Capenex
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAPENEX (CAPENEX)
Composition:
active substance: capecitabine;
1 film-coated tablet contains 150 mg or 500 mg of capecitabine;
excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;
film coating: hypromellose, talc, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical characteristics:
tablets 150 mg: light peach-colored, capsule-shaped, biconvex, film-coated, with the imprint "6" on one side and "H" on the other side;
tablets 500 mg: peach-colored, oval-shaped, biconvex, film-coated, with the imprint "3" on one side and "H" on the other side.
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 compound 5-fluorouracil (5-FU). Capecitabine is activated through several enzymatic steps. The final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue as well as in healthy tissues of the body, although generally at a low level. 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 of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also suppresses RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU can cause thymidine deficiency, leading to unbalanced growth and cell death. Effects on DNA and RNA are more pronounced in cells with higher proliferative activity and greater 5-FU metabolism.
Pharmacokinetics
The pharmacokinetics of capecitabine have been characterized over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters of capecitabine and its metabolites 5’-deoxy-5-fluorocytidine (5’-DFCR) and 5’-deoxy-5-fluorouridine (5’-DFUR) on days 1 and 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 undergoes biotransformation into metabolites 5’-DFCR and 5’-DFUR. Food intake reduces the rate of capecitabine absorption but has no significant effect on the area under the concentration-time curve (AUC) of 5’-DFUR or the subsequent metabolite 5-FU. When administered at a dose of 1250 mg/m² after food intake on day 14, maximum 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 was 7.75, 7.24, 24.6, 2.03, and 36.3 µg × h/mL, respectively.
Distribution. In vitro human plasma studies demonstrated that the protein binding (primarily to albumin) of capecitabine, 5’-DFCR, 5’-DFUR, and 5-FU is 54%, 10%, 62%, and 10%, respectively.
Metabolism. Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5’-DFCR, which is then converted to 5’-DFUR by cytidine deaminase, primarily located in the liver and tumor tissues. Further catalytic activation of 5’-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, although generally at lower levels. Subsequent enzymatic biotransformation of capecitabine to 5-FU results in higher concentrations in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in 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 tissues 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 concentration in healthy tissue to plasma concentration was 8.9 (range: 3.0–25.8, N=8). Thymidine phosphorylase activity was measured to be four times higher in primary colorectal tumors compared to adjacent normal tissues. Immunohistochemical studies indicate that most thymidine phosphorylase is localized in tumor stromal cells.
Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) into the less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-β-ureidopropionic acid (FUPA). The final reaction involves the cleavage of FUPA by β-ureidopropionase into α-fluoro-β-alanine (FBAL), which is excreted in urine. Dihydropyrimidine dehydrogenase activity is rate-limiting. DPD deficiency may lead to increased toxicity of capecitabine.
Elimination. The elimination half-life (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% and fecal excretion for 2.6%. The main urinary metabolite is FBAL, which constitutes 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), nor any effect of docetaxel or paclitaxel on the pharmacokinetics of capecitabine and 5’-DFUR.
Pharmacokinetics in Special Clinical Populations
Population pharmacokinetic analysis was performed after treatment with capecitabine at a dose of 1250 mg/m² twice daily in 505 patients with colorectal cancer. Sex, presence or absence of liver metastases prior to treatment initiation, 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 hepatic metastases. Pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases suggest that the bioavailability of capecitabine and exposure to 5-FU may be increased compared to patients without hepatic impairment. Pharmacokinetic data in patients with severe hepatic impairment are lacking.
Patients with renal impairment. In oncology patients with varying degrees (mild to severe) of renal impairment, the pharmacokinetics of unchanged drug and 5-FU are independent of creatinine clearance (CrCl). CrCl affects the AUC of 5’-DFUR (AUC increases by 35% with a 50% reduction in CrCl) and FBAL (AUC increases by 114% with a 50% reduction in CrCl). FBAL is a metabolite without antiproliferative activity.
