The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Catepen overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low– molecular-weight metabolite of the parent compound.
Single doses of Catepen were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).
Catepen is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]).
HypersensitivityCatepen is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Catepen is contraindicated in patients who have a known hypersensitivity to 5- fluorouracil.
Not applicable.
Summary of the safety profile
The overall safety profile of Catepen is based on data from over 3,000 patients treated with Catepen as monotherapy or Catepen 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 Catepen are listed in Table 5 for Catepen given as monotherapy and in Table 6 for Catepen 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.
Catepen monotherapy
Table 5 lists ADRs associated with the use of Catepen 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 Catepen monotherapy
| Body System | Very Common All grades | Common All grades | Uncommon Severe and/or Life-threatening (grade 3-4) or considered medically relevant | Rare/Very Rare (Post-Marketing Experience) |
| Infections and infestations | - | Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection | Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess | |
| Neoplasm benign, malignant and unspecified | - | - | Lipoma | |
| Blood and lymphatic system disorders | - | Neutropenia, Anaemia | Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leukopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/Prothrombin time prolonged | |
| Immune system disorders | - | - | Hypersensitivity | |
| Metabolism and nutrition disorders | Anorexia | Dehydration, Weight decreased | Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia | |
| Psychiatric disorders | - | Insomnia, Depression | Confusional state, Panic attack, Depressed mood, Libido decreased | |
| Nervous system disorders | - | Headache, Lethargy Dizziness, Parasthesia, Dysgeusia | Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral | Toxic leukoencephalopathy (very rare) |
| Eye disorders | - | Lacrimation increased,Conjunctivitis, Eye irritation | Visual acuity reduced, Diplopia | Lacrimal duct stenosis (rare), Corneal disorders(rare), keratitis (rare), punctate keratitis (rare) |
| Ear and labyrinth disorders | - | - | Vertigo, Ear pain | |
| Cardiac disorders | - | - | Angina unstable, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations | Ventricular fibrillation (rare), QT prolongation (rare), Torsade de pointes (rare), Bradycardia (rare), Vasospasm (rare) |
| Vascular disorders | - | Thrombophlebitis | Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Hot flush, Peripheral coldness | |
| Respiratory, thoracic and mediastinal disorders | - | Dyspnoea, Epistaxis, Cough, Rhinorrhoea | Pulmonary embolism, Pneumothorax, Haemoptysis, Asthma, Dyspnoea exertional | |
| Gastrointestinal disorders | Diarrhoea, Vomiting, Nausea, Stomatitis, Abdominal pain | Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth | Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Abdominal pain lower, Oesophagitis, Abdominal discomfort, Gastrooesophageal reflux disease, Colitis, Blood in stool | |
| Hepatobiliary disorders | - | Hyperbilirubinemia, Liver function test abnormalities | Jaundice | Hepatic failure (rare), Cholestatic hepatitis (rare) |
| Skin and subcutaneous tissue disorders | Palmar-plantar erythrodysaesthesia syndrome** | Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyper-pigmentation, Rash macular, Skin desquamation, Dermatitis, Pigmentation disorder, Nail disorder | Blister, Skin ulcer, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Swelling face, Purpura, Radiation recall syndrome | Cutaneous lupus erythematosus (rare), Severe skin reactions such as Stevens-Johnson Syndrome and toxic Epidermal Necrolysis (very rare) |
| Muskuloskeletal and connective tissue disorders | - | Pain in extremity, Back pain, Arthralgia | Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscular weakness | |
| Renal and urinary disorders | - | - | Hydronephrosis, Urinary incontinence, Haematuria, Nocturia, Blood creatinine increased | |
| Reproductive system and breast disorders | - | - | Vaginal haemorrhage | |
| General disorders and administration site conditions | Fatigue, Asthenia | Pyrexia, Oedema peripheral, Malaise, Chest pain | Oedema, Chills, Influenza like illness, Rigors, Body temperature increased |
** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome can eventually lead to loss of fingerprints
Catepen in combination therapy
Table 6 lists ADRs associated with the use of Catepen 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 Catepen monotherapy or seen at a higher frequency grouping compared to Catepen monotherapy (see Table 5). Uncommon ADRs reported for Catepen in combination therapy are consistent with the ADRs reported for Catepen 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 Catepen therapy can not be excluded.
