Capcitabine shilpa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAPECITABIN SHILPA (CAPECITABIN SHILPA)
Composition:
Active substance: capecitabine;
One film-coated tablet contains 150 mg or 500 mg of capecitabine;
Excipients: anhydrous lactose, microcrystalline cellulose (Avicel PH 101), sodium croscarmellose, hypromellose, microcrystalline cellulose (Avicel PH 102), magnesium stearate;
Film coating: for 150 mg tablets – Opadry Pink 03A84408 (hypromellose, talc, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172)); for 500 mg tablets – Opadry Pink 03A84598 (hypromellose, talc, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: 150 mg tablets are light pink, capsule-shaped, biconvex, film-coated tablets, embossed with "CAP" on one side and "150" on the other;
500 mg tablets are dark pink, capsule-shaped, biconvex, film-coated tablets, embossed with "CAP" on one side and "500" on the other.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues.
ATC code L01B C06.
Pharmacological Properties
Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate and an oral prodrug of the cytotoxic agent 5-fluorouracil (5-FU). Capecitabine undergoes activation through a multi-enzyme process. The final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue as well as in normal body tissues, although generally at low levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination 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 of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also inhibits ribonucleic acid (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 were evaluated 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) 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 subsequently biotransformed into the 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. Following administration at a dose of 1250 mg/m² after food intake on Day 14, maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL 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 studies in human plasma demonstrated protein binding (primarily to albumin) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU at 54%, 10%, 62%, and 10%, respectively.
Metabolism
Capecitabine is metabolized in the liver by carboxylesterase to the intermediate 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 this catalytic activation are present in both tumor and normal tissues, although generally at lower levels. This enzymatic biotransformation leads to 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 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 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 dihydro-5-fluorouracil (FUH2), a less toxic compound. Dihydropyrimidinase cleaves the pyrimidine ring to produce 5-fluoro-ureidopropionic acid (FUPA). The final step is the cleavage of FUPA by β-ureidopropionase to α-fluoro-β-alanine (FBAL), which is excreted in urine. DPD 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. Capecitabine and its metabolites are primarily excreted in urine. Renal excretion accounts for 95.5% of the dose, 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
No effect of capecitabine on the pharmacokinetics of docetaxel and paclitaxel (Cmax and AUC), or of docetaxel and paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR, was observed.
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. Sex, presence or absence of liver metastases at baseline, Karnofsky performance status, total bilirubin, serum albumin, ALT, and AST levels 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 without hepatic dysfunction. 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 not dependent on creatinine clearance (CrCl). However, CrCl affects the AUC of 5'-DFUR (a 50% reduction in CrCl leads to a 35% increase in AUC) and FBAL (a 50% reduction in CrCl leads to a 114% increase in AUC). 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 is associated with a 15% increase in FBAL AUC), likely due to age-related changes in renal function.
Ethnic Factors. After oral administration of 825 mg/m² capecitabine twice daily for 14 days in Japanese patients (N=18), Cmax of capecitabine was 36% lower and AUC 24% lower 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 substantial differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU) were observed.
Clinical characteristics.
Indications.
Colorectal cancer:
- adjuvant treatment of colorectal cancer following surgical resection of stage III (Dukes' stage C) colon cancer;
- metastatic colorectal cancer.
Gastric cancer:
- first-line treatment of advanced gastric cancer in combination with platinum-based agents.
Breast cancer:
- locally advanced or metastatic breast cancer in combination with docetaxel after failure of anthracycline-containing chemotherapy;
- locally advanced or metastatic breast cancer as monotherapy after failure of both taxane- and anthracycline-containing chemotherapy, or when anthracycline therapy is contraindicated.
Contraindications.
Severe, including unexpected, reactions to prior fluoropyrimidine therapy. Hypersensitivity to capecitabine or to any component of the product, or to fluorouracil. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions").
Pregnancy or breastfeeding.
