Mamacarit ®- capsules

INSTRUCTIONS FOR MEDICAL USE

MAMAKARIT®

Trade name of the drug: Mamakarit ®.

Active substance (INN): capecitabine

Dosage form: capsules

CONTENTS:

1 capsule contains:

Active ingredient: Capecitabine 500.0 mg.

Description: Solid gelatin capsules, white, size “0”, filled with powder of white or almost white color.

Pharmacotherapeutic group: Antineoplastic agent.

ATX code: L01BC06

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Capecitabine is fluoropyrimidine carbamate derivative, oral cytostatic agent, which is activated in tumor tissue and has selective cytotoxic effect on it. In vitro capecitabine has no cytotoxic effect, in vivo it is converted into -fluorouracil (FU), which undergoes further metabolism. PV formation occurs mainly in tumor tissue under the action of tumor angiogenic factor – thymidine phosphorylase (dTdPhase), which minimizes the systemic effect of PV on healthy body tissues. Sequential enzymatic biotransformation of capecitabine into FP creates higher concentrations of the drug in tumor tissues than in the surrounding healthy tissues.

The metabolism of FP into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) occurs in both healthy and tumor cells. These metabolites damage cells through two different mechanisms. First, FDUMF and the folate cofactor N5-10-methyltetrahydrofolate bind to thymidylate synthase (TS) to form a covalently bound tertiary complex, which leads to the inhibition of thymidylate formation from uracil. Thymidylate is an essential precursor of thymidine triphosphate, an important component of DNA synthesis. Second, during RNA synthesis, nucleus transcriptional enzymes can mistakenly incorporate FUTP instead of uridine triphosphate (UTP). This metabolic “mistake” disrupts the RNA process and protein synthesis.

Pharmacokinetics

After ingestion, capecitabine is absorbed rapidly and completely, after which it is transformed into its metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCT) and 5′-deoxy-5-fluoruridine (5′-DFUR). Concomitant ingestion decreases the absorption rate of capecitabine, but the area under the concentration-time curve (AUC) of 5′-DFTCT and the next metabolite, 5-fluorouracil (5-FU), are not significantly affected. Capecitabine, 5′-DFCT, 5′-DFUR and 5-FU bind to proteins, less than 60 %, and is independent of concentration (mainly to albumin, about 35 %).

Liver carboxylesterase performs the first metabolic conversion of capecitabine to 5′-DFCP, which is then transformed to 5′-DFUR by cytidine deaminase, which is mainly found in the liver and tumor tissues. The AUC for 5-FU is 6-22 times lower than after intravenous 5-FU jet administration at a dose of 600mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU anabolites. The 5-FU is further catabolized to form inactive metabolites, dihydro-5-fluorouracil (FUN2), 5-fluorouraidopropionic acid (FUPK), and a l l f – f t o r – b e t a – a l a n i n ( F B A L ) ; this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

The half-life of T ½ capecitabine, 5′-DPCR, 5′-DFUR, 5-FU, and F BAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. In the range of therapeutic doses, pharmacokinetic parameters of capecitabine and its metabolites, except for 5-FU, are dose-dependent. Urinary excretion is 95.5%, fecal excretion is 2.6%. The main metabolite in the urine is F-BAL, which accounts for 57% of the dose taken. About 3% of the administered dose is excreted unchanged in the urine.

Pharmacokinetics in special patient groups

Gender, presence or absence of liver metastases before treatment, patient’s general status index, concentration of total bilirubin, serum albumin, ALT and AST activity in patients with colorectal cancer had no significant effect on pharmacokinetics of 5′-DFUR, 5-FU and FBL.

Patients with metastatic liver damage. In patients with mild to moderate hepatic dysfunction due to metastasis, there is no clinically significant change in the pharmacokinetics of capecitabine. There are no data on pharmacokinetics in patients with severe hepatic impairment.