Table 6 Summary of related ADRs reported in patients treated with Catepen in combination treatment in addition to those seen with Catepen monotherapy or seen at a higher frequency grouping compared to Catepen monotherapy
| Body System | Very Common All grades | Common All grades | Rare/Very Rare (Post-Marketing Experience) |
| Infections and infestations | - | Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection , Rhinitis, Influenza, +Infection, Oral herpes | |
| Blood and lymphatic system disorders | +Neutropenia, +Leucopenia, +Anaemia, +Neutropenic fever, Thrombocytopenia | Bone marrow depression, +Febrile Neutropenia | |
| Immune system disorders | - | Hypersensitivity | |
| Metabolism and nutrition disorders | Appetite decreased | Hypokalaemia, Hyponatraemia, Hypomagnesaemia, Hypocalcaemia, Hyperglycaemia | |
| Psychiatric disorders | - | Sleep disorder, Anxiety | |
| Nervous system disorders | Paraesthesia, Dysaesthesia, Peripheral neuropathy, Peripheral sensory neuropathy, Dysgeusia, Headache | Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction, Hypoaesthesia | |
| Eye disorders | Lacrimation increased | Visual disorders, Dry eye, Eye pain, Visual impairment, Vision blurred | |
| Ear and labyrinth disorders | - | Tinnitus, Hypoacusis | |
| Cardiac disorders | - | Atrial fibrillation, Cardiac ischaemia/infarction | |
| Vascular disorders | Lower limb oedema, Hypertension, +Embolism and thrombosis | Flushing, Hypotension, Hypertensive crisis, Hot flush, Phlebitis | |
| Respiratory, thoracic and mediastinal system disorders | Sore throat, Dysaesthesia pharynx | Hiccups, Pharyngolaryngeal pain, Dysphonia | |
| Gastrointestinal disorders | Constipation, Dyspepsia | Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Oral pain, Dysphagia, Rectal haemorrhage, Abdominal pain lower, Oral dysaesthesia, Paraesthesia oral, Hypoaesthesia oral, Abdominal discomfort | |
| Hepatobiliary disorders | - | Hepatic function abnormal | |
| Skin and subcutaneous tissue disorders | Alopecia, Nail disorder | Hyperhidrosis, Rash erythematous, Urticaria, Night sweats | |
| Musculoskeletal and connective tissue disorders | Myalgia, Arthralgia, Pain in extremity | Pain in jaw , Muscle spasms, Trismus, Muscular weakness | |
| Renal and urinary disorders | - | Haematuria, Proteinuria, Creatinine renal clearance decreased, Dysuria | Acute renal failure secondary to dehydration (rare) |
| General disorders and administration site conditions | Pyrexia, Weakness, +Lethargy, Temperature intolerance | Mucosal inflammation, Pain in limb, Pain, Chills, Chest pain, Influenza-like illness, +Fever, Infusion related reaction, Injection site reaction, Infusion site pain, Injection site pain | |
| Injury, poisoning and procedural complications | - | Contusion |
+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+â€, 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 Catepen 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 Catepen 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 Catepen/docetaxel arm for the treatment of metastatic breast cancer. For the Catepen 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 Catepen combination therapy.
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with Catepen monotherapy or Catepen 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 Catepen. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing Catepen starting dose (gram), decreasing cumulative Catepen 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
Catepen 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 Catepen showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen monotherapy and an analysis of patients treated with Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen 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.
Summary of the safety profile
The overall safety profile of capecitabine is based on data from over 3,000 patients treated with capecitabine as monotherapy or capecitabine 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 capecitabine are listed in Table 5 for capecitabine given as monotherapy and in Table 6 for capecitabine 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.
