Capecitabine accord
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPECITABINE ACCORD
Composition:
Active substance: capecitabine;
One tablet contains 150 mg of capecitabine;
Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;
Film coating: hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: light pink, elongated, biconvex, film-coated tablets with "150" engraved on one side and smooth on the other side.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites.
ATC code L01BC06.
Pharmacological Properties
Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate and an oral prodrug of the cytotoxic compound 5-fluorouracil (5-FU). Capecitabine undergoes activation via several enzymatic steps. The final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue as well as in healthy tissues of the body, although generally at low levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect when combined with docetaxel, which may be related to docetaxel-induced upregulation of thymidine phosphorylase activity.
Evidence indicates that the anabolic metabolism of 5-FU inhibits the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also suppresses RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU may cause thymidine deficiency, leading to unbalanced growth and cell death. Effects on DNA and RNA are more pronounced in cells with higher proliferative activity and greater 5-FU metabolism.
Pharmacokinetics
The pharmacokinetics of capecitabine have been characterized over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) were similar on Day 1 and Day 14. On Day 14, the AUC of 5-FU was 30–35% higher. Dose reduction of capecitabine resulted in a greater-than-proportional decrease in 5-FU exposure due to the non-linear pharmacokinetics of the active metabolite.
Absorption
After oral administration, capecitabine is rapidly and completely absorbed and subsequently undergoes biotransformation into metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR). Food intake reduces the rate of capecitabine absorption but has no significant effect on the area under the concentration-time curve (AUC) of 5'-DFUR or the subsequent metabolite 5-FU. When administered after food intake at a dose of 1250 mg/m², maximum concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL on Day 14 were 4.67, 3.05, 12.1, 0.95, and 5.46 µg/mL, respectively. Time to maximum concentration (Tmax) was 1.50, 2.00, 2.00, 2.00, and 3.34 hours, and AUC values were 7.75, 7.24, 24.6, 2.03, and 36.3 µg×h/mL, respectively.
Distribution
In vitro human plasma studies demonstrated that protein binding (primarily to albumin) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU is 54%, 10%, 62%, and 10%, respectively.
Metabolism
Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, primarily located in the liver and tumor tissues. Subsequent catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, although generally at lower levels. Further enzymatic biotransformation of capecitabine to 5-FU results in higher concentrations in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in stromal cells of the tumor. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumors to that in adjacent normal tissue was 3.2 (range: 0.9–8.0). The ratio of 5-FU concentration in tumor tissue to plasma concentration was 21.4 (range: 3.9–59.9, N=8), while the ratio of concentration in healthy tissue to plasma concentration was 8.9 (range: 3.0–25.8, N=8). Thymidine phosphorylase activity was measured to be four times higher in primary colorectal tumors compared to adjacent normal tissues. Immunohistochemical studies indicate that most thymidine phosphorylase is localized in tumor stromal cells.
Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) to form less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-β-ureidopropionic acid (FUPA). The final reaction involves cleavage of FUPA by β-ureidopropionase into α-fluoro-β-alanine (FBAL), which is excreted in urine. Dihydropyrimidine dehydrogenase activity is rate-limiting. DPD deficiency may lead to increased toxicity of capecitabine.
Elimination
The elimination half-life (T₁/₂) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. After oral administration, metabolites of capecitabine are primarily excreted in urine. Renal excretion accounts for 95.5%, fecal excretion for 2.6%. The main urinary metabolite is FBAL, representing 57% of the administered dose. Approximately 3% of the administered dose is excreted unchanged in urine.
Combination Therapy
Phase I studies showed no effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC), nor any effect of docetaxel or paclitaxel on the pharmacokinetics of capecitabine or 5'-DFUR.
Pharmacokinetics in Special Clinical Populations
A population pharmacokinetic analysis was performed in 505 patients with colorectal cancer treated with capecitabine at a dose of 1250 mg/m² twice daily. Gender, presence or absence of liver metastases at baseline, Karnofsky performance status, total bilirubin, serum albumin, ALT, and AST activity had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, or FBAL.
Patients with Liver Metastases. Pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases suggest that bioavailability of capecitabine and exposure to 5-FU may be increased compared to patients without hepatic impairment. Pharmacokinetic data in patients with severe hepatic impairment are lacking.
Patients with Renal Impairment. In oncology patients with varying degrees (mild to severe) of renal impairment, the pharmacokinetics of unchanged drug and 5-FU are independent of creatinine clearance (CrCl). However, CrCl affects AUC of 5'-DFUR (35% increase in AUC with a 50% reduction in CrCl) and FBAL (114% increase in AUC with a 50% reduction in CrCl). FBAL is a metabolite without antiproliferative activity.
Elderly Patients. Based on population pharmacokinetic analysis including patients across a wide age range (27–86 years), of whom 234 (46%) were aged 65 years or older, age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. AUC of FBAL increases with age (a 20% increase in age was associated with a 15% increase in FBAL AUC), likely due to age-related decline in renal function.