Patients with impaired renal function. The results of pharmacokinetic study, conducted in cancer patients with different (from mild to severe) degree of renal failure, indicate that the pharmacokinetics of unchanged drug and 5-FU does not depend on creatinine clearance (CK). CK affects the AUC of 5′-DFUR (35% increase in AUC when CK decreases by 50%) and FBL (114% increase in AUC when CK decreases by 50%). FBAL is a metabolite that has no antiproliferative activity.

Elderly patients. Age has no effect on the pharmacokinetics of 5′-DFUR and 5-FU. AUC of FBL was increased in patients aged 65 years and older (a 20% increase in age was accompanied by a 15% increase in AUC of FBL), which is probably due to changes in renal function.

Indications for use

Breast cancer

  • Combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy including anthracycline drugs is ineffective.
  • monotherapy of locally advanced or metastatic breast cancer resistant to chemotherapy with taxanes or anthracycline-type drugs or in the presence of contraindications to them.

Colorectal cancer

  • Adjuvant therapy for colorectal cancer.
  • Therapy for metastatic colorectal cancer.

Gastric cancer

First-line therapy for advanced gastric cancer.

Dosage and administration

Orally with water, not later than 30 min after a meal.

Monotherapy

1250 mg/m2 twice a day, morning and evening (2500 mg/m2 per day), for 2 weeks, followed by a 7-day break.

Combination therapy

Breast cancer

1250 mg/m2 twice daily for 2 weeks followed by a one-week break in combination with docetaxel (75 mg/m2 as a 1-hour intravenous infusion once every 3 weeks).

Premedication is given before administration of docetaxel according to the instructions for its use

Colorectal cancer and gastric cancer

As part of combination therapy, the recommended dose of capecitabine is 800-1000 mg/m² 2 times per day for two weeks followed by a seven-day break, or 625 mg/m² 2 times per day for a continuous regimen. The addition of immunobiologic agents to combination therapy does not affect the dose of capecitabine. Hyperhydration when using cisplatin and antiemetics premedication when using cisplatin or oxaliplatin in combination with capecitabine is performed according to the instructions for their medical use.

The recommended duration of adjuvant therapy for colorectal cancer is 6 months.

The total daily dose of capecitabine is calculated according to the body surface area (Table 1).

Dose of 1250 mg/m2 (2 times a day)Number of capsules taken in the morningNumber of capsules taken in the evening
Body surface area (m2)Dose per administration (mg)  500 mg500 mg
<1,26150033
1,27-1,38165033
1,39-1,52180033
1,53-1,66200044
1,67-1,78215044
1,79-1,92230044
1,93-2,06250055
2,07-2,18265055
>2,19280055
Table 1. Calculation of Capecitabine Dose (Standard Initial Dose)

Dose adjustment during treatment

Toxic effects during treatment with capecitabine can be eliminated by symptomatic therapy and/or changing the dose of capecitabine (by interrupting treatment or reducing the dose of the drug). In case of grade 1 toxicity the dose is not changed. In case of grade 2 and 3 toxicity the use of capecitabine should be interrupted until its disappearance or reduction of toxicity to grade 1. Capecitabine administration can be resumed at the full dose or with adjustments, according to the recommendations given in Table 2.

If signs of grade 4 toxicity develop, treatment should be stopped or temporarily interrupted until the symptoms subside or decrease to grade 1, after which the drug can be resumed at a dose equal to 50% of the previous dose.

Capecitabine should be discontinued immediately in case of severe or moderate toxicity. If several doses of capecitabine have been missed due to toxicity, these doses are not replenished, but simply continued in the planned cycles of therapy. If the dose has been missed, it should not be continued. The recommendations for dose modification in case of toxic events (according to the National Cancer Institute of Canada Clinical Trials Group Common Toxicity Criteria, NCIC CTG version 1, or the National Cancer Institute of America Common Terminology Criteria for Adverse Events, CTCAE version 3) are also included.

