Apcebin
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT APSIBIN (APCIBIN)
Composition:
Active substance: capecitabine;
1 tablet contains 150 mg or 500 mg of capecitabine;
Excipients: sodium croscarmellose, microcrystalline cellulose (Avicel PH112), hypromellose (6 cps), anhydrous lactose DCL22, magnesium stearate, Opadry pink 03A540004 (hypromellose, titanium dioxide (E 171), talc, iron oxide red (E 172), iron oxide yellow (E 172)) – for 150 mg tablets; Opadry pink 03A540003 (hypromellose, titanium dioxide (E 171), talc, iron oxide red (E 172), iron oxide yellow (E 172)) – for 500 mg tablets.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
150 mg tablets: film-coated tablets, light peach-colored, biconvex, elongated, engraved with "150" on one side and "RDY" on the other;
500 mg tablets: film-coated tablets, peach-colored, biconvex, elongated, engraved with "500" on one side and "RDY" on the other.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01BC06.
Pharmacological Properties
Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate derivative and an oral prodrug of the cytotoxic agent fluorouracil (5-FU). Capecitabine is activated through a multi-enzyme process. The final conversion to 5-FU occurs in tumor tissue under the action of thymidine phosphorylase—an angiogenic factor overexpressed in tumors—thus minimizing systemic exposure of 5-FU to healthy tissues. 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 inhibits 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 for capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) on Day 1 and Day 14 were similar. 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 undergoes biotransformation into metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food intake reduces the rate of absorption of capecitabine but does not significantly affect 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 on Day 14, maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL were 4.47, 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 protein binding (primarily to albumin) of 54%, 10%, 62%, and 10% for capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU, 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, an enzyme primarily located in the liver and tumor tissues. Further catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, but are generally expressed at higher levels in tumors. This enzymatic biotransformation of capecitabine to 5-FU results in higher concentrations of 5-FU in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in tumor stromal cells. 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), whereas the ratio of 5-FU concentration in normal tissue to plasma concentration was 8.9 (range: 3.0–25.8, N=8). Thymidine phosphorylase activity was found to be 4 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 dihydro-5-fluorouracil (FUH₂), a less toxic metabolite. Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-β-ureidopropionic acid (FUPA). The final step is the cleavage of FUPA to α-fluoro-β-alanine (FBAL) by β-ureidopropionase, which is excreted in urine. This process is primarily mediated by DPD, whose activity limits the reaction rate. DPD deficiency may lead to increased toxicity of capecitabine.
Excretion
The elimination half-life (T½) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively.
Capecitabine and its metabolites are primarily excreted in urine. Renal excretion accounts for 95.5% of the administered dose, fecal excretion for 2.6%. The main metabolite in urine 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 and paclitaxel (Cmax and AUC), and no effect of docetaxel or paclitaxel on the pharmacokinetics of capecitabine and 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, and ALT and AST activities had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, and 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 with normal liver function. 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 the AUC of 5'-DFUR (35% increase in AUC with a 50% decrease in CrCl) and FBAL (114% increase in AUC with a 50% decrease in CrCl). FBAL is a metabolite without antiproliferative activity.
Elderly patients. Based on population pharmacokinetic analysis in patients across a wide age range (27–86 years), including 234 patients (46%) aged 65 years or older, age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. However, 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 a 36% lower Cmax and 24% lower AUC of capecitabine compared to Caucasian patients (N=22). For FBAL, Japanese patients had a 25% lower Cmax and 34% lower AUC compared to Caucasian patients. The clinical significance of this difference is unknown. No significant 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 including anthracycline agents;
- Locally advanced or metastatic breast cancer, as monotherapy after ineffective chemotherapy including 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:
a first-line treatment agent 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 for use").
- Pregnancy and breastfeeding period.
- Patients with severe leukopenia, neutropenia, or thrombocytopenia.
- Patients with severe hepatic impairment.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Recent or concomitant treatment with brivudine (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction" regarding interactions with other medicinal products).
- Contraindications to the use of any medicinal product administered in combination.
Special safety measures.
Disposal of unused and expired medicinal product: environmental contamination must be minimized. The medicinal product should not be disposed of via wastewater or household waste. A dedicated waste collection system should be used for disposal, if available.
Interaction with other medicinal products and other forms of interaction.