Capecitabine monotherapy
Table 5 lists ADRs associated with the use of capecitabine 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 capecitabine monotherapy
| Body System | Very Common All grades | Common All grades | Uncommon Severe and/or Life-threatening (grade 3-4) or considered medically relevant | Rare/Very Rare (Post-Marketing Experience) |
| Infections and infestations | - | Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection | Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess | |
| Neoplasm benign, malignant and unspecified | - | - | Lipoma | |
| Blood and lymphatic system disorders | - | Neutropenia, Anaemia | Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leukopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/Prothrombin time prolonged | |
| Immune system disorders | - | - | Hypersensitivity | |
| Metabolism and nutrition disorders | Anorexia | Dehydration, Weight decreased | Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia | |
| Psychiatric disorders | - | Insomnia, Depression | Confusional state, Panic attack, Depressed mood, Libido decreased | |
| Nervous system disorders | - | Headache, Lethargy Dizziness, Parasthesia, Dysgeusia | Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral | Toxic leukoencephalopathy (very rare) |
| Eye disorders | - | Lacrimation increased,Conjunctivitis, Eye irritation | Visual acuity reduced, Diplopia | Lacrimal duct stenosis (rare), Corneal disorders(rare), keratitis (rare), punctate keratitis (rare) |
| Ear and labyrinth disorders | - | - | Vertigo, Ear pain | |
| Cardiac disorders | - | - | Angina unstable, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations | Ventricular fibrillation (rare), QT prolongation (rare), Torsade de pointes (rare), Bradycardia (rare), Vasospasm (rare) |
| Vascular disorders | - | Thrombophlebitis | Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Hot flush, Peripheral coldness | |
| Respiratory, thoracic and mediastinal disorders | - | Dyspnoea, Epistaxis, Cough, Rhinorrhoea | Pulmonary embolism, Pneumothorax, Haemoptysis, Asthma, Dyspnoea exertional | |
| Gastrointestinal disorders | Diarrhoea, Vomiting, Nausea, Stomatitis, Abdominal pain | Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth | Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Abdominal pain lower, Oesophagitis, Abdominal discomfort, Gastrooesophageal reflux disease, Colitis, Blood in stool | |
| Hepatobiliary disorders | - | Hyperbilirubinemia, Liver function test abnormalities | Jaundice | Hepatic failure (rare), Cholestatic hepatitis (rare) |
| Skin and subcutaneous tissue disorders | Palmar-plantar erythrodysaesthesia syndrome** | Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyper-pigmentation, Rash macular, Skin desquamation, Dermatitis, Pigmentation disorder, Nail disorder | Blister, Skin ulcer, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Swelling face, Purpura, Radiation recall syndrome | Cutaneous lupus erythematosus (rare), Severe skin reactions such as Stevens-Johnson Syndrome and toxic Epidermal Necrolysis (very rare) |
| Muskuloskeletal and connective tissue disorders | - | Pain in extremity, Back pain, Arthralgia | Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscular weakness | |
| Renal and urinary disorders | - | - | Hydronephrosis, Urinary incontinence, Haematuria, Nocturia, Blood creatinine increased | |
| Reproductive system and breast disorders | - | - | Vaginal haemorrhage | |
| General disorders and administration site conditions | Fatigue, Asthenia | Pyrexia, Oedema peripheral, Malaise, Chest pain | Oedema, Chills, Influenza like illness, Rigors, Body temperature increased |
** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome can eventually lead to loss of fingerprints
Capecitabine in combination therapy
Table 6 lists ADRs associated with the use of capecitabine 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 capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy (see Table 5). Uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine 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 capecitabine therapy can not be excluded.
Table 6 Summary of related ADRs reported in patients treated with capecitabine in combination treatment in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy
| Body System | Very Common All grades | Common All grades | Rare/Very Rare (Post-Marketing Experience) |
| Infections and infestations | - | Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection , Rhinitis, Influenza, +Infection, Oral herpes | |
| Blood and lymphatic system disorders | +Neutropenia, +Leucopenia, +Anaemia, +Neutropenic fever, Thrombocytopenia | Bone marrow depression, +Febrile Neutropenia | |
| Immune system disorders | - | Hypersensitivity | |
| Metabolism and nutrition disorders | Appetite decreased | Hypokalaemia, Hyponatraemia, Hypomagnesaemia, Hypocalcaemia, Hyperglycaemia | |
| Psychiatric disorders | - | Sleep disorder, Anxiety | |
| Nervous system disorders | Paraesthesia, Dysaesthesia, Peripheral neuropathy, Peripheral sensory neuropathy, Dysgeusia, Headache | Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction, Hypoaesthesia | |
| Eye disorders | Lacrimation increased | Visual disorders, Dry eye, Eye pain, Visual impairment, Vision blurred | |
| Ear and labyrinth disorders | - | Tinnitus, Hypoacusis | |