Severe leukopenia, neutropenia, or thrombocytopenia.
Severe hepatic dysfunction.
Severe renal impairment (creatinine clearance < 30 mL/min).
Concomitant administration of sorivudine or its structural analogs such as brivudine.
Contraindications to any concomitantly administered medicinal product.
Interaction with other medicinal products and other forms of interaction.
Interaction studies have been conducted only in adult patients.
Interaction with other medicinal products
Cytochrome P450 2C9 substrates.
Interaction studies between capecitabine and other drugs metabolized by the cytochrome P450 2C9 isoenzyme, except warfarin, have not been conducted. Caution is advised when administering capecitabine with these drugs (e.g., phenytoin).
Coumarin anticoagulants.
Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may lead to coagulation abnormalities and bleeding, occurring several days or months after initiation of capecitabine therapy, and in some cases within one month after discontinuation of capecitabine. Clinical study data show that following a single 20 mg dose of S-warfarin, administration of capecitabine increased the AUC of warfarin by 57% and the AUC of its active metabolite MHO by 91%. Since the metabolism of R-warfarin was unaffected, this indicates that capecitabine inhibits the 2C9 isoenzyme and does not affect the 1A2 and 3A4 isoenzymes. In patients receiving capecitabine concomitantly with oral coumarin-derived anticoagulants, careful monitoring of coagulation parameters (international normalized ratio or prothrombin time) and dose adjustment of the anticoagulant are required.
Phenytoin.
Cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin toxicity, have been reported with concomitant use of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving capecitabine together with 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 Capcitabine Shilpa, potentially increasing capecitabine 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-based regimens. This may also occur when folic acid is administered to correct folic acid deficiency due to the similarity between folinic and folic acid.
Sorivudine and its analogs.
A clinically significant interaction between sorivudine and 5-FU has been reported in the literature, due to sorivudine's inhibition of dihydropyrimidine dehydrogenase. This interaction may potentially lead to fatal enhancement of fluoropyrimidine toxicity. Therefore, Capcitabine Shilpa must not be administered concomitantly with sorivudine or its structural analogs such as brivudine (see section "Contraindications"). The interval between discontinuation of sorivudine or its analogs and initiation of capecitabine therapy should be at least 4 weeks.
Antacids.
The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of capecitabine has been studied. Such antacids slightly increase plasma concentrations of capecitabine and one of its metabolites (5'-DFCR), but have no effect on 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 Capcitabine Shilpa is 2000 mg/m²/day when administered in combination with interferon alpha-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 as monotherapy with an intermittent dosing schedule is 3000 mg/m²/day. When combined with radiation therapy for rectal cancer, it is 2000 mg/m²/day, either with continuous radiation therapy or a daily 6-week course administered Monday through Friday.
Oxaliplatin.
When capecitabine is administered in combination with oxaliplatin, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum have been observed.
Bevacizumab.
No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites has been observed in the presence of oxaliplatin.
Drug–food interaction
Since available safety and efficacy data are based on administration of capecitabine with food, it is recommended to take Capcitabine Shilpa with food. Taking Capcitabine Shilpa with food slows the absorption rate of capecitabine.
Special precautions for use.
Toxic effects dependent on dose
Toxic effects dependent on dose are manifested as diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (hand-foot skin reactions, palmar-plantar erythrodysesthesia). 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 managed with rehydration and electrolyte replacement in case of dehydration. Standard anti-diarrheal medications (e.g., loperamide) may be administered. Grade II diarrhea according to the National Cancer Institute of Canada (NCIC CTC, version 2) criteria is defined as an increase in the number of bowel movements to 4–6 per day or nocturnal defecation; Grade III diarrhea is defined as an increase in bowel movements to 7–9 per day or fecal incontinence and malabsorption. Grade IV diarrhea is defined as an increase in bowel movements ≥10 per day or massive diarrhea with blood, or the need for parenteral fluid administration. If necessary, the dose of the drug should be reduced (see section "Dosage and administration").