Ethnic Factors. After oral administration of 825 mg/m² capecitabine twice daily for 14 days, Japanese patients (N=18) had 36% lower Cmax and 24% lower AUC of capecitabine compared to Caucasian patients (N=22). Japanese patients also had 25% lower Cmax and 34% lower AUC of FBAL compared to Caucasian patients. The clinical significance of this difference is unknown. No substantial differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU) were observed.
Clinical characteristics.
Indications.
Breast cancer:
- Locally advanced or metastatic breast cancer, in combination with docetaxel after ineffective chemotherapy containing anthracycline agents;
- Locally advanced or metastatic breast cancer, as monotherapy after ineffective chemotherapy containing taxanes and anthracycline agents, or in the presence of contraindications to anthracycline therapy.
Colorectal cancer:
- Colon cancer, in adjuvant therapy following surgical treatment of stage III cancer (Dukes' stage C);
- Metastatic colorectal cancer.
Gastric cancer:
- First-line treatment for advanced gastric cancer, in combination with platinum-based agents.
Contraindications. Severe, including unexpected, reactions to fluoropyrimidine therapy in medical history. Hypersensitivity to capecitabine or to any component of the medicinal product, or to fluorouracil. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions"). Pregnancy or breastfeeding. Severe leukopenia, neutropenia, thrombocytopenia. Severe hepatic dysfunction. Severe renal impairment (creatinine clearance < 30 mL/min). Contraindications to any medicinal product used in combination. Recent or concomitant treatment with brivudine (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction" regarding interactions with other medicinal products).
Special safety precautions.
Procedures for safe handling of cytotoxic medicinal products must be observed.
Interaction with other medicinal products and other forms of interaction.
Interaction studies have been conducted only in adult patients.
Brivudine.
A clinically significant interaction between brivudine and fluoropyrimidines (e.g., capecitabine, 5-fluorouracil, tegafur) due to inhibition of dihydropyrimidine dehydrogenase by brivudine has been described. This interaction, which increases fluoropyrimidine toxicity, may potentially lead to fatal outcomes. Therefore, concomitant use of brivudine and capecitabine is contraindicated (see sections "Contraindications" and "Special precautions"). A waiting period of at least 4 weeks should elapse between the end of brivudine treatment and the initiation of capecitabine therapy. Brivudine treatment may be started 24 hours after the last dose of capecitabine.
Coumarin anticoagulants. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may lead to coagulation abnormalities and bleeding within several days or months after initiation of capecitabine therapy, and in some cases, within one month after discontinuation of capecitabine. In a clinical interaction study, following a single 20 mg dose of S-warfarin, capecitabine treatment increased the AUC of warfarin by 57% and the International Normalized Ratio (INR) by 91%. Since the metabolism of R-warfarin was unaffected, this indicates that capecitabine inhibits the CYP2C9 isoenzyme and does not affect CYP1A2 and CYP3A4 isoenzymes. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) should be closely monitored for coagulation parameters (INR or prothrombin time), and anticoagulant dosage should be adjusted accordingly.
Cytochrome P450 2C9 substrates. Interaction studies between capecitabine and other medicinal products metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system have not been conducted. Caution is required when prescribing capecitabine with these medicinal products (e.g., phenytoin).
Phenytoin. Isolated cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin intoxication, have been observed during concomitant administration of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving capecitabine concomitantly with phenytoin.
Folinic acid/folic acid. Folinic acid does not significantly affect the pharmacokinetics of capecitabine and its metabolites. However, folinic acid affects the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of Capecitabine Accord in monotherapy with an intermittent dosing schedule is 3000 mg/m²/day, whereas in combination with folinic acid (30 mg orally twice daily), it is only 2000 mg/m²/day.
Increased toxicity may occur when switching from 5-FU/LV regimens to capecitabine-based therapy. This may also occur when folic acid is administered to correct folic acid deficiency, due to the structural similarity between folinic and folic acid.
Antacids. The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of capecitabine was studied in patients with tumors. Antacids containing aluminum and magnesium hydroxide slightly increase plasma concentrations of capecitabine and one metabolite (5'-DFCR); they do not affect the three main metabolites (5'-DFUR, 5-FU, and FBAL) of capecitabine.
Allopurinol. An interaction between allopurinol and 5-fluorouracil, potentially reducing the efficacy of 5-fluorouracil, has been observed. Therefore, concomitant use of capecitabine and allopurinol should be avoided.
Interferon alfa. The maximum tolerated dose of Capecitabine Accord is 2000 mg/m²/day when used in combination with interferon alfa-2a (3 million IU/m²/day), compared to 3000 mg/m²/day when used as monotherapy.
Radiation therapy. The maximum tolerated dose of Capecitabine Accord in monotherapy with an intermittent dosing schedule is 3000 mg/m²/day. When combined with radiation therapy for rectal cancer, the maximum tolerated dose is 2000 mg/m²/day with either continuous radiation therapy or a daily 6-week course of radiation therapy administered Monday through Friday.
Oxaliplatin. When capecitabine is used in combination with oxaliplatin, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum were observed.
Bevacizumab. No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites was observed in the presence of oxaliplatin.