Interaction studies have been conducted only in adult patients.
Interaction with other medicinal products
Brivudine.
A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-fluorouracil, tegafur) has been described, resulting from inhibition of dihydropyrimidine dehydrogenase by brivudine. 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 for use"). A waiting period of at least 4 weeks should be observed 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.
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, up to one month after discontinuation of treatment. In a clinical pharmacokinetic interaction study, administration of a single 20 mg dose of S-warfarin resulted in a 57% increase in warfarin AUC and a 91% increase in INR during capecitabine treatment. Since R-warfarin metabolism was unaffected, this indicates that capecitabine inhibits the CYP2C9 isoenzyme and does not affect CYP1A2 and CYP3A4 isoenzymes. Patients receiving both capecitabine and oral anticoagulants (coumarin derivatives) require close monitoring of coagulation parameters (INR or prothrombin time) and appropriate dose adjustment of the anticoagulant.
Cytochrome P450 2C9 substrates.
Interaction studies between capecitabine and other medicinal products metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system, except for warfarin, have not been conducted. Caution is advised when co-administering capecitabine with such agents (e.g. phenytoin).
Phenytoin.
Cases of increased plasma phenytoin concentrations have been reported with concomitant use of capecitabine and phenytoin, accompanied by symptoms of phenytoin intoxication. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving both capecitabine and phenytoin.
Folinic acid/folic acid.
Folinic acid has no significant effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid affects the pharmacodynamics of capecitabine, potentially increasing drug toxicity: the maximum tolerated dose of capecitabine 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 to capecitabine regimens. This may also occur when folic acid is used 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 has been studied. 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 has been observed, potentially reducing the efficacy of 5-fluorouracil. Therefore, concomitant use of capecitabine and allopurinol should be avoided.
Interferon alpha.
The maximum tolerated dose of capecitabine 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 capecitabine is used as monotherapy.
Radiation therapy.
The maximum tolerated dose of capecitabine in monotherapy with an intermittent dosing schedule is 3000 mg/m²/day, whereas in combination with radiation therapy for rectal cancer, it is 2000 mg/m²/day when administered continuously or daily from Monday to Friday during a 6-week course of radiotherapy.
Oxaliplatin.
When capecitabine and oxaliplatin are used in combination, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum have been observed.
Bevacizumab.
Bevacizumab has no clinically significant effect on the pharmacokinetic parameters of capecitabine and its metabolites 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 available safety and efficacy data are based on administration of capecitabine with food, it is recommended to take the medicinal product with meals. Taking capecitabine with food slows the rate of absorption of the drug.
Special precautions for use.
Dose-dependent toxic effects.
Dose-dependent toxic effects are manifested as diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (also known as hand-foot skin reactions, palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema). Most adverse reactions 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 as needed in cases of dehydration. Standard anti-diarrheal agents (e.g., loperamide) should be prescribed as early as possible when indicated. Grade II diarrhea according to the National Cancer Institute of Canada (NCIC CTCAE, 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, massive diarrhea with blood, or requirement for parenteral fluid administration. Dose reduction of the drug may be necessary if diarrhea occurs (see section "Dosage and administration").
Dehydration.
Prevention of dehydration and correction of existing dehydration are essential. 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 cases 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 adjustments should be made as necessary in response to precipitating adverse events.
Hand-foot syndrome.
Hand-foot syndrome is also known as hand-foot skin reactions, palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema.
Grade I hand-foot syndrome does not interfere with daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless swelling, or erythema of palms and/or soles, and/or discomfort.
Grade II hand-foot syndrome is characterized by painful erythema and swelling of hands and/or soles; discomfort caused by these symptoms interferes with daily activities.
Grade III hand-foot syndrome is defined as moist desquamation, ulceration, blistering, acute pain in palms and/or soles, and/or severe discomfort preventing patients from working or performing daily activities. Persistent or severe hand-foot syndrome (Grade II or higher) may eventually lead to loss of fingerprints, potentially affecting patient identification.
In case of Grade II or III hand-foot 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"). Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving capecitabine and cisplatin, as it may reduce the efficacy of cisplatin. Some data suggest that dexpanthenol is effective in preventing hand-foot 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, ventricular tachycardia "Torsades de Pointes", and bradycardia), angina pectoris, myocardial infarction, heart failure, and cardiomyopathy have been reported during capecitabine therapy. Caution is advised when prescribing capecitabine to patients with clinically significant heart disease, arrhythmias, or angina.
