Capetazon
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAPETAZON (CAPETAZON)
Composition:
Active substance: capecitabine;
One film-coated tablet contains 150 mg or 500 mg of capecitabine;
Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;
Film coating:
for 150 mg tablets – Opadry Pink 04F540000 (hypromellose, titanium dioxide (E 171), macrogols, talc, red iron oxide (E 172), yellow iron oxide (E 172));
for 500 mg tablets – Opadry Pink 04F540005 (hypromellose, titanium dioxide (E 171), macrogols, talc, red iron oxide (E 172), yellow iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
150 mg tablets: biconvex, elongated, film-coated tablets, light peach-colored, with smooth surface on both sides;
500 mg tablets: biconvex, elongated, film-coated tablets, peach-colored, with smooth surface on both sides.
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 low levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect when combined with docetaxel, which may be related to docetaxel-induced upregulation of thymidine phosphorylase activity.
Evidence indicates that the anabolic metabolism of 5-FU blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also inhibits RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU may cause thymidine deficiency, leading to unbalanced growth and cell death. Effects on DNA and RNA are more pronounced in cells with higher proliferative activity and increased 5-FU metabolism.
Pharmacokinetics
The pharmacokinetics of capecitabine have been characterized over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters for capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) on Day 1 and Day 14 were similar. On Day 14, the AUC of 5-FU was 30–35% higher. Dose reduction of capecitabine resulted in a greater-than-proportional decrease in 5-FU exposure due to the non-linear pharmacokinetics of the active metabolite.
Absorption
After oral administration, capecitabine is rapidly and completely absorbed and subsequently biotransformed into metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food intake reduces the rate of absorption of capecitabine but does not significantly affect the area under the concentration-time curve (AUC) of 5'-DFUR or its subsequent metabolite 5-FU. When administered 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 human plasma studies demonstrated protein binding (primarily to albumin) of 54%, 10%, 62%, and 10% for capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU, respectively.
Metabolism
Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, primarily located in the liver and tumor tissues. Subsequent catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, although generally at lower levels. This further enzymatic biotransformation of capecitabine to 5-FU results in higher concentrations within tumor tissues. In colorectal tumors, a significant portion of 5-FU localizes in tumor stromal cells. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumors to that in adjacent normal tissue was 3.2 (range: 0.9–8.0). The tumor-to-plasma concentration ratio of 5-FU was 21.4 (range: 3.9–59.9, N=8), while the normal tissue-to-plasma concentration ratio 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-ureidopropionic acid (FUPA). The final step is 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 capecitabine toxicity.
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%, fecal excretion for 2.6%. The main urinary metabolite is FBAL, representing 57% of the administered dose. Approximately 3% of the administered dose is excreted unchanged in urine.
Combination Therapy
Phase I studies showed no effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC), and no effect of docetaxel or paclitaxel on the pharmacokinetics of capecitabine or 5'-DFUR.
Pharmacokinetics in Special Clinical Populations
A population pharmacokinetic analysis was performed in 505 patients with colorectal cancer treated with capecitabine at a dose of 1250 mg/m² twice daily. 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, or FBAL.
Patients with Hepatic 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 independent of creatinine clearance (CrCl). However, CrCl affects the AUC of 5'-DFUR (35% increase in AUC with a 50% reduction in CrCl) and FBAL (114% increase in AUC with a 50% reduction in CrCl). FBAL is a metabolite without antiproliferative activity.
Elderly Patients. Based on population pharmacokinetic analysis data involving 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 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, Japanese patients (N=18) showed a 36% lower Cmax and 24% lower AUC of capecitabine compared to Caucasian patients (N=22). For FBAL, Japanese patients had a 25% lower Cmax and 34% lower AUC compared to Caucasian patients. The clinical significance of this difference is unknown. No substantial differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU) were observed.
Clinical characteristics.
Indications.
Colorectal cancer, metastatic colorectal cancer:
- Adjuvant treatment of stage III colon cancer (Dukes' stage C) following complete 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 regimens containing anthracyclines;
- Locally advanced or metastatic breast cancer, as monotherapy after failure of prior chemotherapy regimens containing both 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 precautions").
Pregnancy or breastfeeding.
Severe leukopenia, neutropenia, or thrombocytopenia.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance < 30 mL/min).
Recent administration or concomitant use of brivudine.