 Toxicity levelChanging the dose over the course of a therapy cycleDose adjustment during the next therapy cycle (% of initial dose)
Level 1Continue with the same doseContinue with the same dose
Level2
  at 1st appearanceInterrupt therapy until resolution to level 0-1  100%
  at 2nd appearanceInterrupt therapy until resolution to level 0-1  75%
 at 3rd appearanceInterrupt therapy until resolution to level 0-1  50%
at 4th appearanceDiscontinue therapy completely 
Level3
  at 1st appearanceInterrupt therapy until resolution to level 0-1  75%
  at 2nd appearanceInterrupt therapy until resolution to level 0-1  50%
at 3rd appearanceDiscontinue therapy completelyNot applicable
Level4
 at 1st appearanceDiscontinue therapy completely OR, if the physician believes it is in the patient’s best interest to continue treatment, interrupt therapy until resolution to grade 0-1    50%
at 2nd appearanceDiscontinue therapy completelyNot applicable
Table 2: Change in Capecitabine Dose with Monotherapy

Hematological toxicity.

If during therapy with capecitabine a decrease in neutrophils <1.5 x 109/l and/or platelets <100 x 109/l is observed, treatment should be interrupted.

General recommendations for combination therapy

If toxicity occurs during combination therapy, the recommendations for capecitabine dose adjustment in Table 2 above and the corresponding recommendations in the instructions for use of other drugs should be followed.

At the beginning of the therapy cycle, if the administration of capecitabine or other drug(s) is expected to be delayed, all drugs should be delayed until conditions for resuming therapy with all drugs are met.

If, during the combination therapy cycle, toxicity does not appear to be related to the use of capecitabine, the therapy with capecitabine should be continued and the dose of the other drug should be adjusted according to the recommendations in the drug’s instructions for medical use.

If the other drug(s) must be discontinued, treatment with capecitabine can be continued if the requirements for resumption of therapy with capecitabine are met. These recommendations apply for all indications and all special patient groups.

Dose adjustment in special cases

Impaired liver function in patients with liver metastases

There is no need to change the starting dose in patients with liver metastases and mild to moderate hepatic dysfunction. However, these patients should be closely monitored. The use of the drug in patients with severe hepatic impairment has not been studied.

Renal dysfunction

In patients with baseline moderate renal failure (Cockroft- Gault formula, 30-50 ml/min) it is recommended to reduce initial single dose of 1250 mg/m2 by 25%, while initial single dose of 1000 mg/m2 in moderate renal failure does not need to be corrected. In patients with mild renal failure (CKD 51-80 ml/min) correction of the initial dose is not required. In severe renal failure capecitabine is contraindicated.

In case of 2nd, 3rd or 4th degree undesirable phenomenon the patient should be closely monitored and the therapy should be immediately stopped with the purpose of further dose adjustment according to the recommendations stated in Table 2. If calculated creatinine clearance decreased during therapy to less than 30 ml/min, therapy with Capecitabine should be discontinued. Recommendations to adjust the dose of the drug in moderate renal insufficiency apply to both monotherapy and combination therapy.

Children

The safety and efficacy of capecitabine in children has not been studied.

Elderly and senile patients

A correction of the initial dose during monotherapy with capecitabine is not required. However, taking into account the fact that the 3rd and 4th degree adverse events when using capecitabine both in monotherapy and in combination with other drugs developed more often in patients over 60 years old than in younger patients, close monitoring of elderly patients is recommended.

When treated in combination with docetaxel it is recommended to decrease initial dose of Capecitabine to 75% (950 mg/m2 twice a day).

When treated in combination with irinotecan in patients aged 65 or older it is recommended to reduce initial dose of Capecitabine to 800 mg/m2 twice daily.

Side effects

Digestive system: diarrhea, nausea, vomiting, stomatitis, abdominal pain, constipation, epigastric pain, dyspepsia, dry mouth, flatulence, anorexia, appetite impairment, oral candidiasis, hyperbilirubinemia, taste disorders.

Nervous system disorders: increased fatigue, weakness, pronounced somnolence, headache, paresthesia, dizziness, sleep disturbances, asthenia.