Hypo- or hypercalcemia.
Hypo- or hypercalcemia have been reported during treatment with capecitabine. Caution is advised in patients with pre-existing hypo- or hypercalcemia.
Central or peripheral nervous system disorders.
Caution is advised when administering capecitabine to patients with disorders of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte imbalance.
Caution is advised when administering capecitabine to patients with diabetes mellitus or electrolyte imbalances, as capecitabine therapy may exacerbate these conditions.
Anticoagulants – coumarin derivatives.
In a drug interaction study with single-dose warfarin, a significant increase in mean AUC of S-warfarin (by 57%) was observed, indicating a potential interaction, likely due to inhibition of CYP2C9 isoenzyme by capecitabine. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) require close monitoring of coagulation parameters (International Normalized Ratio [INR] or prothrombin time), and anticoagulant dosage should be adjusted accordingly.
Brivudine
Brivudine must not be administered concurrently with capecitabine. Fatal cases have been reported following this drug interaction. A waiting period of at least 4 weeks must be observed 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 brivudine intake by patients receiving capecitabine, effective measures should be taken to reduce capecitabine toxicity. Immediate hospitalization is recommended. All necessary measures to prevent systemic infections and dehydration should be initiated.
Hepatic impairment.
Due to lack of safety and efficacy data in patients with hepatic impairment, capecitabine use should be carefully monitored in patients with mild to moderate hepatic dysfunction, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding three times the upper limit of normal or increases in hepatic aminotransferase activity (ALT, AST) exceeding 2.5 times the upper limit of normal occur during treatment, capecitabine should be discontinued. Capecitabine monotherapy may be resumed when bilirubin levels and hepatic transaminase activities decrease below the specified 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 reduces the catabolism rate of 5-fluorouracil. Therefore, patients with DPD deficiency are at increased risk of toxic reactions associated with fluoropyrimidine use, including stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity. Toxic reactions related to DPD deficiency typically occur during the first treatment cycle or after dose escalation.
Complete DPD deficiency
Complete DPD deficiency is rare (occurring in 0.01–0.5% of individuals of Caucasian ethnicity).
There is no established safe dose for patients with complete absence of DPD activity.
Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxic reactions and should not receive the medicinal product Apsibin.
Partial DPD deficiency
Partial DPD deficiency is estimated to occur in 3–9% of individuals of Caucasian ethnicity. Patients with partial DPD deficiency have an increased risk of developing severe and life-threatening toxic reactions. Consideration should be given to using a lower initial dose in such patients to reduce the risk of severe toxicity. DPD deficiency should be considered as a factor to be taken into account alongside other routine dose-reduction measures.
Reducing the initial dose may affect treatment efficacy.
There are insufficient data to recommend a specific dose for patients with partial DPD activity based on specific testing. It has been reported that DPYD*2A and c.1679T>G variants result in greater reduction in enzyme activity and higher risk of adverse reactions compared to other variants. The impact of dose reduction on efficacy is currently uncertain. Therefore, in the absence of severe toxic reactions, subsequent doses may be increased, provided careful patient monitoring is maintained.
Testing for DPD deficiency
Testing for phenotypic and/or genotypic parameters is recommended prior to initiating treatment with the medicinal product, despite uncertainty regarding optimal testing methodology before such therapy. Applicable clinical guidelines should be considered.
Patients with unrecognized DPD deficiency treated with capecitabine, as well as patients with negative results for specific DPYD variants, may still experience life-threatening toxicity similar to acute overdose (see section "Overdose"). In case of acute toxicity of Grade II–IV, treatment should be immediately discontinued. Permanent discontinuation of treatment should be considered based on clinical assessment of onset, duration, and severity of observed toxicity.
Genotypic characteristics of DPD deficiency
Testing for rare DPYD gene mutations before treatment initiation may identify patients with DPD deficiency. Four DPYD genotype variants – c.1905+1G>A (also known as DPYD*2A), c.1679T>G (DPYD*13), c.2846A>T, and c.1236G>A/HapB3 – may cause complete absence or reduced enzymatic activity of DPD. Other rare variants may also be associated with increased risk of severe or life-threatening toxic reactions.
