurred within a few days to several months after initiation of therapy with capecitabine, in one case ; in a month after its completion). Increasing the concentration of phenytoin in plasma. Antacids containing aluminum hydroxide and magnesium, increases the concentration of capecitabine and 5 ‘- DFCR plasma. Sorivudin and increase the toxicity of fluoropyrimidine analogs (inhibit dihydropyrimidine dehydrogenase). Calcium folinate, paclitaxel, docetaxel does not affect the pharmacokinetics of capecitabine and its metabolites.
Symptoms: Nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, inhibition of bone marrow function.
Dosage and method of administration
Dosage and administration: Inside, squeezed water, 30 minutes after a meal (not later). The average daily dose of ; 2500 mg / m ^ 2, 2 doses (morning and evening) for 2 weeks. After a week break, repeat the course. In combination with docetaxel ; 1250 mg / m ^ 2, 2 times a day for 2 weeks, 1 week break (docetaxel – / in infusion for 1 hour at a dose of 75 mg / m ^ 2 1 every 3 weeks).
The daily dose of capecitabine is calculated body surface area. When body surface area less than 1.26 m ^ 2, the total daily dose is 3000 mg; 1.27 – 1.38 m ^ 2 ; 3300 mg; 1.39 – 1.52 m ^ 2 ; 3600 mg; 1.53 – 1.66 m ^ 2 ; 4000 mg; 1.67 – 1.78 m ^ 2 ; 4300 mg; 1.79 – 1.92 m ^ 2 ; 4600 mg; 1.93 – 2.06 m ^ 2 ; 5000 mg; 2.07 – 2.18 m ^ 2 ; 5300 mg; over 2.19 m ^ 2 ; 5600 mg. In patients with mild renal insufficiency (Cl creatinine ; 30 – 50 ml / min) of toxicity or reduce the dose of 75 and 50% of the original as a monotherapy or in combination therapy.
Precautions: During treatment requires careful medical supervision for timely detection of signs of toxicity (diarrhea, nausea, stomatitis, neutropenia, and others.). At occurrence of toxic symptoms, depending on their severity may symptomatic therapy, dose reduction, treatment interruption or elimination. Toxicity of I degree includes small clinical manifestation of side effects; II degree ; diarrhea (4 – 6 times a day or a night stool), the appearance of painful redness, swelling of the hands and / or feet in violation of the patient’s activities of daily living, hyperbilirubinemia 1.5 times the upper limit of normal; III level ; diarrhea (7 – 9 times a day, fecal incontinence and malabsorption syndrome), moist desquamation, ulceration, blistering, sharp pains in the hands and / or feet, dramatically reducing the patient’s daily activities and performance, hyperbilirubinemia 1.5 – 3 times higher the upper limit of normal; Grade IV ; diarrhea (more than 10 times per day, the presence of blood in feces, the need for parenteral therapy), hyperbilirubinemia 3 or more times the upper limit of normal.
When monotherapy in the development of I degree of toxicity dose adjustment is required either in the current or in the subsequent cycles of therapy. If the toxicity of II degree the use of capecitabine should be interrupted to reduce the severity of adverse events to the I degree; resume treatment at a dose of 100, 75 and 50% of the recommended in the first, second and third signs of toxicity of this degree, respectively. At the fourth occurrence of ; therapy is stopped and not resumed. With the development of signs of toxicity III level treatment is interrupted; while reducing the side effects to the extent I welcome resumed at a dose of 75% of the former; the second appearance of signs of toxicity ; 50% of the recommended dose; in the third appearance of ; therapy overturned. If signs of toxicity grade IV treatment should be discontinued; while reducing the side effects to a degree I resume reception at a dose of 50% of the same. If the dose was reduced, it can not increase thereafter, a missed reception ; the dose is not compensated.
In the event of toxicity of capecitabine at a dose adjustment and docetaxel combination therapy is carried out by the general principles. If any – or toxicity phenomena are not serious or life-threatening (alopecia, taste alteration, modification nails) may continue treatment at the same dose. At the beginning of each cycle of therapy, if the expected delay in the introduction of docetaxel or capecitabine, is necessary to postpone the introduction until then, until you can resume therapy with both drugs. If you have to cancel docetaxel, capecitabine treatment can be continued in accordance with the requirements for the resumption of capecitabine therapy.
In patients with mild to moderate liver dysfunction caused by liver metastases with mild renal insufficiency (Cl creatinine 51 – 80 ml / min), the initial dose adjustment is not required.
On the background of coronary heart disease during treatment should be carefully monitored, aimed at identifying signs of cardiotoxicity (manifested ECG changes, possible myocardial infarction, angina, arrhythmia, cardiogenic shock, cardiac arrest, heart failure). Patients with liver metastases require laboratory monitoring of its functions. It should be borne in mind that the age increases sensitivity to the toxic effects of 5 – FU.
It is necessary to refrain from the use in pediatric practice, since safety and efficacy of the use of children to be determined.
Women of childbearing age during treatment should use reliable methods of contraception. If pregnancy occurs during treatment, the patient should be warned of the possible danger to the fetus.
Be wary appoint patients with renal insufficiency. In patients with moderate renal insufficiency (Cl creatinine 30 – 50 ml / min), the frequency of undesirable side effects III – IV degree of severity of the above.
To use caution in patients involved in potentially hazardous activities that require concentration and speed of psychomotor reactions.
In patients taking both capecitabine and oral anticoagulants ;