Skin and subcutaneous tissues: palmar-subcutaneous syndrome, dermatitis, dry skin, alopecia, itching, focal peeling, hyperpigmentation of the skin, skin cracking.

Other: increased lacrimation, fever, possible dehydration, weight loss, possible dyspnea, cough, pain in extremities, lower back pain, myalgia, cardiotoxic effect (most likely in patients with CHD), edema of lower extremities, anemia.

CONTRAINDICATIONS

Hypersensitivity to capecitabine and other fluoropyrimidine derivatives or any drug components.

Established DPD (dihydropyrimidine dehydrogenase) deficiency as for other fluoropyrimidines. Concomitant administration of sorivudine or its structural analogues, such as brivudine. Severe renal insufficiency (creatinine clearance below 30 ml/min).

Severe hepatic insufficiency.

Baseline neutrophil count <1.5 x 109/l and/or platelets <100 x 109/l

Pregnancy and lactation period.

Age under 18 years (effectiveness and safety of use have not been established).

Caution: in case of CHD, liver or kidney function abnormality, age over 60 years old, concomitant use with coumarin-type oral anticoagulants.

DRUG INTERACTIONS

Substrates of cytochrome Р450 2С9. Studies on the interaction of capecitabine and other drugs metabolized by 2C9 isoenzyme of cytochrome Р450 system have not been conducted. Caution should be exercised when prescribing capecitabine concomitantly with these drugs.

Coumarin anticoagulants: Capecitabine enhances the effects of indirect anticoagulants, which may lead to clotting disorders and bleeding in a few days or months from the beginning of therapy with capecitabine; in several cases such phenomena were observed a month after treatment completion. Increases the area under the concentration-time curve (AUC) of warfarin by 57% and the international normalized ratio (INR) by 91%.

Phenytoin: Capecitabine increases the plasma concentration of phenytoin, which is presumably due to inhibition of CYP2C9 isoenzyme by capecitabine. In patients taking capecitabine concomitantly with phenytoin, it is recommended to monitor phenytoin plasma concentrations regularly.

Antacids containing aluminum and magnesium hydroxide: slightly increase plasma concentrations of capecitabine and one metabolite (5′-DPCR); the three main metabolites (5′-DFUR, FU and FBAL) of capecitabine are not affected.

Calcium folinate (leucovorin) does not affect the pharmacokinetics of capecitabine and its metabolites. However, the toxic effect of capecitabine may be enhanced due to the effect of calcium folinate on the pharmacodynamics of the drug.

Sorivudine and its analogues: potentially can lead to fatal enhancement of toxicity of fluoropyrimidines due to inhibition of dihydropyrimidine dehydrogenase by sorivudine. Capecitabine should not be administered simultaneously with sorivudine or its structural analogues such as brivudin, and at least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudin) and the beginning of treatment with capecitabine should be observed.

Allopurinol: due to a possible decrease in the effectiveness of fluorouracil, concomitant administration of allopurinol with capecitabine should be avoided.

Interferon alfa: The maximum tolerated dose (MTD) of capecitabine in combination with interferon alfa-2a is 2000 mg/m2 per day, while the MTD of capecitabine is 3000 mg/m2 for monotherapy.

Radiation therapy: the MPD of capecitabine in combination with radiation therapy is 34% lower than the MPD of capecitabine used in monotherapy.

Oxaliplatin: no clinically significant difference in exposure to capecitabine or its metabolites, free platinum or total platinum was observed with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab: No clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites has been noted.

Cyclophosphamide: increases cytotoxicity of capecitabine due to increased thymidine phosphorylase activity.

Special indications

Patients taking capecitabine should be closely monitored for signs of toxicity. Most adverse events are reversible and do not require permanent withdrawal of capecitabine, although it may be necessary to reduce the dose or temporarily discontinue it. The spectrum of cardiotoxicity during treatment with capecitabine is similar to that of other fluoropyrimidines. Administration of fluoropyrimidines may be accompanied by cardiotoxicity, including ECG changes, myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death. These adverse events are more common in patients with coronary heart disease (CHD).

