Structure and Composition
Film-coated tablets in a box: 60 pcs.
capecitabine 150 mg
Film-coated tablets in a box: 120 pcs.
capecitabine 500 mg
Registration number :
Tab. is covered. shell, 150 mg: 60 pcs.; tab. is covered. shell, 500 mg: 120 pcs. - P-8-242 number 011087 14.05.1999
Antitumor drug for oral administration, a derivative of fluoropyrimidine carbamate.
In vitro capecitabine has no cytotoxic effect. In vivo activated in tumor tissue and transformed into 5-fluorouracil (5-FU), has a selective cytotoxic effect. Formation of 5-FU occurs in the tumor tissue under the influence of tumor angiogenic factors - thymidine phosphorylase, which thus minimizes the systemic exposure of 5-FU to healthy tissue. As a result of selective activation of the contents of 5-FU in the tumor is much higher than levels in healthy tissues.
To study the selective conversion of capecitabine in tumor was conducted a pharmacokinetic study comparing capecitabine concentrations in the tumor, healthy tissue and plasma of cancer patients poperechnoobodochnoy and rectum. After receiving capecitabine orally (at a dose of 1255 mg / m 2 2 times / day for 5-7 days before surgery) concentrations of 5-FU in primary tumor were significantly higher than in surrounding healthy tissue and plasma. The activity of thymidine phosphorylase in primary tumor 4 times higher than in healthy tissue. In human tumors such as breast, stomach, poperechnoobodochnoy and rectum, cervix and ovary, with a lot more thymidine capable of converting 5-DFUR (5'-deoxy-5-ftoruridin) to 5-FU than in healthy tissues.
Efficacy in colon cancer. Data 2 multicenter, randomized, controlled phase III studies conducted on a single plan, confirm the potential use of Xeloda as the drug of choice for metastatic colon cancer (colorectal) cancer. In these studies, 603 patients were randomized to treatment at a dose of Xeloda 2510 mg/m2/sut for 2 weeks followed by one week apart (three-week cycles), while other 604 patients - the treatment of 5-FU and leucovorin (Mayo scheme). The overall response rate of remission was 25.7% in the treatment of Xeloda and 16.7% in the treatment scheme Mayo (p <0.0002). The median time to disease progression was 140 days in the treatment of Xeloda and 144 days when using the scheme Mayo, median - 392 and 391 days, respectively.
Effectiveness of breast cancer. Antitumor activity of Xeloda was evaluated in patients with breast cancer stage IV has already received massive therapy and refractory to previously administered treatment with paclitaxel. In addition, 41% of patients were resistant and 26% absent the effect of prior therapy with anthracyclines, 82% of patients had already received 5-FU. Primary endpoint of the study was objective tumor shrinkage (where they can be determined). Remission was considered a deduction vzaimoperpendikulyarnyh tumor diameter not less than 50% for at least 1 month. Xeloda was administered at a daily dose of 2510 mg/m2 for 2 weeks, then did a week break and re-administered the drug in the form of a three-week cycles.
The overall response rate of remission in the analysis included all patients (135 men) was 20% (27 of remission, including 3 complete). The median time to disease progression was 93 days, median duration of remission - 241 days, median survival - 384 days.
To assess the effect of treatment using prospectively designed clinical response score (pain, need for analgesics and the general condition of Karnofsky). The overall clinical response was 20% (29 patients). Of those patients whose baseline pain was assessed by visual analog scale as more than 20 mm, 47% was noted positive changes in pain intensity (a decrease of 50% or more).
- Locally advanced or metastatic breast cancer after failure of chemotherapy consisting of paclitaxel and anthracyclines medication, or if there are contraindications to anthracycline therapy;
- First-line therapy of metastatic colon cancer.
The recommended dose of Xeloda is 1250 mg / m 2 2 times a day (morning and evening, which corresponds to the total daily dose of 2500 mg/m2) for 14 days followed by seven-day break. The drug is taken orally, not later than 30 minutes after eating, drinking Xeloda tablets with water.