Contraindications associated with 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 of capecitabine with 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 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 Capetazon. In a clinical pharmacokinetic interaction study, following a single 20 mg dose of S-warfarin, treatment with Capetazon increased the AUC of warfarin by 57% and the INR 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. Patients receiving capecitabine concomitantly with oral anticoagulants (vitamin K antagonists) require close monitoring of coagulation parameters (International Normalized Ratio or Prothrombin Time), and dose adjustment of the anticoagulant should be performed as needed.
Phenytoin.
Cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin toxicity, have been reported with concomitant use of Capetazon and phenytoin. Patients receiving capecitabine together with phenytoin should have regular monitoring of plasma phenytoin concentrations.
Folinic acid/folic acid.
Folinic acid does not significantly affect the pharmacokinetics of capecitabine or its metabolites. However, folinic acid affects the pharmacodynamics of Capetazon, potentially increasing the toxicity of capecitabine: the maximum tolerated dose of Capetazon as monotherapy under an intermittent dosing schedule 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 to capecitabine regimens. This may also occur when folic acid is administered to correct folic acid deficiency due to the structural similarity between folinic acid and folic acid.
Brivudine.
A clinically significant interaction between brivudine and fluoropyrimidines (e.g., capecitabine, 5-fluorouracil, tegafur) has been reported in the literature, due to brivudine's inhibition of dihydropyrimidine dehydrogenase. This interaction may potentially lead to fatal enhancement of fluoropyrimidine toxicity. Therefore, brivudine must not be administered concomitantly with capecitabine (see sections "Contraindications" and "Special precautions"). The interval between discontinuation of brivudine and initiation of Capetazon therapy should be at least 4 weeks. Brivudine therapy may be initiated 24 hours after the last dose of capecitabine.
Antacids.
The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of Capetazon was studied. Such antacids slightly increase plasma concentrations of capecitabine and one of its metabolites (5'-DFCR), but do not affect the three major metabolites (5'-DFUR, 5-FU, and FBA) of capecitabine.
Allopurinol.
An interaction between allopurinol and 5-fluorouracil has been observed, potentially reducing the efficacy of 5-fluorouracil. Therefore, concomitant use of Capetazon and allopurinol should be avoided.
Interferon alpha.
The maximum tolerated dose of Capetazon is 2000 mg/m²/day when used in combination with interferon alfa-2a (3 million IU/m²/day), compared to 3000 mg/m²/day when Capetazon is used as monotherapy.
Radiation therapy.
The maximum tolerated dose of Capetazon as monotherapy under an intermittent dosing schedule is 3000 mg/m²/day. When combined with radiotherapy for rectal cancer, the maximum tolerated dose is 2000 mg/m²/day, either with continuous radiotherapy or a daily 6-week course of radiotherapy administered Monday through Friday.
Oxaliplatin.
When capecitabine is used in combination with oxaliplatin, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum were observed.
Bevacizumab.
No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites was observed in the presence of oxaliplatin.
Drug–food interaction
In all clinical trials, patients were instructed to take Capetazon within 30 minutes after a meal. Since the available safety and efficacy data are based on administration of Capetazon with food, it is recommended to take Capetazon with food. Administration of Capetazon with food results in a slower absorption rate of capecitabine.
Special precautions for use.
Toxic effects dependent on dose
Dose-dependent toxic effects manifest 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 agents (e.g., loperamide) may be prescribed. Grade II diarrhea according to the National Cancer Institute of Canada (NCIC CTCAE, version 2) is defined as an increase in bowel movements to 4–6 times per day or nocturnal defecation; Grade III diarrhea is defined as an increase in bowel movements to 7–9 times per day, fecal incontinence, or malabsorption. Grade IV diarrhea is defined as an increase in bowel movements ≥10 times 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 must be prevented and corrected if it occurs. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. Dehydration may lead to acute renal failure, particularly in patients with pre-existing renal impairment or when capecitabine is administered concomitantly with drugs known to have nephrotoxic potential. Acute renal failure due to dehydration may be potentially fatal. Treatment with Kapetazon should be immediately discontinued in case of Grade II (or higher) dehydration, and dehydration should be corrected. Resumption of treatment is possible after adequate correction of dehydration and management/control of precipitating factors (see section "Dosage and administration"). Dose adjustment should be performed if precipitating adverse events occur, as necessary.