Some homozygous and compound heterozygous mutations in the DPYD genetic locus (e.g., combinations of these four variants with at least one allele carrying c.1905+1G>A or c.1679T>G) may result in complete or near-complete absence of DPD enzymatic activity.
Patients with certain known heterozygous DPYD variants (including DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are at increased risk of developing severe toxic reactions when treated with fluoropyrimidines.
The frequency of heterozygous c.1905+1G>A DPYD genotype in Caucasian patients is approximately 1%, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 variants, and 0.07–0.1% for c.1679T>G.
Data on the frequency of these four DPYD variants in populations other than Caucasian are limited. Currently, these four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are considered practically absent in African (African-American) or Asian populations.
Phenotypic characteristics of DPD deficiency
For phenotypic characterization of DPD deficiency, measurement of plasma concentrations of the endogenous DPD substrate uracil (U) is recommended before treatment initiation.
Elevated uracil concentrations prior to treatment are associated with increased risk of toxic reactions. Despite the lack of clear threshold values for uracil levels defining complete or partial DPD deficiency, plasma uracil levels ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and may be associated with increased risk of toxic reactions during fluoropyrimidine therapy. Uracil levels ≥150 ng/mL should be considered indicative of complete DPD deficiency and may be associated with risk of life-threatening or fatal toxic reactions during fluoropyrimidine therapy.
Ophthalmologic complications.
Patients should be carefully 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.
The medicinal product Apsibin may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Capecitabine should 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, Lapp lactase deficiency, or glucose-galactose malabsorption.
Apsibin tablets should not be crushed or split. Contact with crushed or split tablets of Apsibin by patients or caregivers may result in adverse reactions (see section "Adverse reactions").
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 contraceptive methods should be used during treatment and for 6 months after the last dose of capecitabine.
Based on 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.
Pregnancy
The use of capecitabine during pregnancy has not been studied, but it can be assumed that the medicinal product Apsibin may be harmful to the fetus when administered during pregnancy. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Apsibin should not be used during pregnancy.
Period of breastfeeding
It is unknown whether capecitabine passes into human breast milk. Studies on the effect of capecitabine on lactation 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 mice. Because the potential harm to infants receiving breast milk is unknown, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the last dose.
Fertility
There are no data on the effect of capecitabine on fertility. In the pivotal studies of Apsibin, only women of reproductive potential and men who agreed to use acceptable methods of birth control to prevent pregnancy during and after the study period were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery.
The medicinal product has a minor or moderate influence on the ability to drive and operate machinery. Apsibin may cause dizziness, weakness, and nausea.
Method of Administration and Dosage
The medicinal product may be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Careful monitoring is recommended for all patients during the first treatment cycle.
Treatment should be discontinued in the event of disease progression or development of unacceptable toxicity.
Dosage
Apsibin tablets should be taken orally, no later than 30 minutes after food intake, swallowed whole with water. Tablets must not be crushed or split.
Special precautions for disposal and other handling instructions
Procedures for safe handling of cytotoxic medicinal products must be followed.
Monotherapy
Colorectal cancer and breast cancer: the recommended initial daily dose of capecitabine in adjuvant therapy is 2500 mg/m² body surface area, administered in 3-week cycles: taken daily for 2 weeks followed by a 1-week rest period. The total daily dose of capecitabine should be divided into two doses (1250 mg/m² body surface area each in the morning and evening). The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
Combination Therapy
Breast cancer: in combination with docetaxel, the recommended initial dose 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 once every 3 weeks as intravenous infusion). Premedication with oral corticosteroids, such as dexamethasone, should be administered prior to docetaxel administration 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 should be reduced to 800–1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, or 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 the biological agent bevacizumab to the combination regimen does not affect the initial dose of capecitabine.
Antiemetic agents and premedication to ensure adequate hydration should be administered to patients receiving capecitabine in combination with cisplatin or oxaliplatin, prior to the start of cisplatin administration, in accordance with the product instructions for cisplatin and oxaliplatin.
The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
The dose of capecitabine should be calculated based on body surface area. Tables 1 and 2 provide calculations for standard and reduced doses (see "Dose Modifications During Treatment") for initial capecitabine doses of 1250 mg/m² or 1000 mg/m².