Dehydration
Development of dehydration should be prevented, and dehydration, if it occurs, should be corrected promptly. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. Dehydration may lead to acute renal failure, especially 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. In case of Grade II (or higher) dehydration, capecitabine therapy should be immediately discontinued and dehydration 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 performed as needed in case of precipitating adverse events.
Hand-foot syndrome
Hand-foot syndrome, also known as hand-foot skin reactions or palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema, is characterized as follows:
Grade I hand-foot syndrome does not interfere with the patient’s daily activities and manifests as 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 the patient’s daily activities.
Grade III hand-foot syndrome is defined as moist desquamation, ulcer formation, blistering, and severe pain in palms and/or soles, and/or severe discomfort preventing the patient from working or performing daily activities. Persistent or severe hand-foot 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 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. The use of vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving capecitabine concomitantly with cisplatin, as published data suggest this may reduce the efficacy of cisplatin. Some data suggest that dexpanthenol may be 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, torsades de pointes, bradycardia), angina, myocardial infarction, heart failure, and cardiomyopathy have been reported during capecitabine treatment. Caution should be exercised 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.
Diseases of the central or peripheral nervous system
Caution should be exercised when administering capecitabine to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte imbalances
Caution should be exercised when administering capecitabine to patients with diabetes mellitus or electrolyte imbalances, as treatment with capecitabine may worsen 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 cytochrome P450 isoenzyme 2C9 by capecitabine. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) should be closely monitored for coagulation parameters (international normalized ratio or prothrombin time), and the anticoagulant dose should be adjusted accordingly.
Hepatic impairment
Due to lack of safety and efficacy data in patients with hepatic impairment, the use of capecitabine should be carefully monitored in patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding three times the upper limit of normal or an increase in hepatic aminotransferase activity (ALT, AST) more than 2.5 times the upper limit of normal occurs during treatment with capecitabine, the drug should be temporarily discontinued. Monotherapy with capecitabine 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)
Occasionally, unexpected severe toxicity (e.g., stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity) associated with 5-fluorouracil (5-FU) has been observed due to DPD enzyme deficiency.
Patients with low or absent DPD activity, the enzyme responsible for catabolism of fluorouracil, are at increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely determined, it is known that patients with certain homozygous or some combined heterozygous mutations in the DPYD gene locus, which may result in complete or near-complete absence of DPD enzyme activity (as determined by laboratory assays), are at the highest risk of life-threatening or fatal toxicity, and capecitabine therapy should not be administered to such patients (see section "Contraindications"). For patients with complete absence of DPD activity, there is no dose with proven safety.
Patients with partial DPD deficiency (e.g., heterozygous mutations in the DPYD gene), for whom the benefits of capecitabine are considered to outweigh the risks (considering the feasibility of alternative non-fluoropyrimidine-based chemotherapy regimens), should be treated with extreme caution and require frequent monitoring with dose adjustments based on toxicity. There are insufficient data to recommend a specific dose for patients with partial DPD activity based on specific testing.
Patients with unrecognized DPD deficiency treated with capecitabine may experience life-threatening toxicity similar to acute overdose (see section "Overdose"). In case of acute Grade II–IV toxicity, treatment should be immediately discontinued. Permanent discontinuation of treatment should be considered based on clinical assessment of the onset, duration, and severity of observed toxicity.
Ophthalmological complications
Patients should be closely monitored for ophthalmological 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 use of capecitabine 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 anhydrous lactose as an excipient, capecitabine should not be administered to patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Disposal of unused or expired medication: Environmental contamination should be minimized. The drug should not be disposed of via wastewater or household waste. Disposal should be performed using a designated "waste collection system" if available.
Pancreatitis
Cases of pancreatitis following capecitabine administration have been reported in the literature.