Hand-foot syndrome
Hand-foot syndrome, also known as hand-foot skin reactions, 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 is manifested 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 edema 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, bullae formation, acute 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, potentially affecting patient identification. In case of Grade II or III hand-foot syndrome, capecitabine should be discontinued until symptoms resolve or improve to Grade I; upon recurrence of Grade III syndrome, the dose of capecitabine should be reduced. The use of vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving Kapetazon 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 Kapetazon.
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 fatal outcome, cardiac arrest, heart failure, and ECG changes (including very rare cases of QT interval prolongation). These adverse effects are more commonly observed in patients with ischemic heart disease. Cases of cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure, and cardiomyopathy have been reported during treatment with Kapetazon. Caution is required when prescribing Kapetazon to patients with clinically significant heart disease, arrhythmias, or angina pectoris.
Hypo- or hypercalcemia.
Hypo- or hypercalcemia have been reported during treatment with Kapetazon.
Diseases of the central or peripheral nervous system.
Caution is required when prescribing Kapetazon 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 Kapetazon to patients with diabetes mellitus or electrolyte imbalances, as capecitabine use may exacerbate these conditions.
Anticoagulants – coumarin derivatives.
In a drug interaction study with single-dose warfarin, a significant increase in the mean area under the concentration-time curve (AUC) of S-warfarin (by 57%) was observed, indicating an interaction, likely due to inhibition of cytochrome P450 isoenzyme 2C9 by capecitabine. Patients receiving concomitant capecitabine and oral anticoagulants (coumarin derivatives) require close monitoring of coagulation parameters (international normalized ratio or prothrombin time), and anticoagulant dosage should be adjusted accordingly.
Brivudine.
Brivudine must not be administered concurrently with capecitabine. Fatal outcomes have been reported following this drug interaction. The interval between the end of brivudine treatment and the start of Kapetazon therapy should be at least 4 weeks. 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 administration of brivudine to patients receiving capecitabine, effective measures to reduce capecitabine toxicity should be implemented immediately. Immediate hospitalization is recommended. Measures to prevent systemic infections and dehydration should be initiated promptly.
Hepatic impairment.
Due to lack of safety and efficacy data in patients with hepatic impairment, Kapetazon 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) exceeding 2.5 times the upper limit of normal occurs during capecitabine treatment, administration of capecitabine should be suspended. Monotherapy with capecitabine 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-associated 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 treatment with Kapetazon (see section "Contraindications").
Partial DPD deficiency
Partial DPD deficiency is estimated to occur in 3–9% of the Caucasian population. Patients with partial DPD deficiency have an increased risk of severe and potentially life-threatening toxicity. To mitigate 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. In the absence of severe toxicity, subsequent doses may be increased with careful monitoring.
Testing for DPD deficiency
Before initiating treatment with Kapetazon, phenotypic and/or genotypic testing is recommended, despite uncertainties regarding optimal pre-treatment testing methods. Relevant clinical guidelines should be considered. Renal impairment may lead to elevated plasma uracil levels, increasing the risk of misdiagnosis of DPD deficiency in patients with moderate renal impairment. Capecitabine is contraindicated in patients with severe renal impairment (see section "Contraindications").
Genotypic characterization of DPD deficiency
Testing for rare DPYD gene mutations prior to 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 allele c.1905+1G>A or c.1679T>G) are known to cause complete or near-complete absence of DPD enzymatic activity.
Patients with certain heterozygous DPYD variants (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 genotype c.1905+1G>A 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 plasma is recommended before treatment.
Elevated pre-treatment uracil concentrations are associated with increased risk of toxicity. Despite uncertainty regarding threshold values indicating complete or partial DPD deficiency, plasma uracil levels ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and associated with increased risk of fluoropyrimidine toxicity. A plasma uracil level ≥150 ng/mL should be considered indicative of complete DPD deficiency and associated with risk of life-threatening, including fatal, fluoropyrimidine toxicity. Plasma uracil levels should be interpreted with caution in patients with renal impairment (see "Testing for DPD deficiency").
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 as clinically indicated.
Severe skin reactions.
Treatment with Kapetazon may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The drug should be permanently discontinued in patients who develop severe skin reactions during treatment.
Since the drug contains anhydrous lactose as an excipient, Kapetazon should not be administered to patients with congenital galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Disposal of unused or expired medication: environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. "Take-back" systems should be used for disposal, if available.
The tablet must not be crushed or split. Contact with crushed or split tablets by patients or healthcare workers may result in adverse reactions (see section "Adverse reactions").
Use during pregnancy or breastfeeding.