Calculation of standard and reduced initial capecitabine dose of 1250 mg/m²
depending on body surface area
Table 1
| Body surface area (m2) |
Dose 1250 mg/m2 (twice daily) |
||||
| Full dose 1250 mg/m2 |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
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 1000 mg/m2 depending on body surface area
Table 2
| Body surface area (m²) |
Dose 1000 mg/m² (twice daily) |
||||
| Full dose 1000 mg/m² |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
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 |
Dosage adjustment during treatment
General recommendations
Toxicity symptoms during capecitabine treatment can be managed with symptomatic therapy or by modifying the drug dosage (by interrupting treatment or reducing the dose). If the dose has been reduced, it should not be increased again later.
Treatment may be continued at the same dose without interruption or dose reduction in cases of toxicity symptoms that, in the physician's opinion, are unlikely to be serious or life-threatening, such as alopecia, taste alterations, or nail changes.
Patients receiving capecitabine treatment should be advised to discontinue treatment immediately if moderate or severe toxic reactions develop. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be made up; instead, the planned treatment cycles should be continued as scheduled.
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 interrupted if, during treatment and based on unscheduled laboratory tests, neutrophil counts drop below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.
Below are dosage modification recommendations in case of toxicities according to the toxicity grading criteria. The criteria were developed by the National Cancer Institute of Canada (NCIC CTG, version 1).
Capecitabine dose reduction schedule (three-week cycle or continuous treatment)
Table 3
| Toxicity Grades* |
Dose modifications during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
|
No dose adjustment required |
No dose adjustment required |
|
||
|
Interrupt treatment until toxicity resolves to Grade 0-1 |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
Do not use |
|
||
|
Interrupt treatment until toxicity resolves to Grade 0-1 |
75 % |
|
50 % |
|
|
Discontinue the drug |
Do not use |
|
||
|
Discontinue the drug or, if continuation of treatment is considered necessary for patient benefit, interrupt therapy until toxicity resolves to Grade 0-1 |
50 % |
|
Discontinue the drug |
Not applicable |
* 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 Instructions."
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 prescribing information for 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 other agents should also be delayed until all components of the regimen can be resumed.
If toxicities occur during treatment that, in the physician's opinion, are unrelated to capecitabine, treatment with capecitabine should be continued, and the dosage of the other medicinal products in the regimen should be adjusted according to their respective prescribing information.
If discontinuation of other medicinal products in the treatment regimen becomes necessary, capecitabine may be continued once the conditions for re-initiating capecitabine are met.
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 prescribing information for the other medicinal products.
Dosage adjustments in special situations
Patients with hepatic impairment
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide dosage adjustment recommendations. 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 by Cockcroft-Gault at baseline). 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 baseline moderate renal impairment, a reduced initial dose of 75% of the standard dose (1250 mg/m²) is recommended. For patients with a baseline dose of 1000 mg/m² and moderate renal impairment, no initial dose reduction is required. No initial dose adjustment is necessary 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 and immediate discontinuation of treatment are recommended, followed by dose adjustment according to Table 3. Treatment with capecitabine should be discontinued if creatinine levels decrease to below 30 mL/min. Dosage adjustment recommendations for moderate renal impairment are the same for both monotherapy and combination therapy with capecitabine. Dosage calculation recommendations are provided in Tables 1 and 2.
Elderly patients
No initial dose adjustment is required for capecitabine monotherapy. However, treatment-related Grade III and IV adverse reactions occurred more frequently in patients aged ≥ 60 years compared to younger patients.
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.
Close monitoring of patients aged ≥ 60 years is recommended.
In treatment with the medicinal product Apsibin in combination with docetaxel, an increased frequency of Grade III and IV adverse effects due to toxicity was observed in patients over 60 years of age. For patients in this age group receiving combination therapy with capecitabine and docetaxel, a reduced initial dose of capecitabine to 75% (950 mg/m² twice daily) is recommended. If no toxicities occur during treatment with the reduced initial dose of capecitabine in combination with docetaxel in patients aged ≥ 60 years, the dose of capecitabine may be gradually increased to 1250 mg/m² twice daily. Calculations are provided in Table 2.
Children
The safety and efficacy of capecitabine in children have not been established.