Use during pregnancy or breastfeeding
Women of childbearing potential/contraception in men and women
Women of childbearing 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.
Pregnancy
The use of capecitabine in pregnant women has not been studied; however, it can be assumed that administration of capecitabine 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.
Breastfeeding
It is unknown whether capecitabine passes into human breast milk. However, significant levels of capecitabine and its metabolites have been detected in the milk of lactating mice. Therefore, breastfeeding should be discontinued during treatment with capecitabine.
Fertility
There are no data on the effect of capecitabine on fertility. Effects on fertility have been 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.
Method of Administration and Dosage
The medicinal product Capecitabine Shilpa should be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Careful monitoring of all patients is recommended during the first treatment cycle.
Treatment should be discontinued if disease progression or unacceptable toxicity occurs.
The drug should be taken orally, no later than 30 minutes after a meal, with water.
Monotherapy
Colorectal cancer and breast cancer. The recommended initial daily dose of Capecitabine Shilpa as adjuvant therapy is 2,500 mg/m² body surface area, administered in 3-week cycles: daily administration for 2 weeks followed by a 1-week treatment-free interval. The total daily dose of capecitabine should be divided into two doses (1,250 mg/m² body surface area 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 1,250 mg/m² twice daily for 2 weeks followed by a 1-week treatment-free interval (in combination with docetaxel 75 mg/m² administered once every 3 weeks as an intravenous infusion). Premedication with oral corticosteroids such as dexamethasone should be administered prior to docetaxel infusion, in accordance with the docetaxel product information, for patients receiving the combination of capecitabine plus docetaxel.
Colorectal cancer, colorectal carcinoma, gastric cancer. In combination regimens, the initial dose of capecitabine should be reduced to 800–1,000 mg/m² twice daily for 2 weeks followed by a 1-week treatment-free interval, 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 treatment-free interval. The addition of bevacizumab to the combination regimen does not affect the initial dose of capecitabine.
Anti-emetic agents and premedication to ensure adequate hydration should be administered to patients receiving capecitabine in combination with cisplatin or oxaliplatin, prior to cisplatin administration, in accordance with the product information 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 Shilpa should be calculated based on body surface area.
Tables 1 and 2 provide calculations for the standard and reduced (see "Dose Modification During Treatment") initial doses of Capecitabine Shilpa at 1,250 mg/m² or 1,000 mg/m².
Table 1
Calculations of standard and reduced initial doses of Capecitabine Shilpa 1,250 mg/m² according to body surface area
| Dose 1250 mg/m² (twice daily) |
|||||
| Body surface area, m² |
Full dose 1250 mg/m² |
Number of 150 mg and/or 500 mg tablets per administration (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 |
|
| ≤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 |
Table 2
Calculations of standard and reduced initial doses of Capcitabine Shilpa 1000 mg/m2 depending on body surface area
| 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 associated with capecitabine use can be managed by symptomatic therapy and/or by modifying the dose of Capecitabine Shilpa (by interrupting or reducing the dose). If a dose reduction is required, the dose should not be increased again later.
Treatment may be continued at the same dose without interruption or dose reduction in case 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 Shilpa should be advised to discontinue treatment immediately 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 × 10^9/L and/or platelet counts <100 × 10^9/L. Treatment should be suspended if, during unscheduled laboratory monitoring, neutrophil counts fall below 1.0 × 10^9/L or platelet counts fall below 75 × 10^9/L.
Dosage modification recommendations in case of toxicity, according to the National Cancer Institute of Canada (NCIC CTCAE, version 1) toxicity grading criteria, are provided below.