Females of reproductive potential/contraception in males and females
Women of reproductive potential should be advised to avoid pregnancy during treatment with capecitabine. If pregnancy occurs during treatment, the potential adverse effects on the fetus should be explained to the patient. Effective contraception should be used during treatment and for 6 months after the last dose of capecitabine.
Based on genotoxicity data, male patients with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of capecitabine.
Pregnancy
The use of Kapetazon during pregnancy has not been studied, but the drug is expected to be harmful to the fetus if administered during pregnancy. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Kapetazon must not be used during pregnancy.
Breastfeeding
It is unknown whether Kapetazon passes into human breast milk. Studies on the effect of capecitabine on milk production or the presence of capecitabine in human breast milk have not been conducted. Significant amounts of capecitabine and its metabolites have been detected in the milk of lactating mice. Because the potential harm to breastfed infants is unknown, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the last dose.
Fertility
There are no data on the effect of Kapetazon on fertility. 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 specified period thereafter were included in the core studies of Kapetazon. Effects on fertility were observed in animal studies.
Ability to drive and use machines.
The drug has a minor or moderate influence on the ability to drive and operate machinery. Kapetazon may cause dizziness, weakness, and nausea.
Dosage and Administration
Capetazon should only be prescribed by a qualified physician experienced in the use of antineoplastic agents. Careful monitoring during the first treatment cycle is recommended for all patients.
Treatment should be discontinued in case of disease progression or development of unacceptable toxicity.
The tablet should be swallowed whole, no later than 30 minutes after food intake, with water.
The tablet must not be crushed or split.
Monotherapy
Colorectal cancer and breast cancer. The recommended initial daily dose of Capetazon as adjuvant therapy is 2,500 mg/m² body surface area, administered in 3-week cycles: daily for 2 weeks, followed by a 1-week treatment break. The total daily dose of Capetazon 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 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 prescribing information, for patients receiving the combination of capecitabine plus docetaxel.
Colorectal cancer, gastric cancer. In combination regimens, the initial dose of Capetazon 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 Capetazon.
Antiemetics and premedication to ensure adequate hydration should be administered to patients receiving Capetazon in combination with cisplatin or oxaliplatin, prior to cisplatin administration, in accordance with the prescribing 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 Capetazon should be calculated based on body surface area.
Tables 1 and 2 provide calculations for standard and reduced initial doses (see "Dose Modifications During Treatment") of Capetazon at 1,250 mg/m² or 1,000 mg/m².
Calculation of standard and reduced initial doses of Capetazon at 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 |
Calculation of standard and reduced initial dose of Capetazon 1000 mg/m² depending on body surface area
Table 2
| Body surface area, m2 |
Dose 1000 mg/m2 (twice daily) |
||||
| Full dose 1000 mg/m2 |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
Reduced dose (75%) 750 mg/m2 |
Reduced dose (50%) 500 mg/m2 |
||
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤1.26 |
1150 |
1 |
2 |
800 |
600 |
| 1.27–1.38 |
1300 |
2 |
2 |
1000 |
600 |
| 1.39–1.52 |
1450 |
3 |
2 |
1100 |
750 |
| 1.53–1.66 |
1600 |
4 |
2 |
1200 |
800 |
| 1.67–1.78 |
1750 |
5 |
2 |
1300 |
800 |
| 1.79–1.92 |
1800 |
2 |
3 |
1400 |
900 |
| 1.93–2.06 |
2000 |
- |
4 |
1500 |
1000 |
| 2.07–2.18 |
2150 |
1 |
4 |
1600 |
1050 |
| ≥2.19 |
2300 |
2 |
4 |
1750 |
1100 |
Dose Adjustment During Treatment
General Recommendations
Toxicity symptoms during treatment with Capetazon can be managed with symptomatic therapy and/or by modifying the dose of Capetazon (by interrupting treatment or reducing the dose). If the dose has been reduced, it should not be increased again later.
Treatment may be continued at the same dose without interruption or dose reduction in cases of toxicity symptoms that, in the physician's opinion, are unlikely to be serious or life-threatening, such as alopecia, altered taste sensations, or nail changes.
Patients receiving Capetazon treatment 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 toxic effects, the missed doses should not be administered as supplementary doses.
Hematological Toxicity
Capecitabine therapy should not be initiated in patients with baseline neutrophil counts <1.5 × 10⁹/L and/or platelet counts <100 × 10⁹/L. Treatment should be suspended if, during unplanned laboratory tests performed throughout therapy, neutrophil counts drop below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.
