Ксалвобин

Ксалвобин Accord is indicated for the treatment of:

-for the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer.

- metastatic colorectal cancer.

- first-line treatment of advanced gastric cancer in combination with a platinum based regimen.

in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.

Ксалвобин Accord should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic medicinal products. Careful monitoring during the first cycle of treatment is recommended for all patients.

Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose calculations according to body surface area for starting doses of Ксалвобин Accord of 1250 mg/m² and 1000 mg/m² are provided in Tables 1 and 2, respectively.

Posology

Recommended posology

Monotherapy

Colon, colorectal and breast cancer

Given as monotherapy, the recommended starting dose for Ксалвобин in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/m² administered twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.

Combination therapy

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of Ксалвобин should be reduced to 800-1000 mg/m² when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m² twice daily when administered continuously. For combination with irinotecan, the recommended starting dose is 800 mg/m² when administered twice daily for 14 days followed by a 7-day rest period combined with irinotecan 200 mg/m² on day 1. The inclusion of bevacizumab in a combination regimen has no effect on the starting dose of Ксалвобин. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the Ксалвобин plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the Ксалвобин plus oxaliplatin combination.

Adjuvant treatment in patients with stage III colon cancer is recommended for a duration of 6 months.

Breast cancer

In combination with docetaxel, the recommended starting dose of Ксалвобин in the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 14 days followed by a 7-day rest period, combined with docetaxel at 75 mg/m² as a 1 hour intravenous infusion every 3 weeks. Premedication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the Ксалвобин plus docetaxel combination.

Ксалвобин Accord dose calculations

Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of Ксалвобин of 1250 mg/m².

Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of Ксалвобин of 1000 mg/m²

Posology adjustments during treatment

General

Toxicity due to Ксалвобин administration may be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time. For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Patients taking Ксалвобин should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Ксалвобин omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:

Ксалвобин Accord 150 mg and 500mg film-coated tablets

Table 3 Ксалвобин dose reduction schedule (3-weekly cycle or continuous treatment).

Ксалвобин Accord 300 mg film-coated tablets

Table 4 Ксалвобин dose reduction shedule(3-weeklycycle or continuous treatment).

*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0.

Haematology

Patients with baseline neutrophil counts of <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L should not be treated with Ксалвобин. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 x 10⁹/L or that the platelet count drops below 75 x 10⁹/L, treatment with Ксалвобин should be interrupted.

Dose modifications for toxicity when Ксалвобин is used as a 3 weekly cycle in combination with other medicinal products

Dose modifications for toxicity when Ксалвобин is used as a 3 weekly cycle in combination with other medicinal products should be made according to Table 3 above for Ксалвобин and according to the appropriate summary of product characteristics for the other medicinal product(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either Ксалвобин or the other medicinal product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal products are met.

During a treatment cycle for those toxicities considered by the treating physician not to be related to Ксалвобин, Ксалвобин should be continued and the dose of the other medicinal product should be adjusted according to the appropriate Prescribing Information.

If the other medicinal product(s) have to be discontinued permanently, Ксалвобин treatment can be resumed when the requirements for restarting Ксалвобин are met.

This advice is applicable to all indications and to all special populations.

Dose modifications for toxicity when Ксалвобин is used continuously in combination with other medicinal products

Dose modifications for toxicity when Ксалвобин is used continuously in combination with other medicinal products should be made according to Table 3 above for Ксалвобин and according to the appropriate summary of product characteristics for the other medicinal product(s).

Posology adjustments for special populations

Hepatic impairment

Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal impairment

Ксалвобин is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m² is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m². In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in Table 3 above. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, Ксалвобин Accord should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use (see also section “Elderly” below).

Elderly

During Ксалвобин monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients >60 years of age compared to younger patients.

When Ксалвобин was used in combination with other medicinal products, elderly patients (>65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger patients. Careful monitoring of patients >60 years of age is advisable.

- In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age or more. For patients 60 years of age or more, a starting dose reduction of Ксалвобин to 75% (950 mg/m² twice daily) is recommended. If no toxicity is observed in patients >60 years of age treated with a reduced Ксалвобин starting dose in combination with docetaxel, the dose of Ксалвобин may be cautiously escalated to 1250 mg/m² twice daily.

Paediatric population

There is no relevant use of Ксалвобин in the paediatric population in the indications colon, colorectal, gastric and breast cancer.

Method of administration

Ксалвобин Accord tablets should be swallowed with water within 30 minutes after a meal.

- History of severe and unexpected reactions to fluoropyrimidine therapy,

-

- In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity ,

- During pregnancy and lactation,

- In patients with severe leukopenia, neutropenia, or thrombocytopenia,

- In patients with severe hepatic impairment,

- In patients with severe renal impairment (creatinine clearance below 30 ml/min),

- Treatment with sorivudine or its chemically related analogues, such as brivudine ,

- If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used.

Dose limiting toxicities

Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.

Diarrhoea

Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of >10 stools/day or grossly bloody diarrhoea or the need for parenteral support. Dose reduction should be applied as necessary.

Dehydration

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. Dehydration may cause acute renal failure, especially in patients with pre-existing compromised renal function or when Ксалвобин is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration might be potentially fatal. If grade 2 (or higher) dehydration occurs, Ксалвобин treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be applied for the precipitating adverse event as necessary.

Hand-foot syndrome

Hand and foot syndrome also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema.

Grade 1 hand-foot syndrome is defined as numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient's normal activities.

Grade 2 hand-foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living.

Grade 3 hand-foot syndrome is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-foot syndrome occurs, administration of Ксалвобин should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of Ксалвобин should be decreased. When Ксалвобин and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with Ксалвобин Accord.

Cardiotoxicity

Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsade de pointes, and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving Ксалвобин.

Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris.

Hypo- or hypercalcaemia

Hypo- or hypercalcaemia has been reported during Ксалвобин treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia.

Central or peripheral nervous system disease

Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy.

Diabetes mellitus or electrolyte disturbances

Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during Ксалвобин treatment.

Coumarin-derivative anticoagulation

In a interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by Ксалвобин. Patients receiving concomitant Ксалвобин and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly.

Hepatic impairment

In the absence of safety and efficacy data in patients with hepatic impairment, Ксалвобин use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of Ксалвобин should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with Ксалвобин monotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN.

Renal impairment

The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population.

Dihydropyrimidine dehydrogenase (DPD) deficiency

Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity.

Patients with low or absent DPD activity, an enzyme involved in fluorouracil degradation, are at increased risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus, which can cause complete or near complete absence of DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life-threatening or fatal toxicity and should not be treated with Ксалвобин Accord. No dose has been proven safe for patients with complete absence of DPD activity.

For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of Ксалвобин Accord are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution and frequent monitoring with dose adjusment according to toxicity.There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by specific test.

In patients with unrecognised DPD deficiency treated with Ксалвобин, life-threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities.

Ophthalmologic complications

Patients should be carefully monitored for ophthalmological complications such as keratitis and corneal disorders, especially if they have a prior history of eye disorders. Treatment of eye disorders should be initiated as clinically appropriate.

Severe skin reactions

Ксалвобин can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Ксалвобин should be permanently discontinued in patients who experience a severe skin reaction during treatment.

Excipients

As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ксалвобин has minor or moderate influence on the ability to drive and use machines. Ксалвобин may cause dizziness, fatigue and nausea.

Summary of the safety profile

The overall safety profile of Ксалвобин is based on data from over 3,000 patients treated with Ксалвобин as monotherapy or Ксалвобин in combination with different chemotherapy regimens in multiple indications.

The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

Tabulated list of adverse reactions

ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of Ксалвобин are listed in Table 5 for Ксалвобин given as monotherapy and in Table 6 for Ксалвобин given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common (> 1/10), common (> 1/100 to < 1/10) uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Ксалвобин monotherapy

Table 5 lists ADRs associated with the use of Ксалвобин monotherapy based on a pooled analysis of safety data from three major studies including over 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.

Table 5 Summary of related ADRs reported in patients treated with Ксалвобин monotherapy

** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome can eventually lead to loss of fingerprints

Ксалвобин in combination therapy

Table 6 lists ADRs associated with the use of Ксалвобин in combination with different chemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRs are added to the appropriate frequency grouping (very common or common) according to the highest incidence seen in any of the major clinical trials and are only added when they were seen in addition to those seen with Ксалвобин monotherapy or seen at a higher frequency grouping compared to Ксалвобин monotherapy (see Table 5). Uncommon ADRs reported for Ксалвобин in combination therapy are consistent with the ADRs reported for Ксалвобин monotherapy or reported for monotherapy with the combination medicinal product (in literature and/or respective summary of product characteristics).

Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by Ксалвобин therapy can not be excluded.

Table 6 Summary of related ADRs reported in patients treated with Ксалвобин in combination treatment in addition to those seen with Ксалвобин monotherapy or seen at a higher frequency grouping compared to Ксалвобин monotherapy

⁺ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest incidence seen in any of the major combination trials.

Description of selected adverse reactions

Hand-foot syndrome (HFS)

For the Ксалвобин dose of 1250 mg/m² twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-grades HFS was observed in Ксалвобин monotherapy trials (comprising studies in adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of 63% was observed in the Ксалвобин/docetaxel arm for the treatment of metastatic breast cancer. For the Ксалвобин dose of 1000 mg/m² twice daily on days 1 to 14 every 3weeks, a frequency of 22% to 30% of all-grade HFS was observed in Ксалвобин combination therapy.

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with Ксалвобин monotherapy or Ксалвобин in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with Ксалвобин. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing Ксалвобин starting dose (gram), decreasing cumulative Ксалвобин dose (0.1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good ECOG performance status at baseline (0 versus >1).

Diarrhoea

Ксалвобин can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with Ксалвобин showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing Ксалвобин starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year increments), and female gender. The following covariates were statistically significantly associated with a decreased risk of developing diarrhoea: increasing cumulative Ксалвобин dose (0.1*kg) and increasing relative dose intensity in the first six weeks.

Cardiotoxicity

In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 0.1% were associated with the use of Ксалвобин monotherapy based on a pooled analysis from clinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, sudden death, and ventricular extrasystoles.

Encephalopathy

In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from clinical safety data from 7 clinical trials, encephalopathy was also associated with the use of Ксалвобин monotherapy with an incidence of less than 0.1%.

Special populations

Elderly patients

An analysis of safety data in patients > 60 years of age treated with Ксалвобин monotherapy and an analysis of patients treated with Ксалвобин plus docetaxel combination therapy showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients < 60 years of age. Patients > 60 years of age treated with Ксалвобин plus docetaxel also had more early withdrawals from treatment due to adverse reactions compared to patients < 60 years of age.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with Ксалвобин showed that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Gender

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with Ксалвобин showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Patients with renal impairment :

An analysis of safety data in patients treated with Ксалвобин monotherapy (colorectal cancer) with baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions compared to patients with normal renal function (36% in patients without renal impairment n=268, vs. 41% in mild n=257 and 54% in moderate n=59, respectively). Patients with moderately impaired renal function show an increased rate of dose reduction (44%) vs. 33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild renal impairment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: L01BC06

Ксалвобин is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Ксалвобин is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit usually at lower levels. In human cancer xenograft models Ксалвобин demonstrated a synergistic effect in combination with docetaxel, which may be related to the upregulation of thymidine phosphorylase by docetaxel.

There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and which metabolise 5-FU at a more rapid rate.

Colon and colorectal cancer

Monotherapy with Ксалвобин in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase III clinical trial in patients with stage III (Dukes' C) colon cancer supports the use of Ксалвобин for the adjuvant treatment of patients with colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with Ксалвобин (1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo Clinic regimen: 20 mg/m² leucovorin intravenous followed by 425 mg/m² intravenous bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks). Ксалвобин was at least equivalent to intravenous 5-FU/LV in disease-free survival in per protocol population (hazard ratio 0.92; 95% CI 0.80-1.06). In the all-randomised population, tests for difference of Ксалвобин vs 5-FU/LV in disease-free and overall survival showed hazard ratios of 0.88 (95% CI 0.77 - 1.01; p = 0.068) and 0.86 (95% CI 0.74 - 1.01; p = 0.060), respectively. The median follow up at the time of the analysis was 6.9 years. In a preplanned multivariate Cox analysis, superiority of Ксалвобин compared with bolus 5-FU/LV was demonstrated. The following factors were pre-specified in the statistical analysis plan for inclusion in the model: age, time from surgery to randomisation, gender, CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population, Ксалвобин was shown to be superior to 5-FU/LV for disease-free survival (hazard ratio 0.849; 95% CI 0.739 - 0.976; p = 0.0212), as well as for overall survival (hazard ratio 0.828; 95% CI 0.705 - 0.971; p = 0.0203).

Combination therapy in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III (Dukes' C) colon cancer supports the use of Ксалвобин in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (NO16968 study). In this trial, 944 patients were randomised to 3-week cycles for 24 weeks with Ксалвобин (1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m² intravenous infusion over 2-hours on day 1 every 3 weeks); 942 patients were randomised to bolus 5-FU and leucovorin. In the primary analysis for DFS in the ITT population, XELOX was shown to be significantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of RFS supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486) which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV. The efficacy data is based on a median observation time of 59 months for OS and 57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX combination therapy arm (21 %) as compared with that of the 5-FU/LV monotherapy arm (9 %) in the ITT population.

Monotherapy with Ксалвобин in metastatic colorectal cancer

Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials (SO14695; SO14796) support the use of Ксалвобин for first line treatment of metastatic colorectal cancer. In these trials, 603 patients were randomised to treatment with Ксалвобин (1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles). 604 patients were randomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m² leucovorin intravenous followed by 425 mg/m² intravenous bolus 5-FU, on days 1 to 5, every 28 days). The overall objective response rates in the all-randomised population (investigator assessment) were 25.7% (Ксалвобин) vs. 16.7% (Mayo regimen); p <0.0002. The median time to progression was 140 days (Ксалвобин) vs. 144 days (Mayo regimen). Median survival was 392 days (Ксалвобин) vs. 391 days (Mayo regimen). Currently, no comparative data are available on Ксалвобин monotherapy in colorectal cancer in comparison with first line combination regimens.

Combination therapy in first-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of Ксалвобин in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2-arm part in which 634 patients were randomised to two different treatment groups, including XELOX or FOLFOX-4, and a subsequent 2x2 factorial part in which 1401 patients were randomised to four different treatment groups, including XELOX plus placebo, FOLFOX-4 plus placebo, XELOX plus bevacizumab, and FOLFOX-4 plus bevacizumab. See Table 7 for treatment regimens.

Table 7 Treatment regimens in study NO16966 (mCRC)

Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival in the eligible patient population and the intent-to-treat population (see Table 8). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival (see Table 8). A comparison of XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus bevacizumab in terms of progression-free survival (hazard ratio 1.01; 97.5% CI 0.84 - 1.22). The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are also included in Table 8. However, the on-treatment PFS analysis did not confirm the results of the general PFS and OS analysis: the hazard ratio of XELOX versus FOLFOX-4 was 1.24 with 97.5% CI 1.07 - 1.44. Although sensitivity analyses show that differences in regimen schedules and timing of tumor assessments impact the on-treatment PFS analysis, a full explanation for this result has not been found.

Table 8 Key efficacy results for the non-inferiority analysis of Study NO16966

*EPP=eligible patient population; **ITT=intent-to-treat population.

In a randomised, controlled phase III study (CAIRO), the effect of using Ксалвобин at a starting dose of 1000 mg/m² for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer was studied. 820 Patients were randomised to receive either sequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted of first-line Ксалвобин (1250 mg/m² twice daily for 14 days), second-line irinotecan (350 mg/m² on day 1), and third-line combination of Ксалвобин (1000 mg/m² twice daily for 14 days) with oxaliplatin (130 mg/m² on day 1). Combination treatment consisted of first-line Ксалвобин (1000 mg/m² twice daily for 14 days) combined with irinotecan (250 mg /m² on day 1) (XELIRI) and second-line Ксалвобин (1000 mg/m² twice daily for 14 days) plus oxaliplatin (130 mg/m2 on day 1). All treatment cycles were administered at intervals of 3 weeks. In first-line treatment the median progression-free survival in the intent-to-treat population was 5.8 months (95%CI 5.1 - 6.2 months) for Ксалвобин monotherapy and 7.8 months (95%CI 7.0 - 8.3 months; p=0.0002) for XELIRI. However this was associated with an increased incidence of gastrointestinal toxicity and neutropenia during first-line treatment with XELIRI (26% and 11% for XELIRI and first line Ксалвобин respectively).

The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies in patients with metastatic colorectal cancer. The XELIRI regimens included Ксалвобин 1000 mg/m² twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m² on day1. In the largest study (BICC-C), patients were randomised to receive either open label FOLFIRI (n=144), bolus 5-FU (mIFL) (n=145) or XELIRI (n=141) and were additionally randomised to receive either double-blind treatment with celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months for XELIRI (p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9 months for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinal toxicity compared with FOLFIRI (diarrhoea 48% and 14% for XELIRI and FOLFIRI respectively).

In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or XELIRI (n=44) with additional randomisation to either double-blind treatment with celecoxib or placebo. Median PFS and overall survival (OS) times were shorter for XELIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in addition to which excessive rates of diarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI, 5.1% FOLFIRI).

In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI.

Overall response rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end of treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (p=0.56). Toxcity was similar between treatments with the exception of neutropenia reported more commonly in patients treated with FOLFIRI.

Montagnani et al used the results from the above three studies to provide an overall analysis of randomised studies comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC. A significant reduction in the risk of progression was associated with FOLFIRI (HR, 0.76; 95%CI, 0.62-0.95; P <0.01), a result partly due to poor tolerance to the XELIRI regimens used.

Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumab with XELIRI + bevacizumab showed no significant differences in PFS or OS between treatments. Patients were randomised to receive either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRI plus bevacizumab (Arm-B, n-166). For Arm B, the XELIRI regimen used Ксалвобин 1000 mg/m² twice daily for 14 days +irinotecan 250 mg/m² on day 1. Median progression-free survival (PFS) was 10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and response rates 45.5 and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI + bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot skin reactions than patients treated with FOLFIRI + bevacizumab with significantly increased treatment delays, dose reductions and treatment discontinuations.

Data from a multicentre, randomised, controlled phase II study (AIO KRK 0604) supports the use of Ксалвобин at a starting dose of 800 mg/m² for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 120 Patients were randomised to a modified XELIRI regimen with Ксалвобин 800 mg/m² twice daily for two weeks followed by a 7-day rest period), irinotecan (200 mg/m² as a 30 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks) ; 127 patients were randomised to treatment with Ксалвобин (1000 mg/m² twice daily for two weeks followed by a 7-day rest period), oxaliplatin (130 mg/m² as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Following a mean duration of follow-up for the study population of 26.2 months, treatment responses were as shown below:

Table 9 Key efficacy results for AIO KRK study

Combination therapy in second-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use of Ксалвобин in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first line therapy were randomised to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to Table 7. XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population and intent-to-treat population (see Table 10). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival (see Table 10). The median follow up at the time of the primary analyses in the intent-to-treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also included in Table 10.

Table 10 Key efficacy results for the non-inferiority analysis of Study NO16967

*PPP=per-protocol population; **ITT=intent-to-treat population.

Advanced gastric cancer:

Data from a multicentre, randomised, controlled phase III clinical trial in patients with advanced gastric cancer supports the use of Ксалвобин for the first-line treatment of advanced gastric cancer (ML17032). In this trial, 160 patients were randomised to treatment with Ксалвобин (1000 mg/m² twice daily for 2 weeks followed by a 7-day rest period) and cisplatin (80 mg/m² as a 2-hour infusion every 3 weeks). A total of 156 patients were randomised to treatment with 5-FU (800 mg/m² per day, continuous infusion on days 1 to 5 every 3 weeks) and cisplatin (80 mg/m² as a 2-hour infusion on day 1, every 3 weeks). Ксалвобин in combination with cisplatin was non-inferior to 5-FU in combination with cisplatin in terms of progression-free survival in the per protocol analysis (hazard ratio 0.81; 95% CI 0.63 - 1.04). The median progression-free survival was 5.6 months (Ксалвобин + cisplatin) versus 5.0 months (5-FU + cisplatin). The hazard ratio for duration of survival (overall survival) was similar to the hazard ratio for progression-free survival (hazard ratio 0.85; 95% CI 0.64 - 1.13). The median duration of survival was 10.5 months (Ксалвобин + cisplatin) versus 9.3 months (5-FU + cisplatin).

Data from a randomised multicentre, phase III study comparing Ксалвобин to 5-FU and oxaliplatin to cisplatin in patients with advanced gastric cancer supports the use of Ксалвобин for the first-line treatment of advanced gastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2 factorial design to one of the following 4 arms:

- ECF: epirubicin (50 mg/ m² as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m² as a two hour infusion on day 1 every 3 weeks) and 5-FU (200 mg/m² daily given by continuous infusion via a central line).

- ECX: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m² as a two hour infusion on day 1 every 3 weeks), and Ксалвобин (625 mg/m² twice daily continuously).

- EOF: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m² given as a 2 hour infusion on day 1 every three weeks), and 5-FU (200 mg/m² daily given by continuous infusion via a central line).

- EOX: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m² given as a 2 hour infusion on day 1 every three weeks), and Ксалвобин (625 mg/m² twice daily continuously).

The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall survival for Ксалвобин- vs 5-FU-based regimens (hazard ratio 0.86; 95% CI 0.8 - 0.99) and for oxaliplatin- vs cisplatin-based regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1). The median overall survival was 10.9 months in Ксалвобин-based regimens and 9.6 months in 5-FU based regimens. The median overall survival was 10.0 months in cisplatin-based regimens and 10.4 months in oxaliplatin-based regimens.

Ксалвобин has also been used in combination with oxaliplatin for the treatment of advanced gastric cancer. Studies with Ксалвобин monotherapy indicate that Ксалвобин has activity in advanced gastric cancer.

Colon, colorectal and advanced gastric cancer: meta-analysis

A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) supports Ксалвобин replacing 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with Ксалвобин -containing regimens and 3074 patients treated with 5-FU-containing regimens. Median overall survival time was 703 days (95% CI: 671; 745) in patients treated with Ксалвобин -containing regimens and 683 days (95% CI: 646; 715) in patients treated with 5-FU-containing regimens. The hazard ratio for overall survival was 0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that Ксалвобин -containing regimens are non-inferior to 5-FU-containing regimens.

Breast cancer:

Combination therapy with Ксалвобин and docetaxel in locally advanced or metastatic breast cancer

Data from one multicentre, randomised, controlled phase III clinical trial support the use of Ксалвобин in combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomised to treatment with Ксалвобин (1250 mg/m² twice daily for 2 weeks followed by 1-week rest period and docetaxel 75 mg/m² as a 1 hour intravenous infusion every 3 weeks). 256 patients were randomised to treatment with docetaxel alone (100 mg/m² as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the Ксалвобин + docetaxel combination arm (p=0.0126). Median survival was 442 days (Ксалвобин + docetaxel) vs. 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (Ксалвобин + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the Ксалвобин + docetaxel combination arm (p<0.0001). The median time to progression was 186 days (Ксалвобин + docetaxel) vs. 128 days (docetaxel alone).

Monotherapy with Ксалвобин after failure of taxanes, anthracycline containing chemotherapy, and for whom anthracycline therapy is not indicated

Data from two multicentre phase II clinical trials support the use of Ксалвобин monotherapy for treatment of patients after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were treated with Ксалвобин (1250 mg/m² twice daily for 2 weeks followed by 1-week rest period). The overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). The median time to progression was 93 and 98 days. Median survival was 384 and 373 days.

All indications

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with Ксалвобин monotherapy or Ксалвобин in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that patients on Ксалвобин who developed hand-foot syndrome (HFS) had a longer overall survival compared to patients who did not develop HFS: median overall survival 1100 days (95% CI 1007;1200) vs 691 days (95% CI 638;754) with a hazard ratio of 0.61 (95% CI 0.56; 0.66).

Paediatric population

The pharmacokinetics of Ксалвобин have been evaluated over a dose range of 502-3514 mg/m²/day. The parameters of Ксалвобин, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 14. Ксалвобин dose reduction decreases systemic exposure to 5-FU more than dose-proportionally, due to non-linear pharmacokinetics for the active metabolite.

Absorption

After oral administration, Ксалвобин is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of Ксалвобин absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite 5-FU. At the dose of 1250 mg/m² on day 14 with administration after food intake, the peak plasma concentrations (C_max in µg/ml) for Ксалвобин, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak plasma concentrations (T_max in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC_0-∞ values in μg-h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3.

Distribution

In vitro human plasma studies have determined that Ксалвобин, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.

Biotransformation

Ксалвобин is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissues. Further catalytic activation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved in the catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lower levels. The sequential enzymatic biotransformation of Ксалвобин to 5-FU leads to higher concentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to be in large part localised in tumour stromal cells. Following oral administration of Ксалвобин to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacent tissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4 (ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8, n=8). Thymidine phosphorylase activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue. According to immunohistochemical studies, thymidine phosphorylase appears to be in large part localised in tumour stromal cells.

5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of Ксалвобин.

Elimination

The elimination half-life (t_1/2 in hours) of Ксалвобин, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Ксалвобин and its metabolites are predominantly excreted in urine; 95.5% of administered Ксалвобин dose is recovered in urine. Faecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine unchanged

Combination therapy

Phase I studies evaluating the effect of Ксалвобин on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by Ксалвобин on the pharmacokinetics of docetaxel or paclitaxel (C_max and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR.

Pharmacokinetics in special populations

A population pharmacokinetic analysis was carried out after Ксалвобин treatment of 505 patients with colorectal cancer dosed at 1250 mg/m² twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Patients with hepatic impairment due to liver metastases: According to a pharmacokinetic study in cancer patients with mild to moderate liver impairment due to liver metastases, the bioavailability of Ксалвобин and exposure to 5-FU may increase compared to patients with no liver impairment. There are no pharmacokinetic data on patients with severe hepatic impairment.

Patients with renal impairment: Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite without antiproliferative activity.

Elderly: Based on the population pharmacokinetic analysis, which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function.

Ethnic factors: Following oral administration of 825 mg/m² Ксалвобин twice daily for 14 days, Japanese patients (n=18) had about 36% lower C_max and 24% lower AUC for Ксалвобин than Caucasian patients (n=22). Japanese patients had also about 25% lower C_max and 34% lower AUC for FBAL than Caucasian patients. The clinical relevance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).

In repeat-dose toxicity studies, daily oral administration of Ксалвобин to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised bydegenerative/regressive changes, was observed with Ксалвобин. Ксалвобин was devoid of hepatic and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1379 mg/m²/day).

A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by Ксалвобин.

During standard fertility studies, impairment of fertility was observed in female mice receiving Ксалвобин; however, this effect was reversible after a drug-free period. In addition, during a 13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period.

In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.

Ксалвобин was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), Ксалвобин was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).

Not applicable.

No special requirements.