Table 3
Dosage reduction scheme for Capecitabine Shilpa (3-week cycle or continuous treatment)
| Toxicity grade* |
Dose modifications during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
| Grade I |
No dose adjustment required |
No dose adjustment required |
| Grade II |
||
|
Discontinue therapy until toxicity resolves to grade 0-1 |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
do not use |
| Grade III |
||
|
Discontinue therapy until toxicity resolves to grade 0-1 |
75 % |
|
50 % |
|
|
Discontinue the drug |
do not use |
| Grade IV |
||
|
Discontinue the drug or, if continuation of treatment is in the patient's best interest, discontinue therapy until toxicity resolves to grade 0-1 |
50 % |
|
Discontinue the drug |
do not use |
* according to the National Cancer Institute – Common Toxicity Criteria (version 1) of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) or the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute’s Cancer Therapy Evaluation Program, version 4.0. Information on hand-foot syndrome and hyperbilirubinemia is provided in the section "Special Warnings and Precautions for Use".
Dosage modification in the event of toxicity during administration of capecitabine in a 3-week cycle in combination with other medicinal products
Dosage modification in the event of toxicity during administration of capecitabine in a 3-week cycle 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 a treatment course, if a delay in therapy with capecitabine or another medicinal product is required, the administration of all other components of the regimen should also be postponed until all components can be administered again.
If toxicities occur during treatment that, in the physician’s opinion, are not related 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 prescribing information.
If discontinuation of other medicinal products in the capecitabine-containing regimen is necessary, capecitabine may be continued once the conditions for re-initiating capecitabine treatment are met.
These recommendations apply to all indications and all patient groups.
Dosage modification in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products
Dosage modification in the event of 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 recommendations. There is no information regarding hepatic impairment due to cirrhosis or hepatitis.
Patients with renal impairment
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min by the Cockcroft-Gault method 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, it is recommended to reduce the initial dose to 75% of the standard dose (1250 mg/m²). For patients with baseline moderate renal impairment, a reduction from an initial dose of 1000 mg/m² is not required. Patients with mild renal impairment (creatinine clearance 51–80 mL/min) do not require an initial dose adjustment.
Careful monitoring is recommended, and treatment should be interrupted immediately if Grade II, III, or IV adverse events occur, with subsequent dose adjustments according to Table 3. Treatment with capecitabine should be discontinued if creatinine clearance decreases to below 30 mL/min. Dosage adjustment recommendations for moderate renal impairment are the same for both monotherapy and combination therapy with capecitabine.
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 toxicities leading to treatment discontinuation has been observed compared to younger patients. Close monitoring of patients aged ≥60 years is recommended.
In treatment with capecitabine in combination with docetaxel, an increased incidence of Grade III and IV toxicities has been observed in patients over 60 years of age. For this age group receiving combination therapy with capecitabine and docetaxel, it is recommended to reduce the initial dose of capecitabine to 75% (950 mg/m² twice daily). If no toxicities occur during treatment with the reduced initial 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.
Paediatric population
The safety and efficacy of capecitabine in children have not been established.
Overdose
Symptoms of acute overdose: nausea, vomiting, diarrhoea, 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 possible complications.
Adverse Reactions
Safety profile summary
The overall safety profile is based on data from more than 3000 patients who received capecitabine treatment 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 colon cancer is comparable.
The most common and/or clinically significant treatment-related adverse reactions included gastrointestinal reactions (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, and worsening of renal function in patients with pre-existing renal impairment, thrombosis/embolism.
The following frequency categories are used to describe 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 grouping, adverse reactions are listed in order of decreasing incidence.
Monotherapy with capecitabine
The adverse reactions listed below are associated with capecitabine monotherapy, based on a pooled safety analysis of data from three pivotal trials involving 1900 patients (M66001, SO14695, and SO14796). 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 international normalized ratio (INR)/prolonged prothrombin time.
Immune system disorders: uncommon – hypersensitivity reactions; rare – angioedema.
Metabolism and nutrition disorders: very common – anorexia; common – dehydration, weight decreased; uncommon – diabetes mellitus, hypokalemia, appetite disorders, decreased appetite, 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; uncommon – aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disturbance, peripheral neuropathy; very rare – toxic leukoencephalopathy.