Dosage modification recommendations in the event of toxicities are provided below, according to the toxicity grading criteria established by the Canadian National Cancer Institute (NCIC CTG, version 1).
Capetazon Dose Reduction Schedule (3-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 signs of toxicity resolve to Grade 0–1 |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
do not use |
| Grade III |
||
|
Discontinue therapy until signs of toxicity resolve to Grade 0–1 |
75 % |
|
50 % |
|
|
Discontinue the drug |
do not use |
| Grade IV |
||
|
Discontinue the drug, or if continuation of treatment is clinically warranted, discontinue therapy until signs of toxicity resolve to Grade 0–1 |
50 % |
|
Discontinue the drug |
do not use |
* according to the Common Toxicity Criteria (version 1) of the National Cancer Institute of Canada's Clinical Trials Group (NCIC CTG) or the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute of the United States, version 4.0. For information on hand-foot syndrome and hyperbilirubinemia, see section "Special precautions".
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 treatment with Capetazon in a 3-week cycle in combination with other medicinal products must be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
At the beginning of treatment, if a delay in therapy with Capetazon or another medicinal product is required, the administration of all other components of the regimen should also be delayed until the time when all components can be resumed.
If toxicities occur during treatment that, in the physician’s opinion, are not related to capecitabine, treatment with Capetazon should be continued, and the doses of the other medicinal products in the regimen should be adjusted according to their respective instructions for medical use.
If other medicinal products in the treatment regimen need to be discontinued, Capetazon may be continued once the necessary conditions for resuming Capetazon administration 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 must be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
Dose modification in special situations
Patients with hepatic impairment
There is insufficient safety and efficacy data in patients with hepatic impairment to provide dose modification recommendations. There is no information available on hepatic impairment due to cirrhosis or hepatitis.
Patients with renal impairment
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min at baseline according to Cockcroft-Gault). The incidence of grade 3 or 4 adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min at baseline) compared to the general population. For patients with baseline moderate renal impairment, a reduction of the initial dose to 75% of the standard dose (1250 mg/m²) is recommended. For patients with baseline moderate renal impairment, a reduction of the initial dose of 1000 mg/m² is not required. No initial dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 51–80 mL/min).
Close monitoring is recommended, and treatment should be interrupted immediately upon occurrence of grade 2, 3, or 4 adverse events, followed by further dose adjustment according to Table 3. Treatment with Capetazon must be discontinued if creatinine clearance falls below 30 mL/min. Dose modification recommendations for moderate renal impairment are the same for both capecitabine monotherapy and combination therapy.
Elderly patients
No initial dose adjustment is required for capecitabine monotherapy. However, treatment-related adverse reactions of grade 3 and 4 occur more frequently in patients aged ≥ 60 years compared to younger patients.
When Capetazon is used in combination with other medicinal products in elderly patients (≥ 65 years), a higher incidence of grade 3 and 4 toxicities leading to treatment discontinuation has been observed compared to younger patients. Careful monitoring of patients aged ≥ 60 years is recommended.
When treating with Capetazon in combination with docetaxel, an increased incidence of grade 3 and 4 toxicities has been observed in patients over 60 years of age. For patients in this age group receiving combination therapy with Capetazon and docetaxel, it is recommended to reduce the initial dose of Capetazon 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.
Children
The safety and efficacy of Capetazon in children have not been established.
Overdose.
Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Management should include standard therapeutic and supportive measures to address clinical manifestations and prevent possible complications.
Adverse Reactions
Safety profile summary
The overall safety profile of Capetazon is based on data from more than 3000 patients who received treatment with Capetazon as monotherapy or in combination with various chemotherapy regimens for different indications. The safety profile of monotherapy with Capetazon in metastatic breast cancer, metastatic colorectal cancer, and adjuvant therapy of colon cancer 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, and progression of renal function impairment in patients with renal insufficiency, thrombosis/embolism.
Adverse reactions considered by the investigator as possibly, probably, or remotely related to Capetazon administration were observed in clinical trials of Capetazon monotherapy and in clinical trials of Capetazon used in combination with various chemotherapy regimens for different indications.
The following frequency categories were used to describe the incidence of 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 severity.
Monotherapy with Capetazon
The adverse reactions listed below are associated with capcitabine monotherapy and are based on a pooled safety analysis 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)/prothrombin time prolongation.
Immune system disorders: uncommon – hypersensitivity reactions; rare – angioneurotic edema.