Dose of Xeloda rely on body surface area as follows:
Daily dose of 2500 mg / m 2 Number of tablets at each meal (morning and evening)
Surface area (m2) Total daily dose (mg) * 150 mg 500 mg
<1.26 3000 - 3
1.27-1.38 3300 1 3
1.39-1.52 3600 2 3
1.53-1.66 4000 - 4
1.67-1.78 4300 1 4
1.79-1.92 4600 2 4
1.93-2.06 5000 - 5
2.07-2.18 5300 1 5
> 2.19 5600 May 2
* The total daily dose divided into 2 equal acceptance in the morning and evening.
The phenomenon of toxicity in the treatment of Xeloda can eliminate symptomatic therapy and / or change the dose of Xeloda (interrupting treatment or lowering the dose of the drug).
When the toxicity of 1 degree to adjust the dose should not be.
When toxicity 2 and 3 degrees Xeloda should be discontinued. After the severity of adverse events is reduced to 1 degree, receiving Xeloda can resume the full dose, or adjusted in accordance with the recommendations. With the development of signs of toxicity grade 4 treatment should be stopped or temporarily interrupted to relieve or reduce symptoms by 1 degree, and then resume use of the drug at a dose of 50% from the previous. If, due to the toxic effects were omitted several steps of capecitabine, these doses did not fill, but simply continue the planned cycles of therapy. If the dose was reduced, not increase it later. Below are recommendations for changing the dose in the case of toxic phenomena (according to criteria common signs of toxicity developed by the National Cancer Institute of Canada):
- If signs of toxicity of 1 degree dose not change either in this or in subsequent cycles of therapy;
- At the first signs of toxicity grade 2 should discontinue therapy until signs of toxicity are not yet reduced to 0-1 degrees, and resume the next course of treatment with 100% recommended dose.
In the second appearance of signs of toxicity, discontinue treatment until signs of toxicity, while not diminish to the point of 0-1 and resume the next course of treatment with 75% of the recommended dose.
At the third appearance of signs of toxicity, discontinue treatment until signs of toxicity are not yet reduced to the point of 0-1 and resume the next course of treatment with 50% of the recommended dose.
In the fourth appearance of signs of toxicity should repeal the drug and not to renew its welcome;
- At the first signs of grade 3 toxicity, discontinue treatment until such time until signs of toxicity will be reduced to 0-1 degrees, and resume the next course of treatment with 75% of the recommended dose.
In the second appearance of signs of toxicity should discontinue therapy until signs of toxicity are not yet reduced to 0-1 degrees, and resume the next course of treatment with 50% of the recommended dose.
At the third appearance of signs of toxicity should be abolished drug and not to renew its welcome;
- For signs of toxicity grade 4 drug should be discontinued and not to renew his appointment. If in the interest of the patient should continue treatment, the drug should be discontinued until such time until signs of toxicity was reduced to grade 0-1 and resume the next course of treatment with 50% of the recommended dose.
The table presents the adverse events noted in clinical trials of> 2% of patients (n = 875) and regarded as remotely, possibly or probably related to taking Xeloda. Information security is based on three phase II trials in patients with breast cancer (n = 245) and 3 studies (one - phase 1, two - II phase) in men and women with colon cancer (n = 630).
