Capecitabine krka
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPECITABINE KRKA (Capecitabine KRKA)
Composition:
Active ingredient: capecitabine;
1 film-coated tablet contains 150 mg or 500 mg of capecitabine;
Excipients: lactose, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;
film coating: hypromellose, talc, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
for the 150 mg strength: elongated, biconvex, light peach-colored tablets with "150" engraved on one side and smooth on the other side, film-coated;
for the 500 mg strength: elongated, biconvex, peach-colored tablets with "500" engraved on one side and smooth on the other side, film-coated.
Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues. ATC code L01B C06.
Pharmacological Properties
Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, 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, usually at low levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination with docetaxel, which may be related to docetaxel-induced increase in thymidine phosphorylase activity.
It has been established that the anabolic metabolism of 5-FU blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby inhibiting deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also suppresses ribonucleic acid (RNA) and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU may cause thymidine deficiency, leading to unbalanced growth and cell death. The effects on DNA and RNA are more pronounced in cells with higher proliferation rates and increased 5-FU metabolism.
Pharmacokinetics
The pharmacokinetics of capecitabine were determined over a dose range of 502–3514 mg/m²/day. The pharmacokinetic parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) were similar on Day 1 and Day 14. On Day 14, the area under the concentration-time curve (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 the metabolites 5'-DFCR and 5'-DFUR. Food intake reduces the absorption rate of capecitabine but does not significantly affect the AUC of 5'-DFUR or the subsequent metabolite 5-FU. When administered after food intake at a dose of 1250 mg/m² on Day 14, the maximum concentration (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and α-fluoro-β-alanine (FBAL) was 4.67 µg/mL, 3.05 µg/mL, 12.1 µg/mL, 0.95 µg/mL, and 5.46 µg/mL, respectively. The time to reach maximum concentration (Tmax) was 1.5 hours, 2 hours, 2 hours, 2 hours, and 3.34 hours, and the AUC was 7.75 µg•h/mL, 7.24 µg•h/mL, 24.6 µg•h/mL, 2.03 µg•h/mL, and 36.3 µg•h/mL, respectively.
Distribution
In vitro studies of human plasma demonstrated that the protein binding (mainly 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, but usually at lower levels. Subsequent enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in stromal tumor 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 to 8.0). The ratio of 5-FU concentration in tumor tissue to plasma concentration was 21.4 (range: 3.9 to 59.9, N=8), whereas the ratio of concentration in healthy tissue to plasma concentration was 8.9 (range: 3.0 to 25.8, N=8). Thymidine phosphorylase activity was four times higher in primary colorectal tumors compared to adjacent normal tissues. Immunohistochemical studies indicate that most thymidine phosphorylase is localized in stromal tumor cells.
Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) to form the less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-ureidopropionic acid (FUPA). The final reaction is the cleavage of FUPA to FBAL by β-ureidopropionase, which is excreted in urine. DPD activity is rate-limiting. DPD deficiency may lead to increased toxicity of capecitabine (see sections "Contraindications" and "Special Warnings and Precautions for Use").
Excretion
The elimination half-life (T1/2) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL is 0.85 hours, 1.11 hours, 0.66 hours, 0.76 hours, 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 metabolite in urine is FBAL, which constitutes 57% of the administered dose. Approximately 3% of the administered dose is excreted unchanged in urine.
Combination Therapy
In Phase I studies, no effect of capecitabine on the pharmacokinetics of docetaxel and paclitaxel (Cmax and AUC), or of docetaxel and paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR, was observed.
Pharmacokinetics in Special Clinical Populations
A population pharmacokinetic analysis was performed in 505 patients with colorectal cancer treated with capecitabine at a dose of 1250 mg/m² twice daily. Gender, presence or absence of liver metastases at the start of treatment, Karnofsky performance status, total bilirubin concentration, serum albumin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, and FBAL.
Patients with hepatic metastases. According to pharmacokinetic data, patients with mild to moderate hepatic impairment due to metastases may have increased bioavailability of capecitabine and increased 5-FU exposure 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 (35% increase in AUC with a 50% decrease in CrCl) and FBAL (114% increase in AUC with a 50% decrease in CrCl). FBAL is a metabolite without antiproliferative activity.
Elderly patients. According to population pharmacokinetic analysis including patients across a wide age range (27–86 years), of whom 234 patients (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 leads to a 15% increase in FBAL AUC), likely due to changes in renal function.