Elderly patients. Based on population pharmacokinetic analysis data including patients across a wide age range (27–86 years), of whom 234 (46%) were aged 65 years or older, age does not affect the pharmacokinetics of 5’-DFUR and 5-FU. AUC of FBAL increases with age (a 20% increase in age 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 Mongoloid race patients (N=18), Cmax of capecitabine was 36% lower and AUC was 24% lower compared to Caucasian patients (N=22). Similarly, for FBAL, Mongoloid race patients had 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 stage III (Dukes' stage C) colon cancer after surgical resection;
- 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 prior chemotherapy containing anthracyclines;
- Locally advanced or metastatic breast cancer, as monotherapy after failure of prior chemotherapy containing taxanes and anthracyclines, or in patients with contraindications to anthracycline therapy.
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 Warnings and Precautions for Use").
Pregnancy or breastfeeding.
Severe leukopenia, neutropenia, or thrombocytopenia.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance < 30 mL/min).
Recent or concomitant treatment with brivudine (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction" regarding interactions with other medicinal products).
Contraindications to any medicinal product used in combination.
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 reported, due to inhibition of dihydropyrimidine dehydrogenase by brivudine. This interaction, which increases fluoropyrimidine toxicity, may potentially lead to fatal outcomes. Therefore, brivudine must not be administered concomitantly with capecitabine (see sections "Contraindications" and "Special Warnings and Precautions for Use"). A waiting period of at least 4 weeks is required 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.
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 such drugs (e.g., phenytoin).
Coumarin-derivative 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 up to 1 month after discontinuation of capecitabine. In a clinical pharmacokinetic interaction study, following a single 20 mg dose of S-warfarin, treatment with capecitabine increased the AUC of warfarin by 57% and the AUC of its 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-derivative 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, associated with 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 both capecitabine and phenytoin.
Folinic acid / folic acid. Folinic acid does not significantly affect the pharmacokinetics of capecitabine or its metabolites. However, folinic acid affects the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of capecitabine in monotherapy with intermittent dosing is 3000 mg/m²/day, whereas when combined with folinic acid (30 mg orally twice daily), it is only 2000 mg/m²/day. Increased toxicity may occur when switching from 5-FU/LV regimens to capecitabine. This may also occur when folic acid is administered to correct folic acid deficiency, due to the similarity between folinic acid 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 of its metabolites (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 Capenex with allopurinol should be avoided.
Interferon alfa. The maximum tolerated dose of capecitabine is 2000 mg/m²/day when administered 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 Capenex as monotherapy with intermittent dosing is 3000 mg/m²/day. When combined with radiation therapy for rectal cancer, the maximum tolerated dose is 2000 mg/m²/day, administered continuously or daily during a 6-week course of radiation therapy from Monday to Friday.
Oxaliplatin. When capecitabine is administered concomitantly with oxaliplatin, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum were observed.
Bevacizumab. No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites was observed in the presence of oxaliplatin.
Drug–Food Interaction
In all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Since safety and efficacy data are based on administration of capecitabine with food, it is recommended that Capenex be taken with food. Taking Capenex with food slows the absorption rate of capecitabine.
Special precautions for use
Dose-dependent toxic effects include diarrhea, abdominal pain, nausea, stomatitis, palmar-plantar syndrome (palmar-plantar 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 rehydrated, with electrolyte replacement if dehydration occurs. Standard anti-diarrheal agents (e.g., loperamide) may be prescribed. Diarrhea Grade II according to the Canadian National Cancer Institute criteria (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 in bowel movements to 7–9 times 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. If necessary, the dose of the drug should be reduced (see section "Dosage and administration").
Dehydration. Dehydration should be prevented and corrected if it occurs. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. Dehydration may lead to acute renal failure, especially in patients with pre-existing renal impairment or when capecitabine is used concomitantly with drugs known to have nephrotoxic effects. Acute renal failure due to dehydration may be potentially fatal. In case of Grade II (or higher) dehydration, treatment with Capenex 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 considered if precipitating adverse events occur.