Drug–food interaction. In all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Since safety and efficacy data are based on administration of capecitabine with food, it is recommended to take capecitabine with food. Administration of Capecitabine Accord with food results in a slower absorption rate of capecitabine.
Special precautions for use.
Toxic effects dependent on dose. Dose-dependent toxic effects include diarrhea, abdominal pain, nausea, stomatitis, and palmar-plantar syndrome (synonyms: palmar-plantar erythrodysesthesia or chemotherapy-induced peripheral erythema). Most adverse effects are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary interruption of treatment may be necessary.
Diarrhea. Patients with severe diarrhea should be closely monitored and rehydrated, with electrolyte replacement if dehydration occurs. Standard anti-diarrheal agents (e.g., loperamide) should be initiated as early as possible when indicated. Diarrhea Grade II according to the National Cancer Institute of Canada (NCIC CTC, version 2) is defined as an increase in bowel movements to 4–6 times per day or nocturnal defecation; Grade III diarrhea is defined as an increase to 7–9 bowel movements per day, fecal incontinence, or malabsorption; Grade IV diarrhea is defined as ≥10 bowel movements per day or massive diarrhea with blood, or requirement for parenteral fluid administration. If necessary, the dose of the drug should be reduced (see section "Dosage and administration").
Dehydration. Dehydration must be prevented and corrected if it occurs. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. Dehydration may lead to acute renal failure, particularly in patients with pre-existing renal impairment or when capecitabine is used concomitantly with drugs known to have nephrotoxic potential. Acute renal failure due to dehydration may be potentially fatal. Treatment with capecitabine must be immediately discontinued in case of Grade II (or higher) dehydration, and dehydration must be corrected. Resumption of treatment is possible after adequate correction of dehydration and management/control of precipitating causes (see section "Dosage and administration"). Dose adjustment should be considered if precipitating adverse events occur.
Palmar-plantar syndrome (synonyms: palmar-plantar erythrodysesthesia or chemotherapy-induced peripheral erythema). Grade I palmar-plantar syndrome does not interfere with daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless edema, or erythema of palms and/or soles, and discomfort.
Grade II palmar-plantar syndrome is characterized by painful erythema and edema of hands and/or soles; discomfort caused by these symptoms interferes with the patient's daily activities.
Grade III palmar-plantar syndrome is defined as moist desquamation, ulceration, blistering, and severe pain of palms and/or soles and/or severe discomfort preventing the patient from working or performing daily activities.
Persistent or severe palmar-plantar syndrome (Grade II or higher) may eventually lead to loss of fingerprints, which may affect patient identification.
In case of development of Grade II or III palmar-plantar syndrome, capecitabine should be discontinued until symptoms resolve or improve to Grade I; upon recurrence of Grade III syndrome, the dose of capecitabine should be reduced (see section "Dosage and administration"). The use of vitamin B6 (pyridoxine) for symptomatic or secondary prophylactic treatment of palmar-plantar syndrome is not recommended in patients receiving capecitabine and cisplatin concomitantly, as it may reduce the efficacy of cisplatin.
Some data suggest that dexpanthenol is effective in preventing palmar-plantar syndrome in patients receiving capecitabine.
Cardiotoxicity. The spectrum of cardiotoxicity associated with capecitabine treatment is similar to that observed with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death, cardiac arrest, heart failure, and ECG changes (including very rare cases of QT interval prolongation). These adverse effects are more commonly observed in patients with ischemic heart disease. Cases of cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure, and cardiomyopathy have been reported with capecitabine use. Caution is required when prescribing capecitabine to patients with clinically significant cardiac disease, arrhythmias, or angina pectoris.
Hypo- or hypercalcemia. Hypo- or hypercalcemia have been reported during treatment with capecitabine.
Diseases of the central or peripheral nervous system. Caution is required when prescribing capecitabine to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte imbalance. Caution is required when prescribing capecitabine to patients with diabetes mellitus or electrolyte imbalances, as capecitabine may exacerbate these conditions.
Anticoagulants – coumarin derivatives. In a drug interaction study with single-dose warfarin, a significant increase in the mean area under the concentration-time curve (AUC) of S-warfarin (by 57%) was observed, indicating a potential interaction, likely due to inhibition of the CYP2C9 isoenzyme of the cytochrome P450 system by capecitabine. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) should be closely monitored for coagulation parameters (INR or prothrombin time), and anticoagulant dosage should be adjusted accordingly.
Brivudine.
Concomitant use of brivudine with capecitabine is contraindicated. Fatal cases have been reported following this drug interaction. A waiting period of at least 4 weeks should elapse between the end of brivudine treatment and the start of capecitabine therapy. Brivudine treatment may be initiated 24 hours after the last dose of capecitabine (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
In case of accidental ingestion of brivudine by patients receiving capecitabine, effective measures should be taken to reduce capecitabine toxicity. Immediate hospitalization is recommended. All necessary measures should be initiated to prevent systemic infections and dehydration.
Hepatic impairment. Due to lack of safety and efficacy data, capecitabine use should be carefully monitored in patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding the upper limit of normal by more than 3 times or an increase in hepatic aminotransferase activity (ALT, AST) greater than 2.5 times the upper limit of normal occurs during treatment with capecitabine, the drug should be discontinued. Capecitabine monotherapy may be resumed when bilirubin levels and hepatic transaminase activities decrease below these thresholds.
Renal impairment. The incidence of Grade III and IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min) compared to the general patient population.
Deficiency of dihydropyrimidine dehydrogenase (DPD). DPD activity is the rate-limiting factor in the catabolism of 5-fluorouracil (see section "Pharmacokinetics"); therefore, patients with DPD deficiency have an increased risk of toxicity associated with fluoropyrimidines, including stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity.
Toxicity associated with DPD deficiency typically occurs during the first treatment cycle or after dose escalation.
Complete DPD deficiency. Complete DPD deficiency is rare (0.01–0.5% of Caucasian population). Patients with complete DPD deficiency have an increased risk of life-threatening or fatal toxicity and should not receive capecitabine (see section "Contraindications").
Partial DPD deficiency. Partial DPD deficiency is estimated to occur in 3–9% of the Caucasian population. Patients with partial DPD deficiency have an increased risk of severe and potentially life-threatening toxicity. Consideration should be given to reducing the initial dose to reduce this risk. DPD deficiency should be considered as a factor to be taken into account along with other routine dose-reduction measures. Reducing the initial dose may affect treatment efficacy. Subsequent doses may be increased in the absence of severe toxicity, provided close monitoring is maintained.
Testing for DPD deficiency. Testing for DPD phenotype and/or genotype is recommended before initiating treatment with capecitabine, despite uncertainty regarding optimal testing methods prior to treatment initiation. Relevant clinical guidelines should be considered.
In patients with moderate renal impairment, elevated blood urea levels may occur, increasing the risk of false diagnosis of DPD deficiency. Capecitabine is contraindicated in patients with severe renal impairment (see section "Contraindications").
Genotypic characterization of DPD deficiency. Pre-treatment testing for rare mutations in the DPYD gene can identify patients with DPYD deficiency. Four DPYD variants—c.1905+1G>A (also known as DPYD*2A), c.1679T>G (DPYD*13), c.2846A>T, and c.1236G>A/HapB3—may lead to complete absence or reduced enzymatic activity of DPD. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.
Homozygous and compound heterozygous mutations in the DPYD gene locus (e.g., combinations of the four variants with at least one allele c.1905+1G>A or c.1679T>G) are known to cause complete or near-complete absence of DPD enzymatic activity.
Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) have an increased risk of severe toxicity during fluoropyrimidine treatment.
The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene among Caucasians is approximately 1%, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3, and 0.07–0.1% for c.1679T>G.
Data on the frequency of the four DPYD variants in races other than Caucasian are limited. Currently, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are considered practically absent in individuals of African or Asian descent.
Phenotypic characterization of DPD deficiency. Measurement of baseline plasma uracil levels—the endogenous substrate of DPD—is recommended for phenotypic characterization of DPD deficiency.
Elevated uracil concentrations prior to treatment are associated with an increased risk of toxicity. Despite uncertainty regarding threshold values defining complete or partial DPD deficiency, a DPD level in blood ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and associated with an increased risk of fluoropyrimidine toxicity. A blood uracil level ≥150 ng/mL should be considered indicative of complete absence of DPD and associated with life-threatening or fatal fluoropyrimidine toxicity. Blood urea levels in patients with renal impairment should be interpreted with caution (see "Testing for DPD deficiency" above).
Ophthalmologic complications. Patients should be closely monitored for ophthalmologic complications such as keratitis or corneal disorders, especially in those with a history of ocular disorders. Treatment of visual disturbances should be initiated when clinically indicated.
Severe skin reactions. Capecitabine treatment may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The use of capecitabine must be permanently discontinued in patients who develop severe skin reactions during treatment.
Since the drug contains lactose as an excipient, capecitabine should not be administered to patients with congenital galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.
Sodium
This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".
The tablet must not be crushed or split. Contact of patients or healthcare workers with crushed or split tablets may result in adverse reactions (see section "Adverse reactions").
Disposal of unused or expired medicinal product: Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a designated "waste collection system" if available.
Use during pregnancy or breastfeeding.
Women of reproductive potential/contraception in men and women
Women of reproductive potential should be advised to avoid pregnancy during treatment with capecitabine. If pregnancy occurs during treatment, the patient should be informed of the potential adverse effects on the fetus. Effective contraception should be used during treatment and for 6 months after the last dose of capecitabine.
Due to genotoxicity study results, male patients with partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of capecitabine.
The use of capecitabine in pregnant women has not been studied, but it can be assumed that its use during pregnancy may be harmful to the fetus. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Capecitabine should not be used during pregnancy.
It is unknown whether capecitabine passes into human breast milk. Studies on the effect of capecitabine on breast milk production or the presence of capecitabine in human breast milk have not been conducted. Significant amounts of capecitabine and its metabolites have been detected in the milk of lactating animals. Because the potential harm to breastfed infants is unknown, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the last dose.
There are no data on the effect of capecitabine on fertility. In pivotal capecitabine studies, only women of reproductive potential and men who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for a period thereafter were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery.
The drug has a minor or moderate influence on the ability to drive or operate machinery. Capecitabine may cause dizziness, weakness, and nausea.
Dosage and Administration
Capecitabine Accord should only be prescribed by a qualified physician experienced in the use of antineoplastic agents. All patients should be closely monitored during the first cycle of treatment.
Treatment should be discontinued in the event of disease progression or development of unacceptable toxicity.
Standard Dosage
Capecitabine Accord tablets should be swallowed whole, no later than 30 minutes after a meal, with water.
Capecitabine Accord tablets must not be crushed or split.
Monotherapy
Colorectal cancer and breast cancer: The recommended initial daily dose of Capecitabine Accord as adjuvant therapy is 2500 mg/m² of body surface area, administered in 3-week cycles: daily administration for 2 weeks followed by a 1-week rest period. The total daily dose of Capecitabine Accord should be divided into two doses (1250 mg/m² of body surface area in the morning and in the evening). The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
Combination Therapy
Breast cancer: The recommended initial dose of capecitabine for the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, in combination with docetaxel (75 mg/m² every 3 weeks as an intravenous infusion). Premedication with oral corticosteroids such as dexamethasone should be administered prior to docetaxel infusion, according to the docetaxel product instructions, for patients receiving the combination of capecitabine plus docetaxel.
Colorectal cancer, gastric cancer: In combination regimens, the initial dose of Capecitabine Accord should be reduced to 800–1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, or to 625 mg/m² twice daily for continuous administration. When combined with irinotecan (200 mg/m² on day 1), the recommended initial dose is 800 mg/m² twice daily for 2 weeks followed by a 1-week rest period. The addition of bevacizumab to the combination regimen does not affect the initial dose of Capecitabine Accord. The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
Antiemetics and premedication to ensure adequate hydration should be administered to patients receiving Capecitabine Accord in combination with cisplatin or oxaliplatin, prior to cisplatin or oxaliplatin administration, according to the product instructions for cisplatin and oxaliplatin.
The dose of Capecitabine Accord should be calculated based on body surface area. Tables 1 and 2 provide dosage calculations for standard and reduced doses (see "Dose Modifications During Treatment") for initial doses of Capecitabine Accord of 1250 mg/m² or 1000 mg/m².
Calculation of standard and reduced initial doses of Capecitabine Accord
1250 mg/m² according to body surface area
Table 1
| Dose 1250 mg/m2 (twice daily) |
|||||
| Body surface area, m2 |
Full dose 1250 mg/m2 |
Number of tablets |
Reduced dose (75%) 950 mg/m2 |
Reduced dose (50%) 625 mg/m2 |
|
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤1.26 |
1500 |
- |
3 |
1150 |
800 |
| 1.27–1.38 |
1650 |
1 |
3 |
1300 |
800 |
| 1.39–1.52 |
1800 |
2 |
3 |
1450 |
950 |
| 1.53–1.66 |
2000 |
- |
4 |
1500 |
1000 |
| 1.67–1.78 |
2150 |
1 |
4 |
1650 |
1000 |
| 1.79–1.92 |
2300 |
2 |
4 |
1800 |
1150 |
| 1.93–2.06 |
2500 |
- |
5 |
1950 |
1300 |
| 2.07–2.18 |
2650 |
1 |
5 |
2000 |
1300 |
| ≥2.19 |
2800 |
2 |
5 |
2150 |
1450 |
Calculation of the standard and reduced initial dose of Capecitabine Accord
1000 mg/m2 depending on body surface area
Table 2
| Dose 1000 mg/m² (twice daily) |
|||||
| Body surface area, m² |
Full dose 1000 mg/m² |
Number of tablets |
Reduced dose (75%) 750 mg/m² |
Reduced dose (50%) 500 mg/m² |
|
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤1.26 |
1150 |
1 |
2 |
800 |
600 |
| 1.27–1.38 |
1300 |
2 |
2 |
1000 |
600 |
| 1.39–1.52 |
1450 |
3 |
2 |
1100 |
750 |
| 1.53–1.66 |
1600 |
4 |
2 |
1200 |
800 |
| 1.67–1.78 |
1750 |
5 |
2 |
1300 |
800 |
| 1.79–1.92 |
1800 |
2 |
3 |
1400 |
900 |
| 1.93–2.06 |
2000 |
- |
4 |
1500 |
1000 |
| 2.07–2.18 |
2150 |
1 |
4 |
1600 |
1050 |
| ≥2.19 |
2300 |
2 |
4 |
1750 |
1100 |
Dose Adjustment During Treatment
General Recommendations
Toxicity symptoms during treatment with Capecitabine Accord can be managed with symptomatic therapy and/or by adjusting the dose of Capecitabine Accord (by interrupting or reducing the dose). If the dose has been reduced, it should not be increased again later.
Treatment may continue at the same dose without interruption or dose reduction in cases of toxicity symptoms that, in the physician’s opinion, are unlikely to become serious or life-threatening, such as alopecia, altered taste sensation, or nail changes.
Patients receiving Capecitabine Accord should be advised to discontinue treatment in case of moderate or severe toxic reactions. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be made up.
Hematological Toxicity
Capecitabine therapy should not be initiated in patients with baseline neutrophil counts <1.5 × 10⁹/L and/or platelet counts <100 × 10⁹/L. Treatment should be suspended if, during unplanned laboratory testing, neutrophil counts fall below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.
Below are dose modification recommendations for toxicity events according to toxicity grading criteria established by the Canadian National Cancer Institute (NCIC CTG, version 1).
Dose reduction scheme for Capecitabine Accord (three-week cycle or continuous treatment)
Table 3
| Toxicity grade according to NOIK * |
Dose modifications during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
| Grade I |
Do not modify dose |
Do not modify dose |
| Grade II |
||
|
Discontinue therapy until signs of toxicity resolve to grade 0–I |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
Do not administer |
| Grade III |
||
|
Discontinue therapy until signs of toxicity resolve to grade 0–I |
75 % |
|
50 % |
|
|
Discontinue the drug |
Do not administer |
| Grade IV |
||
|
Discontinue the drug or, if continuation of treatment is in the patient's best interest, discontinue therapy until signs of toxicity resolve to grade 0–I. |
50 % |
|
Discontinue the drug |
Do not administer |
*according to the National Cancer Institute of Canada's Common Toxicity Criteria (NCIC CTG), version 1, or the National Cancer Institute of the United States' Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. For information on hand-foot syndrome and hyperbilirubinemia, see section "Special precautions".
Dosage modifications in the event of toxicity during a 3-week cycle of capecitabine in combination with other medicinal products
Dosage adjustments due to toxicity during a 3-week cycle of capecitabine in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
At the beginning of treatment, if a delay in therapy with capecitabine or another medicinal product is required, the administration of the other agents should also be postponed until the time when all components of the regimen can be administered.
If toxicities occur during treatment that, in the physician's opinion, are not related to capecitabine, therapy with capecitabine should be continued, and dosage adjustments of the other medicinal products in the regimen should be made according to their respective instructions for medical use.
If discontinuation of other components of the treatment regimen is necessary, capecitabine may be continued once conditions are met for reinitiating capecitabine therapy.
These recommendations apply to all indications and all patient groups.
Dosage modifications in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products
Dosage adjustments due to toxicity during continuous administration of capecitabine in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
Dose adjustments in special situations
Patients with hepatic impairment
There are insufficient safety and efficacy data in patients with hepatic impairment to provide recommendations for dose adjustment. There is no information available on hepatic impairment due to cirrhosis or hepatitis.
Patients with renal impairment
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min at baseline according to the Cockcroft-Gault formula). The incidence of grade III or IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min at baseline) compared to the general population. For patients with moderate renal impairment at baseline, a reduced starting dose of 75% of the standard dose (1250 mg/m²) is recommended. Patients with moderate renal impairment at baseline do not require a reduced starting dose of 1000 mg/m². No dose adjustment of the starting dose is required for patients with mild renal impairment (creatinine clearance 51–80 mL/min).
In the event of grade II, III, or IV adverse events, careful monitoring, immediate discontinuation of treatment, and dose modification according to Table 3 are recommended. If creatinine clearance decreases to less than 30 mL/min, treatment with capecitabine should be discontinued. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy and combination therapy with capecitabine.
Elderly patients
No adjustment of the initial dose is required for monotherapy with capecitabine. However, treatment-related grade III and IV adverse reactions occurred more frequently in patients aged ≥60 years compared to younger patients.
Careful monitoring of patients aged ≥60 years is recommended. When capecitabine is used in combination with other medicinal products in elderly patients (≥65 years), a higher incidence of grade III and IV adverse effects leading to treatment discontinuation has been observed compared to younger patients.
In treatment with capecitabine in combination with docetaxel, an increased incidence of grade III and IV toxic adverse effects has been observed in patients aged 60 years and older. For patients in this age group receiving combination therapy with capecitabine and docetaxel, a reduced starting dose of capecitabine to 75% (950 mg/m² twice daily) is recommended.
If no toxicities occur during treatment with the reduced starting dose of capecitabine in combination with docetaxel in patients aged ≥60 years, the capecitabine dose may be gradually increased to 1250 mg/m² twice daily.
Children
The safety and efficacy of capecitabine in children have not been established.
Overdose. Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Management should include standard supportive and therapeutic measures to manage clinical manifestations and prevent potential complications.
Adverse Reactions
The overall safety profile of capecitabine is based on data from more than 3000 patients who received treatment with capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications. The safety profile of capecitabine monotherapy in metastatic breast cancer, metastatic colorectal cancer, and adjuvant treatment of colorectal cancer is comparable.
The most common and/or clinically significant treatment-related adverse reactions included gastrointestinal disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, progression of renal impairment in patients with pre-existing renal insufficiency, and thrombosis/embolism.
Adverse reactions considered by the investigator as possibly, probably, or remotely related to capecitabine use were observed during clinical trials of capecitabine monotherapy (in adjuvant treatment of colorectal cancer, treatment of metastatic colorectal cancer, and metastatic breast cancer) and during clinical trials of capecitabine in combination with various chemotherapy regimens. The following frequency categories were used to classify adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Monotherapy
Below are adverse reactions associated with capecitabine monotherapy, based on a pooled analysis of safety data from three pivotal trials. Adverse reactions are categorized according to their overall frequency in the pooled analysis.
Infections and infestations: common – herpes (viral infection), nasopharyngitis, lower respiratory tract infections; uncommon – sepsis, urinary tract infections, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess.
Benign, malignant and unspecified neoplasms: uncommon – lipoma.
Blood and lymphatic system disorders: common – anemia, neutropenia; uncommon – febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased MCH/increased prothrombin time.
Immune system disorders: uncommon – hypersensitivity reactions; rare – angioneurotic edema.
Metabolism and nutrition disorders: very common – anorexia; common – dehydration, weight decreased; uncommon – diabetes mellitus, hypokalemia, appetite disorders, malnutrition, hypertriglyceridemia.
Psychiatric disorders: common – insomnia, depression; uncommon – confusion, acute anxiety with panic reaction, depressed mood, decreased libido.
Nervous system disorders: common – headache, drowsiness, dizziness, paresthesia, taste alteration; uncommon – aphasia, memory impairment, ataxia, syncope, sensory disturbance, peripheral neuropathy; very rare – toxic leukoencephalopathy.
Eye disorders: common – lacrimation, conjunctivitis, eye irritation; uncommon – decreased visual acuity, diplopia; rare – lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis.
Ear and labyrinth disorders: uncommon – vertigo, ear pain.
Cardiac disorders: uncommon – unstable angina, angina pectoris, myocardial ischemia/infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; rare – ventricular fibrillation, QT interval prolongation, torsades de pointes ventricular tachycardia, bradycardia, vasospasm.
Vascular disorders: common – thrombophlebitis; uncommon – deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, flushing, peripheral cold sensation.
Respiratory, thoracic and mediastinal disorders: common – dyspnea, epistaxis, cough, rhinorrhea; uncommon – pulmonary embolism, pneumothorax, hemoptysis, asthma, dyspnea on exertion.
Gastrointestinal disorders: very common – diarrhea, vomiting, nausea, stomatitis, abdominal pain; common – gastrointestinal hemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth; uncommon – intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, esophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, fecal blood.
Hepatobiliary disorders: common – hyperbilirubinemia, abnormal liver function tests; uncommon – jaundice; rare – hepatic failure and cholestatic hepatitis.
Skin and subcutaneous tissue disorders: very common – hand-foot syndrome (based on post-marketing experience, persistent or severe hand-foot erythrodysesthesia may eventually lead to loss of fingerprints (see section "Special precautions")); common – rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, maculopapular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders; uncommon – skin blistering and ulceration, rash, urticaria, photosensitivity reactions, erythema of palms, facial edema, purpura, reversible radiation recall syndrome; rare – cutaneous lupus erythematosus; very rare – severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: common – limb pain, back pain, arthralgia; uncommon – joint swelling, bone pain, facial pain, musculoskeletal rigidity, muscle weakness.
Renal and urinary disorders: uncommon – hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine.
Reproductive system and breast disorders: uncommon – vaginal bleeding.
General disorders: very common – fatigue, asthenia; common – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, fever, influenza-like symptoms, chills, increased body temperature.
In this context, "common adverse reactions" in the "Monotherapy" section refer to severe adverse reactions and/or life-threatening (Grade III-IV) or medically significant adverse reactions.
Combination Therapy
Below are adverse reactions observed during the use of capecitabine in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 patients, in addition to those already reported with monotherapy and/or observed with higher frequency. Some adverse reactions are commonly associated with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an increased risk of these adverse events with capecitabine cannot be excluded.
Infections and infestations: common – herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections*, oral herpes.
Blood and lymphatic system disorders: very common – neutropenia*, leukopenia*, febrile fever*, thrombocytopenia*, anemia*; common – bone marrow suppression, febrile neutropenia.
Immune system disorders: common – hypersensitivity reactions.
Metabolism and nutrition disorders: very common – decreased appetite; common – hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia.
Psychiatric disorders: common – sleep disorders, restlessness.
Nervous system disorders: very common – paresthesia and dysesthesia, peripheral neuropathy, peripheral sensory neuropathy, taste alteration, headache; common – neurotoxicity, tremor, neuralgia, hypersensitivity reactions, hypoesthesia.
Eye disorders: very common – lacrimation; common – visual disturbance, dry eyes, eye pain, decreased visual acuity, blurred vision.
Ear and labyrinth disorders: uncommon – tinnitus, hearing decreased.
Cardiac disorders: common – atrial fibrillation, myocardial ischemia/infarction.
Vascular disorders: very common – lower limb edema, arterial hypertension, thrombosis/embolism*; common – flushing, arterial hypotension, hypertensive crisis, hyperemia, phlebitis.
Respiratory, thoracic and mediastinal disorders: very common – angina, pharyngeal dysesthesia; common – hiccups, pharyngolaryngeal pain, dysphonia.
Gastrointestinal disorders: very common – constipation, dyspepsia; common – upper gastrointestinal hemorrhage, oral mucosal ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, mouth pain, dysphagia, rectal bleeding, lower abdominal pain, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort.
Hepatobiliary disorders: common – abnormal liver function tests.
Skin and subcutaneous tissue disorders: very common – alopecia, nail disorders; common – hyperhidrosis, erythematous rash, urticaria, night sweats.
Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia, limb pain; common – jaw pain, back pain, muscle spasms, trismus, muscle weakness.
Renal and urinary disorders: common – hematuria, proteinuria, decreased renal creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special precautions").
General disorders: very common – increased body temperature, weakness, drowsiness*, sensitivity to heat, asthenia; common – mucositis, limb pain, pain, chills, chest pain, influenza-like symptoms, fever*, infusion reactions, injection site reactions, infusion site pain, injection site pain.
Injury, poisoning and procedural complications: common – contusion.
* Frequency includes all grades of severity, except for adverse reactions marked with "*", which include only Grade III-IV adverse reactions.
Specific Adverse Reactions
Hand-Foot Syndrome
When capecitabine was administered at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, hand-foot syndrome of all grades was reported in 53–60% of patients in monotherapy trials (adjuvant treatment of colorectal cancer, treatment of metastatic colorectal cancer, treatment of breast cancer) and in 63% of patients with metastatic breast cancer in the capecitabine/docetaxel treatment group. When capecitabine was administered at a dose of 1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, hand-foot syndrome of all grades was observed in 22–30% of patients receiving combination therapy with capecitabine.
A meta-analysis of data from more than 4700 patients in 14 clinical trials showed that hand-foot syndrome of all grades occurred in 43% (2066) of patients treated with capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications (colorectal cancer, gastric cancer, breast cancer), with a median onset of 239 days after initiation of capecitabine treatment. Statistically significant covariates associated with an increased risk of hand-foot syndrome across all studied combinations included: higher initial capecitabine dose (in grams), lower cumulative capecitabine dose (0.1 *kg), higher relative dose intensity in the first 6 weeks of treatment, longer duration of treatment (weeks), older age (per 10-year increase), female sex, and better baseline performance status (0 vs ≥1).
Diarrhea
Diarrhea occurred in nearly 50% of patients during capecitabine treatment. According to a meta-analysis of 14 clinical trials, statistically significant covariates associated with an increased risk of diarrhea across all studied combinations included: higher initial capecitabine dose (in grams), longer duration of treatment (weeks), older age (per 10-year increase), and female sex. Covariates associated with a decreased risk of diarrhea included higher cumulative capecitabine dose (0.1 *kg) and higher relative dose intensity in the first 6 weeks of treatment.
Cardiotoxicity
In addition to the above-mentioned cardiac adverse reactions, the following adverse reactions were reported with a frequency of less than 0.1% during capecitabine monotherapy, based on a pooled safety analysis of data from 949 patients in 7 clinical trials: cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.
Encephalopathy
In addition to the adverse reactions listed above, capecitabine monotherapy, based on a pooled safety analysis of data from 7 clinical trials, was associated with encephalopathy at a frequency of less than 0.1%.
Exposure to crushed or broken tablets of Capcitabine Accord
The following adverse reactions have been reported following exposure to crushed or broken tablets of Capcitabine Accord: eye mucous membrane irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, stomach irritation, and vomiting.
Adverse Reactions in Special Patient Populations
Elderly Patients: In patients aged ≥60 years receiving capecitabine monotherapy or combination therapy with capecitabine and docetaxel, there was an increased risk of Grade III and IV adverse reactions and serious treatment-related adverse reactions compared to patients aged <60 years. A higher proportion of patients aged ≥60 years discontinued treatment earlier due to adverse reactions compared to those aged <60 years in the combination therapy group.
Studies have shown that with increasing age (per 10-year increase), there was a statistically significant increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.
Sex
A meta-analysis of data from more than 4700 patients in 14 clinical trials demonstrated that female sex was statistically significantly associated with an increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.
Patients with Renal Impairment
In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), there was a higher frequency of Grade III and IV treatment-related adverse reactions compared to patients with normal renal function (36% in patients without renal impairment, 41% in patients with mild renal impairment, and 54% in patients with moderate renal impairment). Patients with moderate renal impairment more frequently required dose reductions (44%) compared to 33% and 32% of patients without renal impairment and with mild renal impairment, respectively, and more frequently discontinued treatment prematurely (21% during the first two cycles) compared to 5% and 8% in patients with normal renal function and mild renal impairment, respectively.
Reporting of Suspected Adverse Reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of the reach of children.
Packaging. 10 tablets in a blister. 3, 6, or 12 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Accord Healthcare Polska Sp. z o.o. Importer's Warehouse / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.
Manufacturer's address and place of business.
ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.
Marketing Authorization Holder. Accord Healthcare S.L.U.
Inquiries regarding poor quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected].
Address of Marketing Authorization Holder. World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain / World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.