Ethnic factors. After oral administration of 825 mg/m² capecitabine twice daily for 14 days in Japanese patients (N=18), Cmax of capecitabine was 36% lower and AUC was 24% lower compared to Caucasian patients (N=22). Japanese patients also had 25% lower Cmax and 34% lower AUC of FBAL compared to Caucasian patients. The clinical significance of this difference is unknown. No significant differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU) were observed.
Clinical Characteristics.
Indications.
Breast cancer:
- Locally advanced or metastatic breast cancer – the drug is used in combination with docetaxel after ineffective chemotherapy containing anthracycline agents;
- Locally advanced or metastatic breast cancer – the drug is used as monotherapy after ineffective chemotherapy containing taxanes and anthracycline agents, or in the presence of contraindications to anthracycline therapy.
Colorectal cancer:
- Colon cancer – the drug is used in adjuvant therapy after surgical treatment of stage III cancer (stage C according to Dukes);
- Metastatic colorectal cancer.
Gastric cancer:
Used as a first-line agent for the treatment of advanced gastric cancer in combination with platinum-based agents.
Contraindications.
Severe, including unexpected, reactions to fluoropyrimidine therapy in medical history. Hypersensitivity to capecitabine or to any component of the drug, or to fluorouracil.
Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions").
Pregnancy and breastfeeding period.
Severe leukopenia, neutropenia, thrombocytopenia.
Severe hepatic dysfunction.
Severe renal impairment (creatinine clearance < 30 mL/min).
Recent or concomitant treatment with brivudine (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions" 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-FU, tegafur) has been described, due to inhibition of DPD by brivudine. This interaction, which increases fluoropyrimidine toxicity, may potentially lead to fatal outcomes. Therefore, concomitant use of brivudine with capecitabine is contraindicated (see sections "Contraindications" and "Special precautions"). The waiting period between the end of brivudine treatment and initiation of capecitabine therapy should be at least 4 weeks. 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 prescribing capecitabine with these drugs (e.g., phenytoin).
Anticoagulants – coumarin derivatives. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may lead to coagulation disorders and bleeding several days or months after initiation of capecitabine therapy, and in some cases, within one month after discontinuation of Capecitabine KRKA. In a clinical pharmacokinetic interaction study, single 20 mg dose of warfarin administration followed by capecitabine treatment resulted in a 57% increase in AUC of S-warfarin and a 91% increase in the international normalized ratio (INR). Since R-warfarin metabolism was unaffected, this indicates that capecitabine inhibits the 2C9 isoenzyme and does not affect 1A2 and 3A4 isoenzymes. Patients receiving capecitabine concomitantly with oral anticoagulants – coumarin derivatives – require close monitoring of coagulation parameters (INR or prothrombin time) and dose adjustment of the anticoagulant.
Phenytoin. Isolated cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin intoxication, have been reported with concomitant use of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving capecitabine together with phenytoin.
Folinic/folic acid. Folinic acid does not significantly affect the pharmacokinetics of capecitabine and its metabolites. However, folinic acid influences the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of capecitabine in monotherapy intermittent dosing regimen is 3000 mg/m²/day, whereas in combination with folinic acid (30 mg orally twice daily) it is only 2000 mg/m²/day. Increased toxicity may occur when switching from 5-FU/LV (5-fluorouracil and leucovorin) to capecitabine regimens. This phenomenon may also occur with folic acid administration intended to correct folic acid deficiency due to the similarity between folinic and folic acid.
Antacids. The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of capecitabine has been studied. Antacids containing aluminum and magnesium hydroxide slightly increase plasma concentrations of capecitabine and one metabolite (5'-DFCR); they do not affect the three main metabolites (5'-DFUR, 5-FU, and FBAL) of capecitabine.
Allopurinol. An interaction between allopurinol and 5-FU with possible reduction in 5-FU efficacy has been observed. Therefore, concomitant use of Capecitabine KRKA and allopurinol should be avoided.
Interferon alfa. The maximum tolerated dose of capecitabine is 2000 mg/m²/day when used in combination with interferon alfa-2a (3 million IU/m²/day), compared to 3000 mg/m²/day when capecitabine is used as monotherapy.
Radiation therapy. The maximum tolerated dose of capecitabine in monotherapy with intermittent dosing is 3000 mg/m²/day, whereas in combination with radiation therapy for rectal cancer it is 2000 mg/m²/day with continuous radiation therapy or a daily 6-week course of radiation therapy from Monday to 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.
Interaction with food
In all studies, 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, Capecitabine KRKA should be taken with food. Taking capecitabine with food results in a slower absorption rate of capecitabine.
Special precautions for use.
Toxic effects dependent on dose. Diarrhea, abdominal pain, nausea, stomatitis, palmar-plantar syndrome (palmar-plantar skin reactions, palmar-plantar erythrodysesthesia). Most adverse effects are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary interruption of treatment may be necessary.
Diarrhea. Patients with severe diarrhea should be closely monitored, and rehydration and electrolyte replacement should be administered 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 CTC) criteria 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 or massive diarrhea with blood, or the need for parenteral fluid administration. If necessary, the dose of the drug should be reduced (see section "Dosage and administration").
Dehydration. 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, particularly 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. Treatment with Capecitabine KRKA 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 causes. Dose adjustment should be considered if precipitating adverse events occur (see section "Dosage and administration").
Palmar-plantar syndrome (synonyms: palmar-plantar skin reactions, palmar-plantar erythrodysesthesia, chemotherapy-induced peripheral erythema). Grade I palmar-plantar syndrome does not interfere with the patient's daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless edema, or erythema of the palms and/or soles and/or discomfort.
Grade II palmar-plantar syndrome is characterized by painful erythema and edema of the hands and/or soles; discomfort caused by these symptoms interferes with the patient's daily activities. Persistent or severe palmar-plantar syndrome (Grade II or higher) may eventually lead to loss of fingerprints, which may affect patient identification.
Grade III palmar-plantar syndrome is defined as moist desquamation, ulcer formation, blistering, severe pain of the palms and/or soles, and/or severe discomfort preventing the patient from working or performing daily activities.
In case of development of Grade II or III palmar-plantar syndrome, capecitabine intake should be discontinued until symptoms resolve or decrease to Grade I; upon recurrence of Grade III syndrome, the dose of capecitabine should be reduced. Patients receiving both Capecitabine KRKA and cisplatin should not be administered vitamin B6 (pyridoxine) for symptomatic or secondary prophylactic treatment of palmar-plantar syndrome, as this may reduce the efficacy of cisplatin. There is evidence that dexpanthenol is effective in preventing palmar-plantar syndrome in patients receiving capecitabine.
Cardiotoxicity. The spectrum of cardiotoxic effects during capecitabine treatment is similar to that observed with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmia, cardiogenic shock, sudden death, cardiac arrest, heart failure, and ECG changes (including very rare cases of QT interval prolongation). These adverse reactions are more common in patients with ischemic heart disease. Cases of cardiac arrhythmia (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure, and cardiomyopathy have been reported during capecitabine use. Therefore, Capecitabine KRKA should be prescribed with caution to patients with clinically significant heart disease, arrhythmia, or angina pectoris.
Hypo- or hypercalcemia. Hypo- or hypercalcemia have been reported during capecitabine treatment. Capecitabine KRKA should be prescribed with caution to patients with documented hypo- or hypercalcemia.
Diseases of the central or peripheral nervous system. The medicinal product Capecitabine KRKA should be prescribed with caution to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte imbalance. Capecitabine KRKA should be prescribed with caution to patients with diabetes mellitus or electrolyte imbalance, as capecitabine use may exacerbate the course of these conditions.
Anticoagulants – coumarin derivatives. In a drug interaction study with single-dose warfarin, a significant increase in the mean AUC of S-warfarin (by 57%) was observed, indicating an interaction, likely due to inhibition of cytochrome P450 2C9 isoenzyme by capecitabine. In patients receiving capecitabine and oral anticoagulants – coumarin derivatives – close monitoring of coagulation parameters (INR or prothrombin time) and anticoagulant dose adjustment are required.
Brevudine. Brevudine is contraindicated for concomitant use with capecitabine. Fatal cases have been reported after this drug interaction. The waiting period between the end of brevudine treatment and the start of capecitabine therapy should be at least 4 weeks. Brevudine 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 brevudine intake by patients receiving capecitabine, effective measures should be taken to reduce capecitabine toxicity. Immediate hospitalization is recommended. All necessary measures to prevent systemic infections and dehydration should be initiated.
Hepatic impairment. Due to the lack of safety and efficacy data in patients with hepatic impairment, careful monitoring of patients with mild to moderate hepatic impairment is required during treatment with Capecitabine KRKA, regardless of the presence of liver metastases. If hyperbilirubinemia exceeding the upper limit of normal (ULN) by more than 3 times or an increase in hepatic aminotransferase activity (ALT, AST) more than 2.5 times the ULN occurs during capecitabine treatment, the use of capecitabine should be discontinued. Capecitabine monotherapy may be resumed when bilirubin levels and hepatic transaminase activities decrease below the specified thresholds.
Renal impairment. The incidence of Grade III and IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min) compared to the general patient population.
DPD deficiency. DPD activity is a rate-limiting factor in the catabolism of 5-FU (see section "Pharmacological properties"). Therefore, patients with DPD deficiency have an increased risk of fluoropyrimidine-associated toxicity, manifested by, among others, stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity.
Fluoropyrimidine-associated toxicity due to DPD deficiency usually 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 Caucasian individuals). Patients with complete DPD deficiency have a high risk of life-threatening, including fatal, toxicity and must not use Capecitabine KRKA (see section "Contraindications").
Partial DPD deficiency
It is estimated that partial DPD deficiency occurs in 3–9% of Caucasian patients. Patients with partial DPD deficiency have an increased risk of severe and potentially life-threatening toxicity. To minimize this toxicity, consideration should be given to reducing the initial dose. DPD deficiency should be considered a factor to be taken into account in combination with other routine parameters when deciding on dose reduction. Reducing the initial dose may affect treatment efficacy. In the absence of serious toxicity, subsequent doses may be increased under careful monitoring.
Testing for DPD deficiency
Before initiating treatment with Capecitabine KRKA, phenotypic and/or genotypic testing is recommended, despite uncertainty regarding optimal pre-treatment testing methods. Appropriate clinical guidelines should be considered.
Renal impairment may lead to increased blood uracil levels, thus increasing the risk of incorrect diagnosis 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 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 an 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) have an 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 – 1.1%, c.1236G>A/HapB3 variants – 2.6–6.3%, and c.1679T>G – from 0.07% to 0.1%.
Data on the frequency of the four DPYD variants in populations other than Caucasian are limited. To date, 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 prior to treatment, measurement of the endogenous DPD substrate uracil in blood plasma is recommended.
Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainty regarding threshold uracil 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 an increased risk of fluoropyrimidine toxicity. A blood uracil level ≥150 ng/mL should be considered a sign of complete DPD deficiency and associated with a risk of life-threatening, including fatal, fluoropyrimidine toxicity. Blood uracil levels should be interpreted with caution in patients with renal impairment (see section "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 when clinically necessary.
Severe skin reactions. Treatment with Capecitabine KRKA may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The use of Capecitabine KRKA should be permanently discontinued in patients who develop severe skin reactions during treatment.
Since the drug contains anhydrous lactose as an excipient, Capecitabine KRKA should not be administered to patients with congenital galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Capecitabine KRKA tablets should not be crushed or split. Adverse reactions may occur in patients or caregivers upon contact with crushed or split tablets of Capecitabine KRKA (see section "Adverse reactions").
Use during pregnancy or breastfeeding.
Women of reproductive age/contraception in men and women
Women of reproductive age should be advised to avoid pregnancy during treatment with capecitabine. If pregnancy occurs during treatment, the patient should be informed of the potential negative effects on the fetus. Effective contraceptive methods should be used during treatment and for 6 months after the last dose of capecitabine.
Based on genotoxicity study results, male patients and their female partners of reproductive age should use effective contraceptive methods during treatment and for 3 months after the last dose of capecitabine.
Pregnancy
The use of capecitabine in pregnant women has not been studied, but it can be assumed that the use of this medicinal product may be harmful to the fetus when administered to pregnant women. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. The use of capecitabine during pregnancy is contraindicated.
Lactation period
There are no data on the passage of capecitabine into human breast milk. Studies on the effect of capecitabine on breast milk production or the presence of capecitabine in human breast milk have not been conducted. Significant amounts of capecitabine and its metabolites were detected in the breast milk of lactating mice. Since 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 capecitabine on fertility. In the pivotal studies of capecitabine use, only men and women of reproductive age who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for a specified period thereafter were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving vehicles or operating machinery.
The drug has a minor or moderate effect on the ability to drive vehicles and operate complex machinery. Capecitabine may cause dizziness, weakness, and nausea.
Method of Administration and Dosage
Capecitabine KRKA should only be prescribed by a qualified physician experienced in the use of antineoplastic agents. Close monitoring of all patients is recommended during the first cycle of treatment.
Treatment should be discontinued in case of disease progression or development of unacceptable toxicity.
The medication is taken orally, no later than 30 minutes after a meal, with water.
Monotherapy
Colorectal cancer and breast cancer. The recommended initial daily dose of Capecitabine KRKA as adjuvant therapy is 2500 mg/m² body surface area, administered in 3-week cycles: taken daily for 2 weeks, followed by a 1-week rest period. The total daily dose of Capecitabine KRKA should be divided into two doses (1250 mg/m² body surface area in the morning and evening). The recommended total duration of adjuvant therapy for patients with stage III colorectal cancer is 6 months.
Combination Therapy
Breast cancer. When capecitabine is used in combination with docetaxel, the recommended initial dose for the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 2 weeks, followed by a 1-week rest period (in combination with docetaxel 75 mg/m² administered once every 3 weeks as an intravenous infusion). Premedication with oral corticosteroids, such as dexamethasone, should be given prior to docetaxel administration according to the docetaxel product instructions for patients receiving the combination of capecitabine plus docetaxel.
Colorectal cancer, gastric cancer. In combination regimens, the initial dose of Capecitabine KRKA should be reduced to 800–1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, or to 625 mg/m² twice daily for continuous administration. When combined with irinotecan (200 mg/m² on day 1), the recommended initial dose is 800 mg/m² twice daily for 2 weeks followed by a 1-week rest period. The addition of bevacizumab to the combination regimen does not affect the initial dose of Capecitabine KRKA.
Antiemetic agents and premedication to ensure adequate hydration should be administered to patients receiving Capecitabine KRKA in combination with cisplatin or oxaliplatin, prior to cisplatin administration, in accordance with the product instructions for cisplatin and oxaliplatin. The recommended total duration of adjuvant therapy for patients with stage III colorectal cancer is 6 months.
The dose of Capecitabine KRKA is calculated based on body surface area. Tables 1 and 2 provide dosage calculations for standard and reduced doses (see "Dose Modification During Treatment") for initial doses of Capecitabine KRKA of 1250 mg/m² or 1000 mg/m².
Table 1
Calculations of standard and reduced initial doses of Capecitabine KRKA 1250 mg/m²
according to body surface area
| Body surface area, m2 |
Dose 1250 mg/m2 (twice daily) |
||||
| Full dose 1250 mg/m2 |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
Reduced dose (75 %) 950 mg/m2 |
Reduced dose (50 %) 625 mg/m2 |
||
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤1.26 |
1500 |
- |
3 |
1150 |
800 |
| 1.27–1.38 |
1650 |
1 |
3 |
1300 |
800 |
| 1.39–1.52 |
1800 |
- |
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 |
- |
4 |
1800 |
1150 |
| 1.93–2.06 |
2500 |
- |
5 |
1950 |
1300 |
| 2.07–2.18 |
2650 |
1 |
5 |
2000 |
1300 |
| ≥2.19 |
2800 |
- |
5 |
2150 |
1450 |
Table 2
Calculations of standard and reduced initial dose of Capecitabine KRKA 1000 mg/m2
depending on body surface area
| Body surface area, m2 |
Dose 1000 mg/m2 (twice daily) |
||||
| Full dose 1000 mg/m2 |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
Reduced dose (75%) 750 mg/m2 |
Reduced dose (50%) 500 mg/m2 |
||
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤1.26 |
1150 |
1 |
2 |
800 |
600 |
| 1.27–1.38 |
1300 |
- |
2 |
1000 |
600 |
| 1.39–1.52 |
1450 |
1 |
2 |
1100 |
750 |
| 1.53–1.66 |
1600 |
- |
2 |
1200 |
800 |
| 1.67–1.78 |
1750 |
1 |
2 |
1300 |
800 |
| 1.79–1.92 |
1800 |
- |
3 |
1400 |
900 |
| 1.93–2.06 |
2000 |
- |
4 |
1500 |
1000 |
| 2.07–2.18 |
2150 |
1 |
4 |
1600 |
1050 |
| ≥2.19 |
2300 |
- |
4 |
1750 |
1100 |
Dose Modification During Treatment
Toxicities observed during treatment with Capecitabine KRKA can be managed with symptomatic therapy and/or by modifying the dose of Capecitabine KRKA (by interrupting treatment or reducing the dose). If a dose reduction is required, the dose should not be increased thereafter.
Treatment may be continued at the same dose without interruption or dose reduction in the presence of toxicities considered by the physician not to be severe and not life-threatening (e.g., alopecia, altered taste sensation, nail changes).
Patients receiving Capecitabine KRKA 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. Therapy should be suspended if laboratory testing reveals neutrophil counts <1.0 × 109/L or platelet counts <75 × 109/L.
Table 3 provides dose modification recommendations in the event of toxicities, according to the National Cancer Institute of Canada (NCIC CTG, version 1) criteria for commonly observed clinical toxicity signs.
Table 3
Dose Reduction Scheme for Capecitabine KRKA (3-week cycle or continuous treatment)
| Toxicity grade according to NCIC data |
Dose modification during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
| Grade I |
Dose not changed |
Dose not changed |
| Grade II |
||
|
Discontinue therapy until signs of toxicity decrease to Grade 0–I |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
Not applicable |
| Grade III |
||
|
Discontinue therapy until signs of toxicity decrease to Grade 0–I |
75 % |
|
50 % |
|
|
Discontinue the drug |
Not applicable |
| Grade IV |
||
|
Discontinue the drug or, if continuation of treatment is in the patient's best interest, discontinue therapy until signs of toxicity decrease to Grade 0–I |
50 % |
|
Discontinue the drug |
Not applicable |
Dosage modification in the event of toxicity during a 3-week cycle of capecitabine in combination with other medicinal products
Dosage modifications in the event of toxicity occurring during treatment with capecitabine KRKA in a 3-week cycle in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
At the beginning of a treatment cycle, if a delay in therapy with capecitabine KRKA or another medicinal product is necessary, administration of the other agents should also be discontinued until treatment with all components of the regimen can be resumed.
If toxicities occur during treatment that, in the physician’s opinion, are unrelated to capecitabine, therapy with capecitabine KRKA should be continued, and dosage adjustments of the other medicinal products in the regimen should be made according to their respective instructions for medical use.
If discontinuation of other medicinal products (components of the regimen) is necessary, treatment with capecitabine KRKA may be continued once the necessary conditions for re-initiating capecitabine KRKA have been 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 modifications in the event of toxicity during continuous administration of capecitabine KRKA 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.
Dosage adjustments in special situations
Patients with hepatic impairment
There are insufficient safety and efficacy data in patients with hepatic impairment to provide dosage adjustment recommendations. There is no information available on hepatic impairment due to cirrhosis or hepatitis.
Patients with renal impairment
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min at baseline, calculated by the Cockcroft-Gault formula). The incidence of Grade III or IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 ml/min at baseline) compared to the general population. For patients with pre-existing moderate renal impairment, it is recommended to reduce the initial dose to 75% of the standard dose (1250 mg/m²). A reduction of the initial dose to 1000 mg/m² is not required for patients with pre-existing moderate renal impairment. Patients with mild renal impairment (creatinine clearance 51–80 ml/min) do not require initial dose adjustment.
Close monitoring is recommended, and treatment should be interrupted immediately if Grade II, III, or IV adverse events occur, followed by further dose adjustments according to Table 3. Treatment with capecitabine KRKA should be discontinued if creatinine clearance falls below 30 ml/min. Dosage adjustment recommendations for moderate renal impairment are the same for both monotherapy and combination therapy with capecitabine.
Elderly patients
No initial dose adjustment is required for monotherapy with capecitabine. However, in patients aged 60 years and older, Grade III and IV toxicities occurred more frequently than in younger patients.
Careful monitoring of patients aged 60 years and older is recommended. When capecitabine is used in combination with other medicinal products in elderly patients (aged 65 years and older), a higher incidence of Grade III and IV adverse reactions has been observed, leading to treatment discontinuation, compared to younger patients.
In treatment with capecitabine in combination with docetaxel, an increased incidence of Grade III and IV adverse reactions has been observed in patients aged 60 years and older. For patients in this age group receiving combination therapy with capecitabine KRKA and docetaxel, it is recommended to reduce the initial dose of capecitabine KRKA to 75% (950 mg/m² twice daily). In the absence of toxicity in patients aged 60 years and older during treatment with the reduced initial dose of capecitabine in combination with docetaxel, the capecitabine dose may be gradually increased to 1250 mg/m² twice daily.
Children
The safety and efficacy of capecitabine in children have not been established.
Overdose
Symptoms of acute overdose: 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
The overall safety profile of capecitabine has been established based on data from more than 3000 patients who received capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications. The safety profile of capecitabine monotherapy in metastatic breast cancer, metastatic colorectal cancer, and adjuvant treatment of colon cancer is comparable.
The most common and/or clinically significant treatment-related adverse reactions were gastrointestinal disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, progression of renal function impairment in patients with renal insufficiency, and thrombosis/embolism.
Adverse reactions considered probably related to capecitabine administration were observed in monotherapy studies as well as in studies of capecitabine 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 category, adverse reactions are listed in order of decreasing severity.
Capecitabine monotherapy
Table 4 lists adverse reactions associated with capecitabine monotherapy.
Table 4
Adverse reactions in patients receiving capecitabine monotherapy
| System Organ Class |
Very common (all grades) |
Common (all grades) |
Uncommon (severe and/or life-threatening (Grade III–IV) adverse reactions, or medically significant) |
Rare/very rare (post-marketing experience) |
| Infections and infestations |
- |
Herpes (viral infection), nasopharyngitis, lower respiratory tract infections |
Sepsis, urinary tract infections, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess |
Angioedema (rare) |
| Benign, malignant and unspecified neoplasms |
- |
- |
Lipoma |
|
| Blood and lymphatic system disorders |
- |
Anemia, neutropenia |
Febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased INR/prolonged prothrombin time |
|
| Immune system disorders |
- |
- |
Hypersensitivity reactions |
|
| Metabolism and nutrition disorders |
Anorexia |
Dehydration, weight decreased |
Diabetes mellitus, hypokalemia, appetite disorders, undernutrition, hypertriglyceridemia |
|
| Psychiatric disorders |
- |
Insomnia, depression |
Confusional state, acute anxiety with panic reaction, depressed mood, decreased libido |
|
| Nervous system disorders |
- |
Headache, lethargy, dizziness, paraesthesia, taste alteration |
Aphasia, memory impairment, ataxia, syncope, balance disorders, sensory disturbances, peripheral neuropathy |
Toxic leukoencephalopathy (very rare) |
| Eye disorders |
- |
Increased lacrimation, conjunctivitis, eye irritation |
Decreased visual acuity, diplopia |
Lacrimal duct stenosis (rare), corneal disorders (rare), keratitis (rare), punctate keratitis (rare) |
| Ear and labyrinth disorders |
- |
- |
Vertigo, ear pain |
|
| Cardiac disorders |
- |
- |
Unstable angina, angina pectoris, myocardial ischemia/infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations |
Ventricular fibrillation (rare), QT interval prolongation (rare), torsade de pointes (rare), bradycardia (rare), vasospasm (rare) |
| Vascular disorders |
- |
Thrombophlebitis |
Deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, flushing, peripheral coldness |
|
| Respiratory, thoracic and mediastinal disorders |
- |
Dyspnea, epistaxis, cough, rhinorrhea |
Pulmonary embolism, pneumothorax, hemoptysis, asthma, exertional dyspnea |
|
| Gastrointestinal disorders |
Diarrhea, vomiting, nausea, stomatitis, abdominal pain |
Gastrointestinal hemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth |
Intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, esophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in feces |
|
| Hepatobiliary disorders |
- |
Hyperbilirubinemia, liver function test abnormalities |
Jaundice |
Hepatic failure (rare), cholestatic hepatitis (rare) |
| Skin and subcutaneous tissue disorders # |
Palmar-plantar erythrodysesthesia syndrome |
Rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders |
Skin blistering and ulceration, rash, urticaria, photosensitivity reactions, erythema of palms, facial edema, purpura, reversible radiation-like syndrome |
Cutaneous lupus erythematosus (rare), severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare) |
| Musculoskeletal and connective tissue disorders |
- |
Limb pain, back pain, arthralgia |
Joint swelling, bone pain, facial pain, musculoskeletal rigidity, muscle weakness |
|
| Renal and urinary disorders |
- |
- |
Hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine |
|
| Reproductive system and breast disorders |
- |
- |
Vaginal bleeding |
|
| General disorders |
Weakness, asthenia |
Pyrexia, peripheral edema, malaise, chest pain |
Edema, pyrexia, influenza-like symptoms, chills, body temperature increased |
#Based on post-marketing experience, persistent or severe hand-foot syndrome may eventually lead to loss of fingerprints (see section "Dosage and Administration").
Combination Therapy
Table 5 lists adverse reactions observed when capecitabine was administered in combination with various chemotherapy regimens for different indications in more than 3000 patients.
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 events with capecitabine cannot be excluded.
Table 5
Adverse reactions in patients receiving capecitabine as part of combination therapy, in addition to those observed during capecitabine monotherapy or those occurring at a higher frequency compared to capecitabine monotherapy
| System Organ Class |
Very common (all grades) |
Common (all grades) |
Uncommon/rare (post-marketing experience) |
| Infections and infestations |
- |
Herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections*, oral herpes |
|
| Blood and lymphatic system disorders |
Neutropenia*, leukopenia*, febrile neutropenia*, thrombocytopenia, anemia* |
Bone marrow suppression, febrile neutropenia* |
|
| Immune system disorders |
- |
Hypersensitivity reactions |
|
| Metabolism and nutrition disorders |
Decreased appetite |
Hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia |
|
| Psychiatric disorders |
- |
Sleep disorders, restlessness |
|
| Nervous system disorders |
Paresthesia and dysesthesia, peripheral neuropathy, peripheral sensory neuropathy, taste alteration, headache |
Neurotoxicity, tremor, neuralgia, hypersensitivity reactions, hypoesthesia |
|
| Eye disorders |
Increased lacrimation |
Visual disturbance, dry eyes, eye pain, decreased visual acuity, blurred vision |
|
| Ear and labyrinth disorders |
- |
Tinnitus, hearing decreased |
|
| Cardiac disorders |
- |
Atrial fibrillation, ischemia/myocardial infarction |
|
| Vascular disorders |
Peripheral edema, arterial hypertension, thrombosis/embolism* |
Flushing, arterial hypotension, hypertensive crisis, hot flushes, phlebitis |
|
| Respiratory, thoracic and mediastinal disorders |
Throat pain, pharyngeal dysesthesia |
Hiccough, pharyngolaryngeal pain, dysphonia |
|
| Gastrointestinal disorders |
Constipation, dyspepsia |
Upper gastrointestinal hemorrhage, oral mucosal ulceration, gastritis, bloating, gastroesophageal reflux disease, mouth pain, dysphagia, rectal hemorrhage, lower abdominal pain, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort |
|
| Hepatobiliary disorders |
- |
Abnormal liver function tests |
|
| Skin and subcutaneous tissue disorders |
Alopecia, nail disorders |
Hyperhidrosis, erythematous rash, urticaria, night sweats |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, limb pain |
Jaw pain, muscle spasms, trismus, muscle weakness |
|
| Renal and urinary disorders |
- |
Hematuria, proteinuria, decreased creatinine clearance, dysuria |
Acute renal failure due to dehydration (rare) |
| General disorders and administration site conditions |
Pyrexia, asthenia, lethargy*, intolerance to heat |
Mucosal inflammation, limb pain, pain, chills, chest pain, influenza-like symptoms, fever* |
|
| Injury, poisoning and procedural complications |
- |
Contusions |
*Frequency includes all severity grades, except for adverse reactions marked with an asterisk (*), which included only grade III–IV adverse reactions.
Individual 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 break, hand-foot syndrome of all severity grades was reported in 53–60% of patients in monotherapy trials (adjuvant treatment of colorectal cancer, treatment of metastatic colorectal cancer, treatment of breast cancer) and in 63% of patients with metastatic breast cancer in the capecitabine/docetaxel treatment group. With capecitabine administered at a dose of 1000 mg/m² twice daily for 2 weeks followed by a 1-week break, hand-foot syndrome of all severity grades was observed in 22–30% of patients receiving combination therapy with capecitabine.
Diarrhea
Diarrhea occurred in nearly 50% of patients during capecitabine treatment. Factors associated with an increased risk of diarrhea included: higher initial capecitabine dose (in grams), longer duration of treatment (weeks), increased patient age (per 10-year increment), and female sex. Factors associated with a reduced risk of diarrhea included: higher cumulative capecitabine dose (0.1*kg) and relative dose intensity during the first 6 weeks of treatment.
Cardiotoxicity
In addition to the adverse reactions listed above, the following adverse reactions have been reported with a frequency of less than 0.1% during capecitabine monotherapy: cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.
Encephalopathy
In addition to the adverse reactions listed above, capecitabine monotherapy has been 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 and older receiving capecitabine monotherapy or combination therapy with capecitabine and docetaxel, an increased frequency of grade III and IV adverse reactions and serious treatment-related adverse reactions was observed compared to patients under 60 years of age. A higher proportion of patients aged 60 years and older receiving combination therapy with capecitabine and docetaxel discontinued treatment due to adverse reactions compared to patients under 60 years of age.
Sex
Female sex was statistically significantly associated with an increased risk of developing hand-foot syndrome and diarrhea, as well as a reduced risk of neutropenia.
Patients with renal impairment
In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), an increased frequency of grade III and IV treatment-related adverse reactions was observed compared to patients with normal renal function: 41% in patients with mild renal impairment and 54% in patients with moderate renal impairment. In patients with moderate renal impairment, dose reductions were required more frequently (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively. Premature discontinuation of treatment was also more frequent (21% of patients 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 marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of the reach of children.
Packaging. 10 tablets per blister; 3, 6, or 12 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.
Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.