| Cardiac disorders | - | Atrial fibrillation, Cardiac ischaemia/infarction | |
| Vascular disorders | Lower limb oedema, Hypertension, +Embolism and thrombosis | Flushing, Hypotension, Hypertensive crisis, Hot flush, Phlebitis | |
| Respiratory, thoracic and mediastinal system disorders | Sore throat, Dysaesthesia pharynx | Hiccups, Pharyngolaryngeal pain, Dysphonia | |
| Gastrointestinal disorders | Constipation, Dyspepsia | Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Oral pain, Dysphagia, Rectal haemorrhage, Abdominal pain lower, Oral dysaesthesia, Paraesthesia oral, Hypoaesthesia oral, Abdominal discomfort | |
| Hepatobiliary disorders | - | Hepatic function abnormal | |
| Skin and subcutaneous tissue disorders | Alopecia, Nail disorder | Hyperhidrosis, Rash erythematous, Urticaria, Night sweats | |
| Musculoskeletal and connective tissue disorders | Myalgia, Arthralgia, Pain in extremity | Pain in jaw , Muscle spasms, Trismus, Muscular weakness | |
| Renal and urinary disorders | - | Haematuria, Proteinuria, Creatinine renal clearance decreased, Dysuria | Acute renal failure secondary to dehydration (rare) |
| General disorders and administration site conditions | Pyrexia, Weakness, +Lethargy, Temperature intolerance | Mucosal inflammation, Pain in limb, Pain, Chills, Chest pain, Influenza-like illness, +Fever, Infusion related reaction, Injection site reaction, Infusion site pain, Injection site pain | |
| Injury, poisoning and procedural complications | - | Contusion |
+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+â€, 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 capecitabine 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 capecitabine 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 capecitabine/docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine 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 capecitabine combination therapy.
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or capecitabine 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 capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine 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
Capecitabine 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 capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine monotherapy and an analysis of patients treated with capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adjuvant Colon CancerTable 4 shows the adverse reactions occurring in =5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of Catepen administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to Catepen and 10 (1.0%) randomized to 5-FU/LV.
Table 5 shows grade 3/4 laboratory abnormalities occurring in =1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
Table 4 Percent Incidence of Adverse Reactions Reported in =5% of Patients Treated With Catepen or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
| Body System/ Adverse Event | Adjuvant Treatment for Colon Cancer (N=1969) | |||
| Catepen (N=995) | 5-FU/LV (N=974) | |||
| All Grades | Grade 3/4 | All Grades | Grade 3/4 | |
| Gastrointestinal Disorders | ||||
| Diarrhea | 47 | 12 | 65 | 14 |
| Nausea | 34 | 2 | 47 | 2 |
| Stomatitis | 22 | 2 | 60 | 14 |
| Vomiting | 15 | 2 | 21 | 2 |
| Abdominal Pain | 14 | 3 | 16 | 2 |
| Constipation | 9 | - | 11 | <1 |
| Upper Abdominal Pain | 7 | <1 | 7 | <1 |
| Dyspepsia | 6 | <1 | 5 | - |
| Skin and Subcutaneous Tissue Disorders | ||||
| Hand-and-Foot Syndrome | 60 | 17 | 9 | <1 |
| Alopecia | 6 | - | 22 | <1 |
| Rash | 7 | - | 8 | - |
| Erythema | 6 | 1 | 5 | <1 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 16 | <1 | 16 | 1 |
| Pyrexia | 7 | <1 | 9 | <1 |
| Asthenia | 10 | <1 | 10 | 1 |
| Lethargy | 10 | <1 | 9 | <1 |
| Nervous System Disorders | ||||
| Dizziness | 6 | <1 | 6 | - |
| Headache | 5 | <1 | 6 | <1 |
| Dysgeusia | 6 | - | 9 | - |
| Metabolism and Nutrition Disorders | ||||
| Anorexia | 9 | <1 | 11 | <1 |
| Eye Disorders | ||||
| Conjunctivitis | 5 | <1 | 6 | <1 |
| Blood and Lymphatic System Disorders | ||||
| Neutropenia | 2 | <1 | 8 | 5 |
| Respiratory Thoracic and Mediastinal Disorders | ||||
| Epistaxis | 2 | - | 5 | - |
Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in =1% of Patients Receiving Catepen Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
| Advers e Event | Catepen (n=995) Grade 3/4 % | IV 5-FU/LV (n=974) Grade 3/4 % |
| Increased ALAT (SGPT) | 1.6 | 0.6 |
| Increased calcium | 1.1 | 0.7 |
| Decreased calcium | 2.3 | 2.2 |
| Decreased hemoglobin | 1.0 | 1.2 |
| Decreased lymphocytes | 13.0 | 13.0 |
| Decreased neutrophils* | 2.2 | 26.2 |
| Decreased neutrophils/granulocytes | 2.4 | 26.4 |
| Decreased platelets | 1.0 | 0.7 |
| Increased bilirubin† | 20 | 6.3 |
| *The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the Catepen arm and 4.9% in the IV 5-FU/LV arm. †It should be noted that grading was according to NCIC CTC Version 1 (May, 1994 ). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 x upper limit of normal (ULN) range, and grade 4 a value of > 3.0 x ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of>3.0 to 10.0 x ULN, and grade 4 values >10.0 x ULN. |
Table 6 shows the adverse reactions occurring in =5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of Catepen administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LVtreated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to Catepen and 32 (5.4%) randomized to 5-FU/LV.
Table 6 Pooled Phase 3 Colorectal Trials : Percent Incidence of Adverse Reactions in =5% of Patients
| Adverse Event | Catepen (n=596) | 5-FU/LV (n=593) | ||||
| Total % | Grade 3% | Grade 4% | Total % | Grade 3% | Grade 4% | |
| Number of Patients With > One Adverse Event | 96 | 52 | 9 | 94 | 45 | 9 |
| Body System/Adverse Event | ||||||
| GI | ||||||
| Diarrhea | 55 | 13 | 2 | 61 | 10 | 2 |
| Nausea | 43 | 4 | - | 51 | 3 | <1 |
| Vomiting | 27 | 4 | <1 | 30 | 4 | <1 |
| Stomatitis | 25 | 2 | <1 | 62 | 14 | 1 |
| Abdominal Pain | 35 | 9 | <1 | 31 | 5 | - |
| Gastrointestinal Motility Disorder | 10 | <1 | - | 7 | <1 | - |
| Constipation | 14 | 1 | <1 | 17 | 1 | - |
| Oral Discomfort | 10 | - | - | 10 | - | - |
| Upper GI Inflammatory Disorders | 8 | <1 | - | 10 | 1 | - |
| Gastrointestinal Hemorrhage | 6 | 1 | <1 | 3 | 1 | - |
| Ileus | 6 | 4 | 1 | 5 | 2 | 1 |
| Skin and Subcutaneous | ||||||
| Hand-and-Foot Syndrome | 54 | 17 | NA | 6 | 1 | NA |
| Dermatitis | 27 | 1 | - | 26 | 1 | - |
| Skin Discoloration | 7 | <1 | - | 5 | - | - |
| Alopecia | 6 | - | - | 21 | <1 | - |
| General | ||||||
| Fatigue/Weakness | 42 | 4 | - | 46 | 4 | - |
| Pyrexia | 18 | 1 | - | 21 | 2 | - |
| Edema | 15 | 1 | - | 9 | 1 | - |
| Pain | 12 | 1 | - | 10 | 1 | - |
| Chest Pain | 6 | 1 | - | 6 | 1 | <1 |
| Neurological | ||||||
| Peripheral Sensory Neuropathy | 10 | - | - | 4 | - | - |
| Headache | 10 | 1 | - | 7 | - | - |
| Dizziness* | 8 | <1 | - | 8 | <1 | - |
| Insomnia | 7 | - | - | 7 | - | - |
| Taste Disturbance | 6 | 1 | - | 11 | <1 | 1 |
| Metabolism | ||||||
| Appetite Decreased | 26 | 3 | <1 | 31 | 2 | <1 |
| Dehydration | 7 | 2 | <1 | 8 | 3 | 1 |
| Eye | ||||||
| Eye Irritation | 13 | - | - | 10 | <1 | - |
| Vision Abnormal | 5 | - | - | 2 | - | - |
| Respiratory | ||||||
| Dyspnea | 14 | 1 | - | 10 | <1 | 1 |
| Cough | 7 | <1 | 1 | 8 | - | - |
| Pharyngeal Disorder | 5 | - | - | 5 | - | - |
| Epistaxis | 3 | <1 | - | 6 | - | - |
| Sore Throat | 2 | - | - | 6 | - | - |
| Musculoskeletal | ||||||
| Back Pain | 10 | 2 | - | 9 | <1 | - |
| Arthralgia | 8 | 1 | - | 6 | 1 | - |
| Vascular | ||||||
| Venous Thrombosis | 8 | 3 | <1 | 6 | 2 | - |
| Psychiatric | ||||||
| Mood Alteration | 5 | - | - | 6 | <1 | - |
| Depression | 5 | - | - | 4 | <1 | - |
| Infections | ||||||
| Viral | 5 | <1 | - | 5 | <1 | - |
| Blood and Lymphatic | ||||||
| Anemia | 80 | 2 | <1 | 79 | 1 | <1 |
| Neutropenia | 13 | 1 | 2 | 46 | 8 | 13 |
| Hepatobiliary | ||||||
| Hyperbilirubinemia | 48 | 18 | 5 | 17 | 3 | 3 |
| –Not observed NA = Not Applicable *Excluding vertigo | ||||||