Metabolism and nutrition disorders: very common – anorexia; common – dehydration, weight decreased; uncommon – diabetes mellitus, hypokalemia, appetite disorders, malnutrition, hypertriglyceridemia.
Psychiatric disorders: common – insomnia, depression; uncommon – confusion, acute anxiety with panic reaction, depressed mood, decreased libido.
Nervous system disorders: common – headache, drowsiness, dizziness, paresthesia; uncommon – aphasia, memory impairment, ataxia, syncope, sensory disturbances, 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, flushing, peripheral cold 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, liver function test abnormalities; uncommon – jaundice; rare – liver 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")); 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, palmar erythema, 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 and administration site conditions: very common – weakness, asthenia; common – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, fever, influenza-like symptoms, chills, body temperature increased.
In this context, "common adverse reactions" in the section "Monotherapy with Capetazon" refer to severe adverse reactions and/or life-threatening (Grade 3–4) or medically significant adverse reactions.
Combination therapy
The adverse reactions listed below were observed during treatment with Capetazon in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 patients, in addition to those already reported during 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 exacerbation of these adverse reactions with Capetazon 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 decreased.
Cardiac disorders: common – atrial fibrillation, myocardial ischemia/infarction.
Vascular disorders: very common – lower limb edema, arterial hypertension, thrombosis/embolism*; common – flushing, arterial hypotension, hypertensive crisis, hyperemia, phlebitis.
Respiratory, thoracic and mediastinal disorders: very common – angina, pharyngeal dysesthesia; common – hiccups, pharyngolaryngeal pain, dysphonia.
Gastrointestinal disorders: very common – constipation, dyspepsia; common – upper gastrointestinal hemorrhage, oral mucosal ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, mouth pain, dysphagia, rectal bleeding, lower abdominal pain, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort.
Hepatobiliary disorders: common – liver function test abnormalities.
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 creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special precautions").
General disorders and administration site conditions: 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 3–4 reactions.
Selected adverse reactions
Hand-foot syndrome
With capcitabine administered at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week break, 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 capcitabine/docetaxel treatment group. With capcitabine administered at 1000 mg/m² twice daily for 2 weeks followed by a 1-week break, hand-foot syndrome of all grades was observed in 22–30% of patients receiving combination therapy with capcitabine.
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 treated with capcitabine 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 capcitabine treatment (95% CI 201–288). The following covariates were statistically significantly associated with an increased risk of hand-foot syndrome across all studied combinations: increased initial capcitabine dose (in grams), decreased cumulative capcitabine dose (0.1*kg), increased relative dose intensity during the first 6 weeks of treatment, increased treatment duration (weeks), increased patient age (per 10-year increment), female sex, and good baseline performance status (0 vs. ≥1).
Diarrhea
Diarrhea occurred in nearly 50% of patients during treatment with Capetazon. 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: increased initial capcitabine dose (in grams), increased treatment duration (weeks), increased patient age (per 10-year increment), female sex. The following covariates were statistically significantly associated with a decreased risk of diarrhea: increased cumulative capcitabine dose (0.1*kg) and 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 capcitabine 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, monotherapy with Capetazon, 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 capcitabine tablets
The following adverse reactions have been reported following exposure to crushed or split capcitabine tablets: eye mucous membrane irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.
Adverse reactions in special patient populations
Elderly patients. In patients aged ≥60 years receiving Capetazon monotherapy or combination therapy with Capetazon 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 Capetazon and docetaxel discontinued treatment earlier due to adverse reactions compared to those aged <60 years.
A meta-analysis of data from over 4700 patients in 14 clinical trials demonstrated that across all study combinations, increasing age (per 10-year increment) 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 Capetazon monotherapy (for colorectal cancer), there was a higher frequency 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.
Shelf life.
2 years.
Storage conditions.
Store below 30 °C.
Keep out of reach of children.
Packaging.
10 tablets in a blister, 6 blisters in a cardboard box (for 150 mg strength); 12 blisters in a cardboard box (for 500 mg strength).
Prescription status.
Prescription only.
Manufacturer.
RELIANCE LIFE SCIENCES PRIVATE LIMITED (PLANT 6)
Manufacturer's address.
Dhirubhai Ambani Life Sciences Centre (DALS), Thane, Belapur Road, Rabale, Navi Mumbai, 400701, India
Marketing Authorization Holder.
M.BIOTECH LimiteD
Address of Marketing Authorization Holder.
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom