Supplementary treatment after stage III colon cancer (stage C by Dukes). Treatment of metastatic colorectal cancer. First-line treatment of advanced gastric cancer in combination with platinum-containing schemes. Treatment, in combination with docetaxel, of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy; the previous cytotoxic treatment should contain anthracyclines. Monotherapy of patients with locally advanced or metastatic breast cancer after failure of treatment with taxanes and anthracycline-containing regimens or in patients whose further treatment with anthracyclines is contraindicated.
Capecitabine is a cytotoxic-free fluoropyrimidine carbamate that acts as an oral precursor of the cytotoxic 5-fluorouracil (5-FU) molecule. 5-FU metabolism in the anabolic pathway blocks the methylation of deoxyuridylic acid to thymidylic acid, which results in the synthesis of deoxyribonucleic acid (DNA). Incorporation of 5-FU also leads to the inhibition of RNA and protein synthesis. Due to the essential role of DNA and RNA for cell division and growth, the 5-FU deficiency of thymidine can lead to cell growth and death disorders. The effects of DNA and RNA synthesis disorders are greatest in rapidly dividing cells that rapidly metabolize 5-FU. Capecitabine has a synergistic effect in combination with docetaxel, which may be related to the increase in docetaxel-induced thymidine phosphorylase (the enzyme responsible for the final conversion of capecitabine to 5-FU). Capecitabine, after oral administration, is absorbed quickly and to a large extent. It is initially metabolised in the liver via a carboxyl esterase to 5'-DFCR, which is then converted to 5'-DFUR under the influence of cytidine deaminase, occurring mainly in the liver and in cancerous tissues. Further catalytic activation of 5'-DFUR occurs under the influence of thymidine phosphorylase to 5-FU. Enzymes involved in catalytic activation are present in tumor tissues as well as in lower concentrations in healthy tissues. This sequential, enzymatic biotransformation of capecitabine into 5-FU leads to a higher drug concentration in tumor tissues. Capecitabine, 5'-DFCR, 5'-DFUR and 5-FU bind to the protein, mainly albumin, at 54%, 10%, 62% and 10% respectively. 5-FU is then catabolized by pyrimidine dehydrogenase to less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidine cleaves the pyrimidine ring, resulting in the formation of 5-fluoroureidopriopione acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL), which is excreted in the urine. Pyrimidine dehydrogenase (DPD) activity is a limiting factor for the reaction rate. DPD deficiency can lead to increased capecitabine toxicity. The half-life of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL is 0.85, 1.11, 0.66, 0.76 and 3.23 h, respectively. Capecitabine and its metabolites are excreted mainly in the urine; 95.5% of the administered dose of capecitabine is detected in the urine. Elimination with faeces is minimal (2.6%). The main metabolite excreted in the urine is FBAL, which corresponds to 57% of the applied dose. About 3% of the administered dose of the drug is excreted in the urine in unchanged form.
Contraindications:
Hypersensitivity to capecitabine, Fluorouracil or to any of the excipients. Interview with heavy and unusual reactions to fluoropyrimidine therapy. Known deficiency of pyrimidine dehydrogenase (DPD). Severe leukopenia, neutropenia and thrombocytopenia. Severe hepatic failure. Severe renal failure (creatinine clearance <30 ml / min). Treatment with sorivudine or its analogues, e.g. brivudine. If there are contraindications to the use of any of the drugs used in the combination regimen with capecitabine, this drug should not be used. Pregnancy and breastfeeding.
Precautions:
Dose suppressing side effects include: diarrhea, abdominal pain, nausea, inflammation of the mouth and palmar-plantar syndrome. Most of the side effects are reversible and permanent withdrawal is not required, although the administration of subsequent doses may be stopped or the doses may be reduced.If severe diarrhea occurs, patients should be closely monitored and, if dehydrated, refill with fluids and electrolytes; standard anti-diarrheal treatment may be used; if necessary, reduce the dose of capecitabine. If grade 2 (or higher) dehydration occurs, administration of capecitabine should be discontinued immediately and the hydration corrected. Do not resume treatment until the patient's hydration is sufficient and the factor that triggered the dehydration will not be corrected or controlled sufficiently. The dose modification used should correspond to the adverse event causing the dehydration. If Grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine should be discontinued until resolution or relief to grade 1. After Grade 3 hand-foot syndrome, the Next dose should be lowered. In the case of treatment with capecitabine in combination with Cisplatin, the use of vitamin B is not recommended6 for the treatment of symptomatic or secondary prophylaxis of the palm-plantar syndrome, due to reports suggesting that such therapy may reduce the effectiveness of cisplatin. Due to the risk of cardiotoxicity, special care should be taken in patients with a history of severe cardiac disease, arrhythmia and angina pectoris. Caution should be exercised in patients with previously confirmed hypo - or hypercalcaemia; with diseases of the central and peripheral nervous system (eg in the case of metastases to O. or Neuropathy); with diabetes or electrolyte disorders (risk of aggravation of these disorders); treated with oral anticoagulants (risk of haemorrhage, monitoring of INR or prothrombin time and a suitably modified dose of an anticoagulant). Patients with mild or moderate hepatic impairment should be carefully monitored, regardless of presence or absence, of liver metastases. Treatment with capecitabine should be discontinued if the associated increase in bilirubin is> 3 times ULN or elevated liver transaminases (ALT, AST) will be> 2.5 times ULN. Treatment with capecitabine as monotherapy can be resumed when bilirubin is reduced to ≤3 x ULN or when liver aminotransferases decrease to ≤2.5 x ULN. In patients with moderate renal impairment (creatinine clearance 30-50 ml / min) and in elderly patients, Grade 3 or 4 adverse reactions are more common. Careful monitoring of the course of treatment of patients ≥60 years old is recommended. Patients treated with capecitabine who have not been diagnosed with pyrimidine dehydrogenase (DPD) have not been identified before, potentially life threatening toxic symptoms of acute drug overdose may occur. If symptoms of grade 2-4 occur, the treatment must be discontinued immediately until the observed symptom of toxicity disappears. The decision to discontinue the drug should be taken on the basis of clinical evaluation, time of onset, duration and severity of observed toxicity. There are no data on the use of capecitabine in children and adolescents in the treatment of colorectal, rectal, stomach and breast cancer. Due to the lactose content, the drug should not be used in patients with rare hereditary galactose intolerance, lactase deficiency (Lapp type) or malabsorption of glucose-galactose.
Pregnancy and lactation:
Capecitabine is contraindicated during pregnancy (may cause fetal harm). Effective methods of contraception should be used during treatment. Breast-feeding should be discontinued during treatment with capecitabine (animals have significant amounts of capecitabine and its metabolites in milk).
Side effects:
Capecitabine monotherapy. Very common (all grades): anorexia, diarrhea, vomiting, nausea, stomatitis, abdominal pain, palmar plantar erythrodystesis, fatigue, asthenia. Common (all stages): herpes infection, nasopharyngitis, lower respiratory tract infections, neutropenia, anemia, dehydration, weight loss, insomnia, depression, headache and dizziness, lethargy, paresthesia, impaired taste, increased tearing, conjunctivitis, eye irritation, thrombophlebitis, shortness of breath, nosebleed, cough, watery runny nose, gastrointestinal bleeding, constipation, upper abdominal pain, dyspeptic symptoms, flatulence, dry mouth, loose stools, hyperbilirubinemia, incorrect parameters liver function, rash, alopecia, erythema, dry skin, pruritus, hyperpigmentation of the skin, skin rash, flaking of the skin, skin inflammation, pigmentation disorders, changes in the nails, pain in the limbs, back pain, joint pain, fever, peripheral edema, bad well-being, chest pain.Uncommon (grade 3-4 or considered significant): sepsis, urinary tract infection, inflammation of the subcutaneous tissue, tonsillitis, pharyngitis, candidiasis of the mouth, influenza, gastroenteritis, fungal infections, infection, tooth abscess, lipoma, neutropenic fever, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, haemolytic anemia; increase in INR value / increased prothrombin time, hypersensitivity, diabetes, hypokalemia, eating disorders, malnutrition, hypertriglyceridaemia, confusion, panic attacks, depressed mood, decreased libido, aphasia, memory impairment, ataxia, syncope, balance disorders, sensory disturbances, peripheral neuropathy , decreased visual acuity, double vision, labyrinthine dizziness, ear pain, unstable angina, angina pectoris, myocardial ischemia, atrial fibrillation, arrhythmias, tachycardia, sinus tachycardia, palpitations, deep vein thrombosis, hypertension, punctate punctate, hypotension, hot flushes, peripheral feeling of cold, pulmonary embolism, pneumothorax, hemoptysis, asthma, exercise dyspnoea, intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, inflammation esophageal reflux, abdominal discomfort, gastro-oesophageal reflux, colitis, blood in the stool, jaundice, blisters, skin ulcer, rash, urticaria, hypersensitivity reactions to light, palmar erythema, face edema, purpura, recurrence of post-radiation symptoms next injection, joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscle weakness, hydronephrosis, incontinence, hematuria, nocturia, increased blood creatinine, genital bleeding, edema, chills, flu-like symptoms , muscle stiffness, increased body temperature. In addition, clinical trials have been reported with a frequency of <0.1% (monotherapy): cardiomyopathy, heart failure, sudden death, additional ventricular contractions, encephalopathy.Capecitabine in combination therapy - side effects occurring in addition to the symptoms observed after taking the drug alone or when they occur in the higher frequency group than with monotherapy. Very common (all grades): neutropenia, leukopenia, anemia, neutropenic fever, thrombocytopenia, decreased appetite, paraesthesia, sensory disturbances, peripheral neuropathy, peripheral sensory neuropathy, abnormal sensation of taste, headache, excessive lachrymation, lower limb edema, hypertension, embolism and thrombosis, sore throat, throat sensation, constipation, indigestion, alopecia, nails disorders, muscle pain, arthralgia, limb pain, fever, weakness, drowsiness, temperature intolerance. Common (all stages): shingles, urinary tract infection, oral candidiasis, upper respiratory tract infection, rhinitis, influenza, infection, cold sores, bone marrow depression, febrile neutropenia, hypersensitivity, hypokalaemia, hyponatremia, hypomagnesaemia, hypocalcemia, hyperglycemia, sleep disorders, anxiety, neurotoxicity, tremors, neuralgia, hypersensitivity reactions, hypoaesthesia, visual disturbances, dry eye syndrome, eye pain, visual impairment, blurred vision, tinnitus, hearing loss, atrial fibrillation, ischemia / myocardial infarction, hot flushes, hypotension, hypertensive crisis, sudden redness of the face, phlebitis, hiccups, sore throat and larynx, dysphonia, upper gastrointestinal bleeding, mouth ulcers, gastritis, enlarged abdominal girth, gastro-oesophageal reflux disease, oral pain, dysphagia bleeding from the rectum, b lower abdominal pain, oral cavity, impaired mouth sensation, hypoaesthesia of the mouth area, abdominal discomfort, liver dysfunction, hyperhidrosis, erythematous rash, urticaria, night sweats, jaw pain, muscle cramps, trismus, muscle weakness , hematuria, proteinuria, decrease in creatinine renal clearance, painful urination (dysuria), mucositis, pain in the extremities, pain, chills, chest pain, flu-like symptoms, fever, infusion reaction, injection site reaction, pain at the infusion site, pain at the injection site, contusions.After placing the medicine on the market. Rare: tear duct stenosis, ventricular fibrillation, QT prolongation, ventricular tachycardiatorsade de pointes and bradycardia, vasoconstriction, hepatic failure and cholestatic hepatitis. In women, a statistically significantly increased risk of palmar-plantar syndrome and diarrhea was observed as well as a decreased risk of neutropenia. In elderly patients (≥60 years) and in patients with renal insufficiency, the incidence of Grade 3 and 4 adverse reactions is increased.
Dosage:
Orally. The preparation should only be prescribed by qualified doctors experienced in the use of anticancer drugs. Careful monitoring of all patients during the first treatment cycle is recommended. Treatment should be discontinued if the disease progresses or symptoms of significant intolerance are observed.monotherapy. Colon cancer, colon and rectum cancer, breast cancer: the recommended starting dose is 1250 mg / m2 pc. administered twice daily (morning and evening; this corresponds to a total daily dose of 2,500 mg / m2 pc.) for 14 days, then a 7-day break. Complementary treatment of patients with stage III colon cancer should be carried out for 6 months.Combination therapy. Colon cancer and stomach cancer. It is recommended to reduce the initial dose to 800-1000 mg / m2 pc, when given twice a day for 14 days followed by a 7-day break, or up to 625 mg / m2 pc. 2 times a day when administered without interruption. Inclusion of the combined biological medicine in the treatment regimen does not necessitate a change in the starting dose of capecitabine. Patients receiving combination therapy with Cisplatin should be pre-treated for maintenance of appropriate hydration and antiemetics as described in the cplplatin SmPC prior to cisplatin administration. In patients who receive capecitabine in combination with oxaliplatin, as prescribed in the Smol oxaliplatin SPC, premedication is recommended. The duration of adjuvant treatment in patients with stage III colon cancer should be 6 months.Breast cancer. In the case of mating with docetaxel, the recommended starting dose of capecitabine is 1250 mg / m2 pc. 2 times a day for 14 days, followed by a 7-day break, the dose of docetaxel is 75 mg / m2 pc. in a 1-hour intravenous infusion repeated every 3 weeks. Patients receiving combination capecitabine and docetaxel therapy prior to docetaxel administration should be given pre-oral corticosteroids, such as Dexamethasone, in accordance with docetaxel SmPC.Dosage adjustment during treatment. The toxic effects of capecitabine can be reduced by symptomatic treatment and / or dose adjustment (interruption of treatment or reduction of dose). Once reduced, the dose should not be increased during further treatment. In the case of side effects which, in the opinion of the treating physician, are unlikely to become serious or life-threatening, eg alopecia, taste disorders, changes in the nail, treatment can be continued at the same dose level without reducing or retarding it administration of the drug. Patients receiving capecitabine should be advised to discontinue treatment immediately if moderate or severe toxicity develops. The doses of capecitabine, omitted due to toxic symptoms, are not replenished at a later time.Recommended dose changes of capecitabine due to toxicity (in three-week cycle or continuous therapy). 1st degree of toxicity:dosage without changes.2nd degree of toxicity: 1st symptom - during treatment, discontinue treatment until toxic resolution to grade 0-1, give 100% of the dose during the next cycle / administration; 2nd symptom - during treatment, discontinue treatment until toxic resolution to grade 0-1, during the next cycle / administration administer 75% of the dose; 3rd symptom - during treatment, discontinue treatment until toxic resolution to grade 0-1, during the next cycle / administration give 50% of the dose; 4th symptom - discontinue the drug permanently. 3. degree of toxicity: 1st symptom - during treatment, discontinue treatment until toxic resolution to grade 0-1, during the next cycle / administration report 75% of the dose; 2nd symptom - during treatment, discontinue treatment until toxic resolution to grade 0-1, during the next cycle / administration give 50% of the dose; 3rd symptom - discontinue the drug permanently.4th degree of toxicity: 1st symptom - discontinuation of the drug permanently or if the physician considers the continuation of treatment as in the best interest of the patient, discontinue treatment until the toxicity to 0-1, then during the next cycle / administration give 50% of the dose; 2nd symptom - discontinue the drug permanently. Patients with baseline neutrophil count <1.5 x 109/ l and / or the number of thrombocytes <100 x 109/ l should not be treated with capecitabine. If routine laboratory testing during the treatment cycle shows a reduction in neutrophil count <1.0 x 109/ l or decreased platelet count <75 x 109/ l, capecitabine treatment should be discontinued.Dose changes due to toxicity when capecitabine is used in the 3-week cycle in combination with other drugs. Dosage changes should be made in accordance with the above guidelines for capecitabine and in accordance with the relevant SmPC in a combination. If at the beginning of the treatment cycle, it is advisable to temporarily discontinue capecitabine or the drugs used in the combination, all medications should be discontinued until the criteria for re-inclusion are met. In the event of a toxicity during the therapeutic cycle which, in the opinion of the treating physician, is not due to the use of capecitabine (eg neurotoxicity, ototoxicity), treatment with capecitabine should be continued and the dose of the drug used in the combination should be changed according to the relevant drug documentation. If the drug (s) used in combination should be permanently discontinued, capecitabine may be resumed if the criteria for initiating therapy are met. This recommendation applies to all indications and to every patient population.Dose changes due to toxicity when capecitabine is used in continuous therapy in combination with other drugs. Changes should be made in accordance with the above instructions for capecitabine and in accordance with the relevant SmPC (s) of the drug (s) used in combination.Special groups of patients. Hepatic dysfunction. The lack of sufficient data on the safety and efficacy of the drug in patients with hepatic failure does not allow for the recommendation of dose modification. There is also no information on the use of the drug in case of liver damage in cirrhosis or hepatitis. Capecitabine is contraindicated in patients with severe hepatic impairment.Impaired renal function. Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml / min). In patients with moderate renal impairment (creatinine clearance 30-50 ml / min) at the time of treatment planning, it is advisable to reduce the dose to 75% of the initial dose of 1250 mg / m2. In patients with moderate renal failure at the time of planning, there is no need to lower the dose for the initial dose of 1000 mg / m2. In patients with mild renal impairment (creatinine clearance 51-80 ml / min) no modification of the dosage is required when planning treatment. If the calculated creatinine clearance decreases during treatment <30 ml / min, capecitabine should be discontinued. Dose modifications in the case of renal dysfunction refer to both monotherapy and combination therapy.Elderly patients. In the case of monotherapy with capecitabine, there is no need to lower the starting dose of the drug. In combination with docetaxel, a starting dose of capecitabine is recommended to 75% (950 mg / m2 pc. 2 times a day); if no side effects are observed, the dose of capecitabine can be carefully increased to 1250 mg / m2 pc. 2 times a day. In combination with irinotecan, a reduction of the initial dose of capecitabine to 800 mg / m is recommended2 2 times a day.Way of giving. The tablets should be swallowed with water, within 30 minutes after a meal.
(C)