The following data are shown for the combination study with Catepen and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the Catepen and docetaxel combination arm the treatment was Catepen administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1- hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in =5% of Patients Participating in the Catepen and Docetaxel Combination vs Docetaxel Monotherapy Study
| Adverse Event | Catepen 1250 mg/m2 /bid With Docetaxel 75 mg/m2 /3 weeks (n=251) | Docetaxel 100 mg/m2 /3 weeks (n=255) | ||||
| Total % | Grade 3% | Grade 4% | Total % | Grade 3% | Grade 4% | |
| Number of Patients With at Least One Adverse Event | 99 | 76.5 | 29.1 | 97 | 57.6 | 31.8 |
| Body System/Adverse Event | ||||||
| GI | ||||||
| Diarrhea | 67 | 14 | <1 | 48 | 5 | <1 |
| Stomatitis | 67 | 17 | <1 | 43 | 5 | - |
| Nausea | 45 | 7 | - | 36 | 2 | - |
| Vomiting | 35 | 4 | 1 | 24 | 2 | - |
| Constipation | 20 | 2 | - | 18 | - | - |
| Abdominal Pain | 30 | <3 | <1 | 24 | 2 | - |
| Dyspepsia | 14 | - | - | 8 | 1 | - |
| Dry Mouth | 6 | <1 | - | 5 | - | - |
| Skin and Subcutaneous | ||||||
| Hand-and-Foot Syndrome | 63 | 24 | NA | 8 | 1 | NA |
| Alopecia | 41 | 6 | - | 42 | 7 | - |
| Nail Disorder | 14 | 2 | - | 15 | - | - |
| Dermatitis | 8 | - | - | 11 | 1 | - |
| Rash Erythematous | 9 | <1 | - | 5 | - | - |
| Nail Discoloration | 6 | - | - | 4 | <1 | - |
| Onycholysis | 5 | 1 | - | 5 | 1 | - |
| Pruritus | 4 | - | - | 5 | - | - |
| General | ||||||
| Pyrexia | 28 | 2 | - | 34 | 2 | - |
| Asthenia | 26 | 4 | <1 | 25 | 6 | - |
| Fatigue | 22 | 4 | - | 27 | 6 | - |
| Weakness | 16 | 2 | - | 11 | 2 | - |
| Pain in Limb | 13 | <1 | - | 13 | 2 | - |
| Lethargy | 7 | - | - | 6 | 2 | - |
| Pain | 7 | <1 | - | 5 | 1 | - |
| Chest Pain (non-cardiac) | 4 | <1 | - | 6 | 2 | - |
| Influenza-like Illness | 5 | - | - | 5 | - | - |
| Neurological | ||||||
| Taste Disturbance | 16 | <1 | - | 14 | <1 | - |
| Headache | 15 | 3 | - | 15 | 2 | - |
| Paresthesia | 12 | <1 | - | 16 | 1 | - |
| Dizziness | 12 | - | - | 8 | <1 | - |
| Insomnia | 8 | - | - | 10 | <1 | - |
| Peripheral Neuropathy | 6 | - | - | 10 | 1 | - |
| Hypoaesthesia | 4 | <1 | - | 8 | <1 | - |
| Metabolism | ||||||
| Anorexia | 13 | 1 | - | 11 | <1 | - |
| Appetite Decreased | 10 | - | - | 5 | - | - |
| Weight Decreased | 7 | - | - | 5 | - | - |
| Dehydration | 10 | 2 | - | 7 | <1 | <1 |
| Eye | ||||||
| Lacrimation Increased | 12 | - | - | 7 | <1 | - |
| Conjunctivitis | 5 | - | - | 4 | - | - |
| Eye Irritation | 5 | - | - | 1 | - | - |
| Musculoskeletal | ||||||
| Arthralgia | 15 | 2 | - | 24 | 3 | - |
| Myalgia | 15 | 2 | - | 25 | 2 | - |
| Back Pain | 12 | <1 | - | 11 | 3 | - |
| Bone Pain | 8 | <1 | - | 10 | 2 | - |
| Cardiac | ||||||
| Edema | 33 | <2 | - | 34 | <3 | 1 |
| Blood | ||||||
| Neutropenic Fever | 16 | 3 | 13 | 21 | 5 | 16 | Respiratory |
| Dyspnea | 14 | 2 | <1 | 16 | 2 | - |
| Cough | 13 | 1 | - | 22 | <1 | - |
| Sore Throat | 12 | 2 | - | 11 | <1 | - |
| Epistaxis | 7 | <1 | - | 6 | - | - |
| Rhinorrhea | 5 | - | - | 3 | - | - |
| Pleural Effusion | 2 | 1 | - | 7 | 4 | - |
| Infections | ||||||
| Oral Candidiasis | 7 | <1 | - | 8 | <1 | - |
| Urinary Tract Infection | 6 | <1 | - | 4 | - | - |
| Upper Respiratory Tract | 4 | - | - | 5 | 1 | - |
| Vascular | ||||||
| Flushing | 5 | - | - | 5 | - | - |
| Lymphoedema | 3 | <1 | - | 5 | - | - |
| Psychiatric | ||||||
| Depression | 5 | - | - | 5 | 1 | - |
| –Not observed NA = Not Applicable | ||||||
Table 8 Percent of Patients With Laboratory Abnormalities Participating in the Catepen and Docetaxel Combination vs Docetaxel Monotherapy Study
| Adverse Event | Catepen 1250 mg/m2 /bid With Docetaxel 75 mg/m2 /3 weeks (n=251) | Docetaxel 100 mg/m2 /3 weeks (n=255) | ||||
| Body System/ Adverse Event | Total % | Grade 3 % | Grade 4 % | Total % | Grade 3 % | Grade 4 % |
| Hematologic | ||||||
| Leukopenia | 91 | 37 | 24 | 88 | 42 | 33 |
| Neutropenia/ Granulocytopenia | 86 | 20 | 49 | 87 | 10 | 66 |
| Thrombocytopenia | 41 | 2 | 1 | 23 | 1 | 2 |
| Anemia | 80 | 7 | 3 | 83 | 5 | <1 |
| Lymphocytopenia | 99 | 48 | 41 | 98 | 44 | 40 |
| Hepatobiliary | ||||||
| Hyperbilirubinemia | 20 | 7 | 2 | 6 | 2 | 2 |
The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250
In repeat-dose toxicity studies, daily oral administration of Catepen 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 Catepen. Catepen 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 Catepen.
During standard fertility studies, impairment of fertility was observed in female mice receiving Catepen; 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.
Catepen 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), Catepen was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
In repeat-dose toxicity studies, daily oral administration of capecitabine 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 capecitabine. Capecitabine 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 capecitabine.
During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; 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.
Capecitabine 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), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
Catepen 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.
Catepen 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.