The system of bodies / type of adverse events Xeloda mg/m2/sut to 2500, with interruptions, n = 875
All degrees 3 degrees 4 degrees
n (%) n (%) n (%)
From the digestive system
Diarrhea 427 (48.8) 95 (10.9) 18 (1.8)
Nausea 370 (42.3) 28 (3.2) -
Vomiting 234 (25.7) 28 (3.2) 2 (0.2)
Stomatitis, all kinds of * 212 (24.2) 29 (3.3) 1 (0.1)
Abdominal pain 106 (12.1) 26 (3) 1 (0.1)
Constipation 74 (8.5) 5 (0.6) -
Epigastric pain 60 (6.9) 7 (0.8) -
Dyspepsia 54 (6.2) 1 (0.1) -
Dry mouth 35 (4) - -
Flatulence 34 (3.9) 1 (0.1) -
Soft stool 21 (2.4) 1 (0.2) -
Palmar-plantar syndrome, 456 (52.2) 135 (15.4) -
Dermatitis 89 (10.2) 3 (0.3) -
Dry skin 63 (7.2) 1 (0.1) -
Eritemazotnaya rash 55 (6.3) 1 (0.1) -
Alopecia 46 (5.3) - -
Pruritus 31 (3.5) 2 (0.2) -
Patchy desquamation 22 (2.5) - -
Giperpegmentatsiya skin 32 (3.7) 1 (0.1) -
Skin cracks 23 (2.6) - -
From the body as a whole
Fatigue 213 (24.3) 23 (2.6) -
Raising the temperature 82 (9.4) 2 (0.2) -
Weakness 54 (6.2) 6 (0.7) -
Asthenia 358 (4) 6 (0.7) -
Pain in the limbs 33 (3.8) 1 (0.1) -
Severe drowsiness 27 (3.1) 1 (0.1) -
The nervous system
Headache 51 (5.8) 4 (0.5) -
Paresthesias 43 (4.9) - -
Dizziness (except on a system) 45 (5.1) 1 (0.1) -
Taste disturbance 41 (4.7) 2 (0.2) -
Insomnia 35 (4) - -
Metabolic and nutritional
Anorexia 90 (10.3) 10 (1.1) -
Decrease in appetite 68 (7.8) 4 (0.5) -
Dehydration 43 (4.9) 15 (1.7) 4 (0.5)
Reduction in body weight 29 (3.3) - -
On the part of the vision
Strengthening tearing 55 (6.3) - -
Conjunctivitis 25 (2.9) - -
Eye irritation 18 (2.1) - -
From the respiratory system
Shortness of breath 38 (4.3) 3 (0.3) -
Cough 19 (2.2) 1 (0.1) -
From the musculoskeletal system
Pain 24 (2.7) - -
Arthralgia 18 (2.1) - -
Edema of lower limbs 34 (3.9) - -
From the hematopoietic system
Anemia 20 (2.3) 3 (0.3) -
* All types of stomatitis: stomatitis, inflammation of the mucous membranes of the mouth, ulcerative stomatitis.
Myalgia and skin cracks were, according to researchers, even remotely connected with the reception of Xeloda in less than 2% of the patients who participated in the 6 months ended clinical trials (n = 875). Prior to the completion of these 6 studies, these reactions even remotely associated with taking Xeloda, were observed in 2.1% of patients.
Adverse events listed below reflect the well-known aspects of the toxic effect of fluoropyrimidines and they were regarded by researchers as an even remotely associated with taking Xeloda and met in the 6 months ended clinical trials in less than 2% of patients (n = 875).
From the digestive system: erosive and ulcerative lesions of the mucous membranes (esophagitis, gastritis, duodenitis, colitis, gastro-intestinal bleeding).
Cardio-vascular system: cardialgia, angina, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, atrial arrhythmias (including atrial fibrillation), ventricular extrasystoles.
CNS: confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, impaired balance and coordination).
From the hemopoietic system: inhibition of bone marrow hemopoiesis, pancytopenia.
Dermatological reactions: photosensitivity, a syndrome resembling radiation dermatitis, oniholizis, brittleness, discoloration, and dystrophy of nails.
From the body as a whole: chest pain.
Infectious complications: infection, concomitant myelosuppression, weakened immunity, and violate the integrity of the mucous membranes, local and systemic fatal (bacterial, viral and fungal), sepsis.
The following table shows the changes in laboratory parameters identified among the 875 patients, regardless of their connection with the admission of capecitabine.
Parameter Capecitabine 2500 mg/m2/sut, intermittent reception, n = 875
All degrees of toxicity,% toxicity grade 3 and 4,% shift by 1-2 degrees compared to the baseline,% shift by 3-4 degrees compared to the baseline,%
Reduced hemoglobin levels 40.7 4.2 40.1 0.6
Reducing the number of neutrophils 17/05 02/03 07/14 07/02
Reducing the number of granulocytes 2.1 0.2 1.8 0.2
Reducing the number of lymphocytes 57.5 43.2 53.5 4
Reducing the number of platelets 08.19 01.07 18.05 01.03
Increased levels of bilirubin 38.2 19.9 21.9 16.2
Increased ALT 1916 0.6 15.5 0.5
Increased AST 24.3 0.8 24.1 0.2
Increases in serum creatinine 9.9 0.6 5.9 0.5
Increased activity of alkaline phosphatase 8.26 0 8.26 0
- Hypersensitivity to capecitabine;
- Serious and unexpected reactions to medication fluoropyrimidines or hypersensitivity to fluorouracil (metabolite of capecitabine) in history;
- Simultaneous reception sorivudina and its structural analogs.
Pregnancy and lactation
Xeloda should not be used during pregnancy. If the drug must be assigned during pregnancy or if pregnancy occurs, the patient is already receiving the drug, it should warn about possible dangers to the fetus.
Clinical trials of Xeloda in pregnancy is not, however, on the basis of pharmacological and toxicological characteristics, we can assume that Xeloda can have damaging effects on the fetus.
Women of childbearing age should be advised to avoid pregnancy during treatment with Xeloda.
It is unknown whether to select a capecitabine and its metabolites in breast milk. Because of possible adverse reactions in infants, nursing mothers use the drug should be avoided unless the benefits of therapy to the mother does not exceed the potential risk to the child.
In experimental studies on animal reproduction appointment of capecitabine was accompanied by an increase in the death of embryos and the teratogenic effect, which is the expected effect of fluoropyrimidine derivatives. Capecitabine should be considered potentially teratogenic in humans.
In a study with single oral administration of Xeloda lactating mice in their milk was found a significant number of metabolites of capecitabine.
Patients treated with Xeloda should be carefully monitored for occurrence of toxicity. Most adverse events are reversible and do not require permanent discontinuation of the drug, although it may be necessary to reduce the dose or temporary interruption of the reception.
The spectrum of cardiotoxicity in the treatment of Xeloda is similar to that using other fluoropyrimidines and includes changes in the ECG, myocardial infarction, angina, arrhythmias, heart failure and heart failure. These adverse events are more common in patients with coronary artery disease.
In rare cases, there are unexpectedly severe toxic effects associated with 5-FU, in the form of stomatitis, diarrhea, neutropenia and neurotoxicity caused by insufficient activity of dihydropyrimidine dehydrogenase (DPD).
In patients with moderate renal insufficiency (creatinine clearance 30-50 ml / min), as well as in the treatment of 5-FU, the frequency of adverse events 3 and 4 of the severity of the above, so the appointment of Xeloda in such patients should use caution.
Treatment Xeloda can cause diarrhea, sometimes severe. The median time to onset of symptoms of diarrhea 2.4 degrees was 31 days. Patients with severe diarrhea should be carefully monitored by conducting them replace fluids and electrolytes in the case of dehydration. If you see diarrhea 2, 3 and grade 4 treatment Xeloda should be interrupted until the disappearance of diarrhea or reduce its intensity to degree 1. Diarrhea grade 3 and 4 treatment Xeloda to be renewed with a decrease in dose. It is recommended that standard antidiarrhoeal drugs (eg loperamide).
The frequency of toxic effects on the gastrointestinal tract in patients aged 60-79 years was the same as in the general population of patients. In patients 80 and older reversible gastrointestinal symptoms Grade 3 or 4, such as diarrhea, nausea, stomatitis, developed more often.
Xeloda may cause the development of hand-foot syndrome (syn. - palmar-plantar eritrodizesteziya or akralnaya erythema induced by chemotherapy), which is a manifestation of cutaneous toxicity (median time to development - 79 days, range - ot11 to 360 days), severity which varies from 1 to 3. In the event of 2 or 3 degrees of hand-foot syndrome Xeloda should be interrupted until symptoms disappear or decrease by 1 degree; syndrome grade 3 subsequent doses of Xeloda should be reduced.
At higher levels of serum bilirubin 4.2 degree receiving Xeloda should be stopped immediately prior to the disappearance of hyperbilirubinemia or decrease it by 1 degree.
Patients with impaired liver function should be carefully monitored. Effect of liver disease, not due to liver metastases, as well as severe hepatic insufficiency on the distribution of Xeloda is not known. In patients taking coumarin anticoagulants and kapitsetabin should regularly monitor the parameters of coagulation.
Use in pediatrics
Safety and efficacy of Xeloda in children has not been studied.
In clinical studies, overdose of Xeloda was not.