Hand-foot syndrome (synonyms: palmar-plantar skin reactions, palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema). Grade I hand-foot syndrome does not interfere with the patient's daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless edema, 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, ulceration, 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 2 or higher) may eventually lead to loss of fingerprints, which may affect 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. The use of vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving Capenex and cisplatin, as published data suggest this may reduce the efficacy of cisplatin. Some data indicate that dexpanthenol is effective in preventing hand-foot syndrome in patients receiving capecitabine.
Cardiotoxicity. The spectrum of cardiotoxicity with capecitabine 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 is required when prescribing Capenex to patients with clinically significant heart disease, arrhythmias, or angina.
Hypo- or hypercalcemia. Hypo- or hypercalcemia have been reported during capecitabine treatment.
Diseases of the central or peripheral nervous system. Caution is required when prescribing Capenex to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte disturbances. Caution is required when prescribing Capenex to patients with diabetes mellitus or electrolyte imbalances, as 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 the CYP2C9 isoenzyme of the cytochrome P450 system by capecitabine. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) should be closely monitored for coagulation parameters (international normalized ratio or prothrombin time), and the anticoagulant dose should be adjusted accordingly.
Brivudine. Brivudine must not be used concomitantly with capecitabine. Fatal cases have been reported following this drug interaction. A waiting period of at least 4 weeks should elapse between the end of brivudine treatment and the start of capecitabine therapy. Brivudine treatment may be initiated 24 hours after the last dose of capecitabine (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
In case of accidental brivudine intake by patients receiving capecitabine, effective measures should be taken to reduce capecitabine toxicity. Immediate hospitalization is recommended. All necessary measures should be initiated to prevent systemic infections and dehydration.
Hepatic impairment. Due to lack of safety and efficacy data in patients with hepatic impairment, Capenex should be carefully monitored in patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding the upper limit of normal by more than 3 times or an increase in hepatic aminotransferase activity (ALT, AST) by more than 2.5 times the upper limit of normal occurs during capecitabine treatment, the drug should be withheld. 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 is a rate-limiting factor in the catabolism of 5-fluorouracil (see section "Pharmacological properties"). Therefore, patients with DPD deficiency are at increased risk of fluoropyrimidine-related toxicity, including stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity. DPD deficiency-related toxicity typically occurs during the first treatment cycle or after dose escalation.
Complete DPD deficiency
Complete DPD deficiency is a rare condition (0.01–0.5% of individuals of Caucasian ethnicity). Patients with complete DPD deficiency are at high risk of life-threatening, including fatal, toxicity and must not receive capecitabine (see section "Contraindications").
Partial DPD deficiency
Partial DPD deficiency is estimated to occur in 3–9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. To reduce this risk, consideration should be given to reducing the initial dose. DPD deficiency should be considered alongside other routine factors when deciding on dose reduction. Reducing the initial dose may affect treatment efficacy. If no severe toxicity occurs, subsequent doses may be increased under close monitoring.
Testing for DPD deficiency
Before initiating capecitabine treatment, phenotypic and/or genotypic testing is recommended, despite uncertainty regarding optimal pre-treatment testing methods. Relevant clinical guidelines should be considered.
Genotypic characterization of DPD deficiency
Testing for rare DPYD gene mutations before treatment may identify patients with DPD deficiency.
Four DPYD variants – c.1905+1G > A [also known as DPYD*2A], c.1679T > G [DPYD*13], c.2846A > T, and c.1236G > A/HapB3 – may cause complete absence or reduced enzymatic activity of DPD. Other rare variants may also be associated with increased risk of severe, including life-threatening, toxicity. Certain homozygous or combined heterozygous mutations in the DPYD gene locus (e.g., combinations of the four variants with at least one c.1905+1G > A or c.1679T > G allele) are known to cause complete or near-complete absence of DPD enzymatic activity. Patients with certain heterozygous DPYD variants (particularly c.1905+1G > A, c.1679T > G, c.2846A > T, and c.1236G > A/HapB3) are at increased risk of severe toxicity during fluoropyrimidine treatment.
In Caucasian patients, the frequency of the heterozygous c.1905+1G > A genotype in the DPYD gene is approximately 1%, c.2846A > T is 1.1%, c.1236G > A/HapB3 variants are 2.6–6.3%, and c.1679T > G is 0.07–0.1%.