Overdose
Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Management should include standard therapeutic and supportive measures to address clinical manifestations and prevent potential complications.
Adverse reactions.
Summary of safety profile
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 monotherapy with capecitabine in metastatic breast cancer, metastatic colorectal cancer, and adjuvant treatment of colon cancer is comparable.
The most common and/or clinically significant treatment-related adverse reactions were gastrointestinal disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, worsening of renal function in patients with pre-existing renal impairment, and thrombosis/embolism.
Adverse reactions considered by the investigator to be possibly, probably, or remotely related to capecitabine administration (see Table 4) were obtained from clinical studies of capecitabine monotherapy (see Table 5) and from clinical studies of capecitabine used in combination with various chemotherapy regimens for different indications.
The following frequency categories are used to describe the incidence of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.
Monotherapy with capecitabine
The adverse reactions associated with capecitabine monotherapy listed in Table 4 below are based on a pooled safety analysis from three pivotal studies involving 1900 patients (M66001, SO14695, and SO14796). Adverse reactions are assigned to the appropriate frequency category according to their overall incidence in the pooled analysis.
Summary of adverse reactions associated with capecitabine in patients receiving
capecitabine as monotherapy
Table 4
| System Organ Class |
Very Common All Grades |
Common All Grades |
Uncommon Severe and/or life-threatening (Grade III–IV) or medically significant adverse reactions |
Rare/Very rare (reactions observed during post-marketing period) |
| Infections and infestations |
|
Herpes (viral infection), nasopharyngitis, lower respiratory tract infections |
Sepsis, urinary tract infections, cellulitis (soft tissue inflammation), tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess |
|
| Benign, malignant and unspecified neoplasms |
|
|
Lipoma |
|
| Blood and lymphatic system disorders |
|
Neutropenia, |
Febrile neutropenia, |
|
| Immune system disorders |
|
|
Hypersensitivity |
Angioneurotic edema |
| Metabolism and nutrition disorders |
Anorexia |
Dehydration, weight decreased |
Diabetes mellitus, |
|
| Psychiatric disorders |
|
Insomnia, depression |
Confusion, |
|
| Nervous system disorders |
|
Headache, lethargy, dizziness, paraesthesia, taste alteration |
Aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disturbances, peripheral neuropathy |
Toxic leukoencephalopathy (very rare) |
| Eye disorders |
|
Lacrimation, conjunctivitis, eye irritation |
Decreased visual acuity, diplopia |
Lacrimal duct stenosis (rare), corneal disorders (rare), keratitis (rare), punctate keratitis (rare) |
| Ear and labyrinth disorders |
|
|
Vertigo (dizziness), ear pain |
|
| Cardiac disorders |
|
|
Unstable angina, angina pectoris, myocardial ischemia/infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations |
Ventricular fibrillation (rare), QT interval prolongation (rare), polymorphic ventricular tachycardia [Torsade de pointes] (rare), bradycardia (rare), vasospasm (rare) |
| Vascular disorders |
|
Thrombophlebitis |
Deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, flushing, peripheral cold sensation |
|
| Respiratory, thoracic and mediastinal disorders |
|
Dyspnea, epistaxis, cough, rhinorrhea |
Pulmonary arterial thromboembolism, pneumothorax, hemoptysis, bronchial asthma, dyspnea on exertion |
|
| Gastrointestinal disorders |
Diarrhea, vomiting, nausea, stomatitis, abdominal pain |
Gastrointestinal hemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth |
Intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, esophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in feces |
|
| Hepatobiliary disorders |
|
Hyperbilirubinemia, abnormal liver function biochemical tests |
Jaundice |
Liver failure (rare), cholestatic hepatitis (rare) |
| Skin and subcutaneous tissue disorders |
Palmar-plantar erythrodysesthesia syndrome* |
Rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, maculopapular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders |
Blisters, skin ulcers, rash, urticaria, photosensitivity reaction, palmar erythema, facial edema, purpura, flare-up of radiation therapy side effects |
Cutaneous lupus erythematosus (rare), severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare) |
| Musculoskeletal and connective tissue disorders |
|
Limb pain, back pain, arthralgia |
Joint swelling, bone pain, facial pain, musculoskeletal rigidity, muscle weakness |
|
| Renal and urinary disorders |
|
|
Hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine |
|
| Reproductive system and breast disorders |
|
|
Vaginal bleeding |
|
| General disorders and administration site conditions |
Increased fatigue, generalized weakness |
Hyperthermia, peripheral edema, malaise, chest pain |
Edema, fever, influenza-like symptoms, chills, body temperature increased |
|
* Based on post-marketing experience, persistent or severe hand-foot syndrome may occasionally lead to loss of fingerprints (see section "Special precautions for use").
Combination therapy
The adverse reactions listed in Table 5 below were recorded during administration of capecitabine in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 patients. These reactions are in addition to those already recorded during monotherapy and/or occurred more frequently ("very common" or "common") in any of the main clinical trials, and were included in the table only when they differed from those observed during capecitabine monotherapy or occurred more frequently than with capecitabine monotherapy (see Table 4).
Uncommon adverse reactions observed with capecitabine used in combination therapy are consistent with adverse reactions recorded during capecitabine monotherapy or monotherapy with another medicinal product in such combination (as reported in publications and/or the respective Summary of Product Characteristics for the medicinal product).
Certain adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an exacerbation of these adverse reactions with the use of Apsibin cannot be excluded.
Summary of ADRs associated with capecitabine observed in patients receiving capecitabine as part of combination therapy, in addition to reactions occurring during capecitabine monotherapy or observed more frequently than with capecitabine monotherapy.
Table 5
| System Organ Class |
Very common All grades |
Common All grades |
Uncommon/rare (post-marketing experience) |
| Infections and infestations |
|
Herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infection, rhinitis, influenza, infection*, oral mucosal herpes |
|
| Blood and lymphatic system disorders |
Neutropenia*, leukopenia*, anemia*, febrile neutropenia*, thrombocytopenia |
Bone marrow suppression, febrile neutropenia* |
|
| Immune system disorders |
|
Hypersensitivity |
|
| Metabolism and nutrition disorders |
Decreased appetite |
Hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia |
|
| Psychiatric disorders |
|
Sleep disorder, anxiety |
|
| Nervous system disorders |
Paraesthesia, dysaesthesia, peripheral neuropathy, peripheral sensory neuropathy, taste alteration, headache |
Neurotoxicity, tremor, neuralgia, hypersensitivity reaction, hypoesthesia |
|
| Eye disorders |
Increased lacrimation |
Visual disturbance, dry eye, eye pain, blurred vision, visual impairment |
|
| Ear and labyrinth disorders |
|
Tinnitus, hearing impairment |
|
| Cardiac disorders |
|
Atrial fibrillation, myocardial ischemia/infarction |
|
| Vascular disorders |
Peripheral edema, arterial hypertension, embolism* and thrombosis |
Hyperemia, arterial hypotension, hypertensive crisis, flushing, phlebitis |
|
| Respiratory, thoracic and mediastinal disorders |
Throat pain, dysaesthesia of pharynx, tonsillitis |
Hiccups, throat and larynx pain, dysphonia |
|
| Gastrointestinal disorders |
Constipation, dyspepsia |
Upper gastrointestinal bleeding, oral mucosal ulceration, gastritis, bloating, gastroesophageal reflux disease, mouth pain, dysphagia, rectal bleeding, lower abdominal pain, oral dysaesthesia, oral paraesthesia, oral hypoesthesia, abdominal discomfort |
|
| Hepatobiliary disorders |
|
Abnormal liver function tests |
|
| Skin and subcutaneous tissue disorders |
Alopecia, nail disorders |
Hyperhidrosis, erythematous rash, urticaria, night sweats |
|
| Musculoskeletal and connective tissue disorders |
Myalgia, arthralgia, limb pain |
Jaw pain, muscle spasms, tonic contraction of masticatory muscles (trismus), muscle weakness |
|
| Renal and urinary disorders |
|
Hematuria, proteinuria, decreased creatinine renal clearance, dysuria |
Acute renal failure due to dehydration (rare) |
| General disorders |
Pyrexia, weakness, asthenia*, sensitivity to increased temperature |
Mucosal inflammation, limb pain, pain, chills, chest pain, influenza-like symptoms, increased body temperature*, infusion reactions, injection site reaction, infusion site pain, injection site pain |
|
| Injury, poisoning and procedural complications |
|
Contusion |
|
* For each term, the frequency count was based on adverse reactions of all grades. For reactions marked with an asterisk (*), the frequency count was based only on Grade III–IV adverse reactions. Adverse reactions are listed according to the highest frequency observed in any of the main studies evaluating capecitabine in combination therapy regimens.