Eye disorders: common – lacrimation, conjunctivitis, eye irritation; uncommon – visual acuity reduced, 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, 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, hot flushes, cold extremities sensation.
Respiratory, thoracic and mediastinal disorders: common – dyspnea, epistaxis, cough, rhinorrhea; uncommon – pulmonary embolism, pneumothorax, hemoptysis, asthma, exertional dyspnea.
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 erythrodysesthesia syndrome (based on post-marketing experience, persistent or severe hand-foot erythrodysesthesia may eventually lead to loss of fingerprints (see section "Special precautions for use")); common – rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorder, 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 stiffness, 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 – weakness, asthenia; common – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, prostration, influenza-like symptoms, chills, increased body temperature.
In this context, "common adverse reactions" in the "Monotherapy with capecitabine" section refer to severe (Grade III–IV) and/or life-threatening adverse reactions or medically significant adverse reactions.
Combination therapy
The following adverse reactions were 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 in any of the main clinical trials.
Some adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an increased incidence or severity of these reactions cannot be excluded when capecitabine is used in combination.
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 neutropenia*, 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, visual disturbance, blurred vision.
Ear and labyrinth disorders: common – tinnitus, hearing decreased.
Cardiac disorders: common – atrial fibrillation, myocardial ischemia/infarction.
Vascular disorders: very common – lower limb edema, arterial hypertension, thrombosis/embolism*; common – hot flushes, 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 disorder; common – hyperhidrosis, erythematous rash, urticaria, night sweats.
Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia, limb pain; common – jaw pain, muscle spasms, trismus, muscle weakness.
Renal and urinary disorders: common – hematuria, proteinuria, decreased creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special precautions for use").
General disorders: very common – increased body temperature, weakness, drowsiness*, heat sensitivity, asthenia; common – mucosal inflammation, 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
With capecitabine 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 of severity was reported in 53–60% of patients in monotherapy trials (adjuvant treatment of colon 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. With capecitabine 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 of severity 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 showed that hand-foot syndrome of all grades occurred in 43% (2066) of patients receiving capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications (colon cancer, colorectal cancer, gastric cancer, breast cancer), with a median onset of 239 days after initiation of capecitabine treatment (95% CI 201–288). The following covariates were statistically significantly associated with an increased risk of hand-foot syndrome across all studied combinations: 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 patient 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 therapy. According to 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 capecitabine dose (in grams), longer duration of treatment (weeks), older patient age (per 10-year increase), female sex. The following covariates were statistically significantly associated with a decreased risk of diarrhea: higher cumulative capecitabine dose (0.1*kg) and higher relative dose intensity in the first 6 weeks of treatment.
Cardiotoxicity
In addition to the cardiac adverse reactions listed above, 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 (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 adverse reactions listed above, capecitabine monotherapy, based on a pooled safety analysis from 7 clinical trials, was associated with encephalopathy at a frequency of less than 0.1%.
Adverse reactions in special patient populations
Elderly patients. In patients aged ≥60 years receiving capecitabine monotherapy or combination therapy with capecitabine and docetaxel, an increased risk of Grade III and IV adverse reactions and serious treatment-related adverse reactions was observed compared to patients aged <60 years. A higher proportion 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 in all combination studies, 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, combining data from all studies, 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 impaired renal function
In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), a higher frequency of Grade III and IV treatment-related adverse reactions was observed 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 required more frequently (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively, and premature discontinuation of treatment occurred more frequently (21% 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 at a temperature not exceeding 30 °C. Keep out of reach of children.
Packaging.
For 150 mg tablets:
10 tablets in a blister, 6 blisters in a cardboard box
60 tablets in a bottle, 1 bottle in a cardboard box.
For 500 mg tablets:
10 tablets in a blister, 12 blisters in a cardboard box
120 tablets in a bottle, 1 bottle in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Shilpa Medicaments Limited, India.
Manufacturer's address and location of operations.
Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India.