Data on the frequency of the four DPYD variants in populations other than Caucasian are limited. Currently, the four DPYD variants (c.1905+1G > A, c.1679T > G, c.2846A > T, and c.1236G > A/HapB3) are considered practically absent in patients of African (American) or Asian origin.
Phenotypic characterization of DPD deficiency
For phenotypic characterization of DPD deficiency, measurement of endogenous DPD substrate uracil in blood plasma before treatment is recommended.
Elevated pre-treatment uracil levels are associated with increased risk of toxicity. Despite uncertainty regarding threshold values indicating complete or partial DPD deficiency, a plasma uracil level ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and associated with increased risk of fluoropyrimidine toxicity. A blood uracil level ≥150 ng/mL should be considered indicative of complete DPD deficiency and associated with risk of life-threatening, including fatal, fluoropyrimidine toxicity.
Renal impairment is associated with increased blood uracil levels, which may lead to a false diagnosis of DPD deficiency and, consequently, to underdosing of capecitabine.
Ophthalmological complications. Patients should be closely monitored for ophthalmological complications such as keratitis or corneal disorders, especially if there is a history of ocular disorders. Treatment of visual disturbances should be initiated if clinically indicated.
Severe skin reactions. Treatment with Capenex may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Capenex should be permanently discontinued in patients who develop severe skin reactions during treatment.
Since the drug contains anhydrous lactose as an excipient, Capenex should not be administered to patients with congenital galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Disposal of unused and expired medication: Environmental release of the medicinal product 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.
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 capecitabine treatment. If pregnancy occurs during treatment, the patient should be informed of the potential adverse effects on the fetus. Effective contraception 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 Capenex in pregnant women has not been studied, but it can be assumed that the use of Capenex may be harmful to the fetus. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Capenex should not be used during pregnancy.
Lactation period. It is unknown whether capecitabine passes into human breast milk. Studies on the effect of capecitabine on lactation or its presence in human breast milk have not been conducted. Significant amounts of capecitabine and its metabolites were detected in the milk of lactating mice. Since the potential harm to breastfed infants is unknown, breastfeeding should be discontinued during capecitabine treatment and for 2 weeks after the last dose.
Fertility. There are no data on the effect of Capenex on fertility. In pivotal studies, only women of reproductive potential and men who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for a defined period thereafter were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery
The drug has a minor or moderate effect on the ability to drive or operate machinery. Capenex may cause dizziness, weakness, and nausea.
Method of Administration and Dosage
Capenex shall be prescribed only by a qualified physician experienced in the use of antineoplastic medicinal products. Close monitoring of all patients is recommended during the first treatment cycle.
Treatment should be discontinued in case of disease progression or development of unacceptable toxicity.
The medicinal product should be taken orally, no later than 30 minutes after food intake, with water. Capenex tablets must not be crushed or split.
Monotherapy
Colorectal cancer and breast cancer. The recommended initial daily dose of Capenex 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 Capenex 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 break (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 Capenex should be reduced to 800–1,000 mg/m² twice daily for 2 weeks followed by a 1-week break, 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 break. The addition of bevacizumab to the combination regimen does not affect the initial dose of Capenex.
Antiemetics and premedication to ensure adequate hydration should be administered to patients receiving Capenex in combination with cisplatin or oxaliplatin, according to the product instructions for cisplatin and oxaliplatin, prior to cisplatin administration. The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
The dose of Capenex should be calculated based on body surface area.
Tables 1 and 2 provide calculations for standard and reduced initial doses (see "Dose Modification During Treatment") of Capenex at 1,250 mg/m² or 1,000 mg/m².
Calculation of standard and reduced initial doses of Capenex 1,250 mg/m² according to body surface area
Table 1
| Dose 1250 mg/m2 (twice daily) |
|||||
| Body surface area, m2 |
Full dose 1250 mg/m2 |
Number of 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 |
Standard and reduced initial dose calculations for Capenex 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 1 administration, mg |
Dose per 1 administration, mg |
|
| ≤1.26 |
1150 |
1 |
2 |
800 |
600 |
| 1.27–1.38 |
1300 |
2 |
2 |
1000 |
600 |
| 1.39–1.52 |
1450 |
3 |
2 |
1100 |
750 |
| 1.53–1.66 |
1600 |
4 |
2 |
1200 |
800 |
| 1.67–1.78 |
1750 |
5 |
2 |
1300 |
800 |
| 1.79–1.92 |
1800 |
2 |
3 |
1400 |
900 |
| 1.93–2.06 |
2000 |
- |
4 |
1500 |
1000 |
| 2.07–2.18 |
2150 |
1 |
4 |
1600 |
1050 |
| ≥2.19 |
2300 |
2 |
4 |
1750 |
1100 |
Dose Adjustment During Treatment
General Recommendations. Toxicity symptoms during treatment with Capenex can be managed with symptomatic therapy and/or by modifying the dose of Capenex (by interrupting or reducing treatment). 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 considered by the physician to be unlikely to become serious or life-threatening, such as alopecia, taste alterations, or nail changes.
Patients receiving Capenex treatment should be advised to discontinue treatment immediately in the event of moderate or severe toxic reactions. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be made up.
Hematological Toxicity. Capecitabine therapy should not be initiated in patients with baseline neutrophil counts < 1.5 × 10⁹/L and/or platelet counts < 100 × 10⁹/L. Treatment should be suspended if, during treatment and based on unscheduled laboratory tests, neutrophil levels fall below 1.0 × 10⁹/L or platelet levels fall below 75 × 10⁹/L.
Below are dose modification recommendations in the event of toxicity, according to the toxicity grading criteria developed by the Canadian National Cancer Institute (NCIC CTG, version 1).
Capecitabine Dose Reduction Schedule (three-week cycle or continuous treatment)
Table 3
| 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 signs resolve to grade 0–1 |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue drug |
do not use |
| Grade III |
||
|
Discontinue therapy until toxicity signs resolve to grade 0–1 |
75 % |
|
50 % |
|
|
Discontinue drug |
do not use |
| Grade IV |
||
|
Discontinue drug or, if continuation of treatment is in the patient’s best interest, discontinue therapy until toxicity signs resolve to grade 0–1 |
50 % |
|
Discontinue drug |
do not use |
* according to the National Cancer Institute of Canada's Common Toxicity Criteria (version 1) (NCIC CTG) 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 modification in case of toxicity during administration of capecitabine in a three-week cycle in combination with other medicinal products. Dosage adjustments due to toxicity during treatment with Capenex in a three-week cycle in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
At the beginning of treatment, if postponement of therapy with Capenex or another medicinal product is required, the administration of all other components of the regimen should also be postponed until the time when all components can be resumed.
If toxic events occur during treatment that, in the physician’s opinion, are not related to capecitabine, therapy with Capenex should be continued, and the dosage of the other medicinal products in the regimen should be adjusted according to their respective instructions for medical use.
If discontinuation of other medicinal products in the treatment regimen becomes necessary, Capenex may be continued once the conditions for re-initiating Capenex therapy are met.
These recommendations apply to all indications and all patient groups.
Dosage modification in case of toxicity during continuous administration of capecitabine in combination with other medicinal products. Dosage adjustments due to toxicity during continuous administration of capecitabine in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
Dose adjustments in special situations
Patients with hepatic impairment. There is insufficient safety and efficacy data in patients with hepatic impairment to provide recommendations for dose adjustment. No information is available on 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 at baseline, as calculated by the Cockcroft-Gault formula). The incidence of grade 3 or 4 adverse reactions is increased in patients with moderate renal impairment (creatinine clearance of 30–50 mL/min at baseline) compared to the general population. For patients with moderate renal impairment at baseline, it is recommended to reduce the initial dose to 75% of the standard dose (1250 mg/m²). A dose reduction is not required for an initial dose of 1000 mg/m² in patients with moderate renal impairment. No initial dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 51–80 mL/min).
Careful monitoring is recommended, and treatment should be interrupted immediately upon occurrence of grade 2, 3, or 4 adverse events, followed by dose adjustments according to Table 3. Treatment with Capenex should be discontinued if creatinine clearance falls below 30 mL/min. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy with capecitabine and combination therapy.
Elderly patients. Initial dose adjustment is not required for monotherapy with capecitabine. However, treatment-related grade 3 and 4 adverse reactions occurred more frequently in patients aged ≥60 years compared to younger patients.
When Capenex is used in combination with other medicinal products in elderly patients (≥65 years), a higher incidence of grade 3 and 4 toxicity has been observed, leading to treatment discontinuation compared to younger patients. Close monitoring of patients aged ≥60 years is recommended.
When treating with capecitabine in combination with docetaxel, an increased incidence of grade 3 and 4 toxicities has been observed in patients aged 60 years and older. For patients in this age group receiving combination therapy with Capenex and docetaxel, it is recommended to reduce the initial dose of Capenex to 75% (950 mg/m² twice daily). If no toxicity is observed 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.
Children. The safety and efficacy of Capenex 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 aimed at correcting clinical manifestations and preventing possible 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 capecitabine monotherapy in metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer therapy is comparable.
The most common and/or clinically significant treatment-related adverse reactions were gastrointestinal reactions (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot 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 as possibly, probably, or remotely related to capecitabine administration were observed in clinical trials of capecitabine monotherapy and in clinical trials 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 (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10000 to < 1/1000), very rare (< 1/10000). Within each frequency group, adverse reactions are listed in order of decreasing incidence.
Monotherapy with Capenex
Below are the adverse reactions associated with capecitabine monotherapy based on a pooled analysis of safety data from three pivotal studies 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 – angioneurotic edema.
Metabolism and nutrition disorders: very common – anorexia; common – dehydration, weight decreased; uncommon – diabetes mellitus, hypokalemia, appetite disorders, malnutrition, hypertriglyceridemia.
Psychiatric disorders: common – insomnia, depression; uncommon – confusion, acute anxiety with panic reaction, depressed mood, decreased libido.
Nervous system disorders: common – headache, lethargy, dizziness, paresthesia, dysgeusia; uncommon – aphasia, memory impairment, ataxia, syncope, balance disorders, sensory disturbances, peripheral neuropathy; very rare – toxic leukoencephalopathy.
Eye disorders: common – lacrimation, conjunctivitis, eye irritation; uncommon – decreased visual acuity, diplopia; rare – lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis.
Ear and labyrinth disorders: uncommon – vertigo, ear pain.
Cardiac disorders: uncommon – unstable angina, angina pectoris, myocardial ischemia, myocardial infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; rare – ventricular fibrillation, QT interval prolongation, torsades de pointes ventricular tachycardia, bradycardia, vasospasm.
Vascular disorders: common – thrombophlebitis; uncommon – deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, flushing, peripheral coldness.
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 Warnings and Precautions for Use")); common – rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders; uncommon – skin blistering and ulceration, rash, urticaria, photosensitivity reactions, erythema of palms, facial swelling, purpura, reversible radiation recall syndrome; rare – cutaneous lupus erythematosus; very rare – severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: common – limb pain, back pain, arthralgia; uncommon – joint swelling, bone pain, facial pain, musculoskeletal rigidity, muscle weakness.
Renal and urinary disorders: uncommon – hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine.
Reproductive system and breast disorders: uncommon – vaginal bleeding.
General disorders: very common – weakness, asthenia; common – hyperthermia, peripheral edema, malaise, chest pain; uncommon – edema, prostration, influenza-like symptoms, chills, pyrexia.
In this context, "common adverse reactions" in the section "Monotherapy with Capenex" refer to severe adverse reactions and/or life-threatening adverse reactions (Grade 3–4), or medically significant adverse reactions.
Combination Therapy
Below are the adverse reactions observed with capecitabine in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 additional patients, beyond those already reported with monotherapy and/or observed with higher frequency in any of the pivotal clinical trials.