Individual 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 break, hand-foot syndrome of all severity grades occurred 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 break, hand-foot syndrome of all severity grades was observed in 22–30% of patients receiving combination therapy with capecitabine.
A meta-analysis of data from over 4700 patients in 14 clinical trials demonstrated that hand-foot syndrome of all severity grades occurred in 43% (2066) of patients receiving 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 (95% CI 201–288). Statistically significant covariates associated with an increased risk of hand-foot syndrome across all studied combinations included: higher initial dose of capecitabine (in grams), lower cumulative dose of capecitabine (0.1*kg), higher relative dose intensity during the first 6 weeks of treatment, longer duration of treatment (weeks), older patient age (per 10-year increase), female sex, and better baseline patient performance status (0 vs ≥1).
Diarrhea
Diarrhea occurred in nearly 50% of patients during treatment with capecitabine. According to the results of a meta-analysis of data from over 4700 patients in 14 clinical trials, the following covariates were statistically significantly associated with an increased risk of diarrhea across all studied combinations: higher initial dose of capecitabine (in grams), longer duration of treatment (weeks), older patient age (per 10-year increase), and female sex. Statistically significant covariates associated with a reduced risk of diarrhea included: higher cumulative dose of capecitabine (0.1*kg) and higher relative dose intensity during the first 6 weeks of treatment.
Cardiotoxicity
In addition to the listed cardiac adverse reactions, the following adverse reactions occurred at a frequency of less than 0.1% during capecitabine monotherapy, based on a pooled safety analysis of data from 949 patients enrolled in 7 clinical trials (2 Phase III and 5 Phase II trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.
Encephalopathy
In addition to the listed adverse reactions, capecitabine monotherapy, based on a pooled safety analysis of data from 7 clinical trials, was associated with encephalopathy occurring at a frequency of less than 0.1%.
Angioedema
Patients should seek immediate medical attention if any of the following symptoms occur (urgent medical treatment may be required): swelling of the face, lips, tongue, or throat, making swallowing or breathing difficult, itching, and rash. These may be signs of Quincke's edema.
Rare adverse reactions (may affect up to 1 in 1000 individuals) include: angioedema (swelling of the face, lips, tongue, or throat, itching, and rash).
Exposure to crushed or split capecitabine tablets
The following adverse reactions have been reported following exposure to crushed or split capecitabine tablets: eye 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 greater number of patients aged ≥60 years receiving combination therapy with capecitabine and docetaxel discontinued treatment earlier due to adverse reactions compared to patients aged <60 years.
A meta-analysis of data from over 4700 patients in 14 clinical trials demonstrated that, across all studied combinations, increasing age (per 10-year increase) was statistically significantly associated with an increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.
Sex
A meta-analysis of data from over 4700 patients in 14 clinical trials, with combined data from all studies, demonstrated that female sex was statistically significantly associated with an increased risk of hand-foot syndrome and diarrhea, as well as a reduced risk of neutropenia.
Patients with renal impairment
In patients with pre-treatment renal impairment receiving capecitabine monotherapy (for colorectal cancer), there was an increased frequency of Grade III and IV treatment-related adverse reactions compared to patients with normal renal function (36% in patients without renal impairment (N=268), 41% in patients with mild renal impairment (N=257), and 54% in patients with moderate renal impairment (N=59)). In patients with moderate renal impairment, dose reductions were more frequently required (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively. Premature discontinuation of treatment was also more common (21% of patients during the first two cycles) compared to 5% and 8% in patients without renal impairment and with mild renal impairment, respectively.
Shelf life. 2 years.
Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.
Packaging.
Film-coated tablets, 150 mg. 10 tablets in a blister pack.
1 or 6 blisters in a cardboard box.
Film-coated tablets, 500 mg. 10 tablets in a blister pack.
1 or 12 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Dr. Reddy’s Laboratories Ltd, FTO-7
Manufacturer’s address and location of business operations.
Units No. R1–R9, Phase III, VSE3, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India