In rare cases during treatment with fluorouracil unexpected severe toxicity in the form of stomatitis, diarrhea, neutropenia and neurotoxicity due to insufficient activity of dihydropyrimidine dehydrogenase have been observed.

Treatment with capecitabine may cause diarrhea, sometimes severe. The average time before the first signs of grade 2-4 diarrhea was 31 days. Patients with severe diarrhea should be monitored closely, with fluid and electrolyte replacement if dehydrated. Grade 2 diarrhea is defined as increased frequency of stools up to 4-6 times per day, or stools at night; grade 3 diarrhea – as increased stools up to 7-9 times per day, or incontinence and malabsorption syndrome; grade 4 diarrhea – as increased stools up to 10 or more times per day, or blood macro-appearance in stool, or necessity of parenteral maintenance therapy. If stage 2, 3, or 4 diarrhea occurs, therapy with capecitabine should be discontinued until diarrhea has disappeared or has reduced to stage 1. For grade 3 and 4 diarrhea, treatment with capecitabine should be resumed with dose reduction. Standard anti-diarrheal medications (e.g., loperamide) are recommended. Frequency of gastrointestinal toxic events during capecitabine treatment in patients aged 60-79 years old was the same as in general population of patients. In patients aged 80 years and older reversible gastrointestinal disorders of the 3rd and 4th grades, such as diarrhea, nausea and stomatitis, developed more frequently. The drug capecitabine may cause palmar plantar syndrome (palmar plantar erythrodysesthesia, or chemotherapy-induced acral erythema), which is characterized by numbness, paresthesias, tingling, swelling, redness, scaling, blistering and severe pain syndrome. Grade 2 palm plantar syndrome is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms disrupts the patient’s daily activities. Grade 3 palm plantar syndrome is defined as moist desquamation, ulceration, blistering and severe pain in the hands and/or feet, as well as severe discomfort that makes it impossible for the patient to do any type of daily activity. If grade 2 or 3 palmar-todermal syndrome occurs, the use of capecitabine should be interrupted until the symptoms disappear or are reduced to grade 1; if grade 3 syndrome occurs, subsequent doses of capecitabine should be reduced. Patients with mild to moderate impairment of liver function due to metastases should be closely monitored. If serum bilirubin level rises >3.0 x IUF (upper limit of normal) or liver aminotransferase activity (ALT, AST) rises >2.5 x IUF, the drug capecitabine should be stopped immediately until toxicity disappears or is reduced to grade 1.

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

In patients taking coumarin (indirect) anticoagulants and capecitabine it is necessary to monitor blood clotting system regularly. Appointment of coumarin anticoagulants is possible not earlier than 1 month after termination of therapy with capecitabine because of possible hypocoagulation and bleeding development.

Safety and efficacy of capecitabine use in children has not been studied.

During therapy with capecitabine and for at least 3 months after its completion, reliable contraceptive methods should be used. If pregnancy occurs during the therapy, the patient should be aware of the potential threat to the fetus.

Influence on the ability to drive a car and operate complex mechanisms

During therapy with capecitabine it is necessary to observe caution while driving motor transport and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Overdose

Symptoms: nausea, vomiting, diarrhea, mucous membrane inflammation (mucositis), gastrointestinal tract irritation and bleeding, as well as bone marrow suppression.

Treatment: symptomatic. An antidote to capecitabine is not known.

Form of production

Capsules 500 mg №10, №20 (2×10), №30 (3×10) in a single package or №20, №30 in a bottle.

STORAGE CONDITIONS

Store in a dry place, protected from light, at a temperature not exceeding 25 ° C. Keep out of the reach of children!

Shelf life

3 years. Do not use after the expiration date.

Conditions for dispensing from pharmacies

Reliased by doctor’s prescription.

    ×