Some adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension with bevacizumab). However, an exacerbation of these adverse reactions with Capenex cannot be excluded.
Infections and infestations: common – herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections*, oral herpes.
Blood and lymphatic system disorders: very common – neutropenia*, leukopenia*, febrile 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, blurred vision.
Ear and labyrinth disorders: common – tinnitus, hearing loss.
Cardiac disorders: common – atrial fibrillation, myocardial ischemia/infarction.
Vascular disorders: very common – lower limb edema, arterial hypertension, thrombosis/embolism*; common – erythema, arterial hypotension, hypertensive crisis, flushing, phlebitis.
Respiratory, thoracic and mediastinal disorders: very common – angina, pharyngeal dysesthesia; common – hiccup, pharyngolaryngeal pain, dysphonia.
Gastrointestinal disorders: very common – constipation, dyspepsia; common – upper gastrointestinal hemorrhage, oral mucosal ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, mouth pain, dysphagia, rectal bleeding, lower abdominal pain, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort.
Hepatobiliary disorders: common – abnormal liver function tests.
Skin and subcutaneous tissue disorders: very common – alopecia, nail disorders; common – hyperhidrosis, erythematous rash, urticaria, night sweats.
Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia, limb pain; common – jaw pain, muscle spasms, trismus, muscle weakness.
Renal and urinary disorders: common – hematuria, proteinuria, decreased renal creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special Warnings and Precautions for Use").
General disorders: very common – pyrexia, weakness, lethargy*, 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 3–4 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 was reported in 53–60% of patients in monotherapy trials (adjuvant colon cancer therapy, metastatic colorectal cancer treatment, breast cancer treatment) and in 63% of patients with metastatic breast cancer in the capecitabine/docetaxel treatment group. With capecitabine administered at 1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, hand-foot syndrome of all grades was observed in 22–30% of patients receiving combination therapy with capecitabine.
A meta-analysis of data from more than 4700 patients across 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). Statistically significant covariates associated with increased risk of hand-foot syndrome across all studied combinations included: higher initial capecitabine dose (in grams), lower cumulative capecitabine dose (0.1*kg), higher relative dose intensity during the first 6 weeks of treatment, longer treatment duration (weeks), older age (per 10-year increase), female sex, and better baseline performance status (0 vs ≥1).
Diarrhea. Diarrhea occurred in nearly 50% of patients during capecitabine treatment. A meta-analysis of data from more than 4700 patients across 14 clinical trials showed that statistically significant covariates associated with increased risk of diarrhea across all studied combinations included: higher initial capecitabine dose (in grams), longer treatment duration (weeks), older age (per 10-year increase), and female sex. Statistically significant covariates associated with decreased risk of diarrhea included: higher cumulative capecitabine dose (0.1*kg) and higher relative dose intensity during 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 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%.
Exposure to crushed or split capecitabine tablets
Following exposure to crushed or split capecitabine tablets, the following adverse reactions have been reported: 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 3 and 4 adverse reactions and serious treatment-related adverse reactions 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 more than 4700 patients in 14 clinical trials demonstrated that across all combination studies, older age (per 10-year increase) was statistically significantly associated with increased risk of hand-foot syndrome and diarrhea, and decreased risk of neutropenia.
Sex. A meta-analysis of data from more than 4700 patients in 14 clinical trials, pooling data from all studies, demonstrated that female sex was statistically significantly associated with increased risk of hand-foot syndrome and diarrhea, and decreased risk of neutropenia.
Patients with Renal Impairment. In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), there was a higher incidence of Grade 3 and 4 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, and premature discontinuation of treatment was more common (21% during the first two cycles) compared to 5% and 8% in patients without renal impairment and with mild renal impairment, respectively.
Reporting of Suspected Adverse Reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.
Shelf Life. 2 years.
Storage Conditions
Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.
Packaging
10 tablets in a blister, 3 or 6 blisters in a cardboard box.
Prescription Category. Prescription only.
Manufacturer. Hetero Labs Limited, India.
Manufacturer's Address and Location of Operations
Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.