Colorectal CancerPharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: L01BC06
Catepen is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Catepen 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 Catepen 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 Catepen 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 Catepen for the adjuvant treatment of patients with colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with Catepen (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). Catepen 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 Catepen 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 Catepen 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, Catepen 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 Catepen 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 Catepen (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 Catepen in metastatic colorectal cancer
Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials (SO14695; SO14796) support the use of Catepen for first line treatment of metastatic colorectal cancer. In these trials, 603 patients were randomised to treatment with Catepen (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% (Catepen) vs. 16.7% (Mayo regimen); p <0.0002. The median time to progression was 140 days (Catepen) vs. 144 days (Mayo regimen). Median survival was 392 days (Catepen) vs. 391 days (Mayo regimen). Currently, no comparative data are available on Catepen 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 Catepen 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)
| Treatment | Starting Dose | Schedule | |
| FOLFOX-4 or FOLFOX-4 + Bevacizumab | Oxaliplatin | 85 mg/m2 intravenous 2 hr | Oxaliplatin on Day 1, every 2 weeks Leucovorin on Days 1 and 2, every 2 weeks 5-fluorouracil intravenous bolus/infusion, each on Days 1 and 2, every 2 weeks |
| Leucovorin | 200 mg/m2 intravenous 2 hr | ||
| 5-Fluorouracil | 400 mg/m2 intravenous bolus, followed by 600 mg/ m2 intravenous 22 hr | ||
| Placebo or Bevacizumab | 5 mg/kg intravenous 30-90 mins | Day 1, prior to FOLFOX-4, every 2 weeks | |
| XELOX or XELOX+ Bevacizumab | Oxaliplatin | 130 mg/m2 intravenous 2 hr | Oxaliplatin on Day 1, every 3 weeks Catepen oral twice daily for 2 weeks (followed by 1 week off- treatment) |
| Catepen | 1000 mg/m2 oral twice daily | ||
| Placebo or Bevacizumab | 7.5 mg/kg intravenous 30-90 mins | Day 1, prior to XELOX, every 3 weeks | |
| 5-Fluorouracil: intravenous bolus injection immediately after leucovorin | |||
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
| PRIMARY ANALYSIS | |||
| XELOX/ XELOX+P/ XELOX+BV (EPP*: N=967; ITT**: N=1017) | FOLFOX-4/ FOLFOX-4+P /FOLFOX-4+BV (EPP*: N = 937; ITT**: N= 1017) | ||
| Population | Median Time to Event (Days) | HR (97.5% CI) | |
| Parameter: Progression-free Survival | |||
| EPP ITT | 241 244 | 259 259 | 1.05 (0.94; 1.18) 1.04 (0.93; 1.16) |
| Parameter: Overall Survival | |||
| EPP ITT | 577 581 | 549 553 | 0.97 (0.84; 1.14) 0.96 (0.83; 1.12) |
| ADDITIONAL 1 YEAR OF FOLLOW UP | |||
| Population | Median Time to Event (Days) | HR (97.5% CI) | |
| Parameter: Progression-free Survival | |||
| EPP ITT | 242 244 | 259 259 | 1.02 (0.92; 1.14) 1.01 (0.91; 1.12) |
| Parameter: Overall Survival | |||
| EPP ITT | 600 602 | 594 596 | 1.00 (0.88; 1.13) 0.99 (0.88; 1.12) |
*EPP=eligible patient population; **ITT=intent-to-treat population.
In a randomised, controlled phase III study (CAIRO), the effect of using Catepen 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 Catepen (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 1), and third-line combination of Catepen (1000 mg/m2 twice daily for 14 days) with oxaliplatin (130 mg/m2 on day 1). Combination treatment consisted of first-line Catepen (1000 mg/m2 twice daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line Catepen (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 Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen (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
| XELOX + bevacizumab
(ITT: N=127) | Modified XELIRI+ bevacizumab
(ITT: N= 120) | Hazard ratio 95% CI P value | |
| Progression-free Survival after 6 months | |||
| ITT 95% CI | 76% 69 - 84% | 84% 77 - 90% | - |
| Median progression free survival | |||
| ITT 95% CI | 10.4 months 9.0 - 12.0 | 12.1 months 10.8 - 13.2 | 0.93 0.82 - 1.07 P=0.30 |
| Median overall survival | |||
| ITT 95% CI | 24.4 months 19.3 - 30.7 | 25.5 months 21.0 - 31.0 | 0.90 0.68 - 1.19 P=0.45 |
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 Catepen 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
| PRIMARY ANALYSIS | |||
| XELOX (PPP*: N=251; ITT**: N=313) | FOLFOX-4 (PPP*: N = 252; ITT**: N= 314) | ||
| Population | Median Time to Event (Days) | HR (95% CI) | |
| Parameter: Progression-free Survival | |||
| PPP ITT | 154 144 | 168 146 | 1.03 (0.87; 1.24) 0.97 (0.83; 1.14) |
| Parameter: Overall Survival | |||
| PPP ITT | 388 363 | 401 382 | 1.07 (0.88; 1.31) 1.03 (0.87; 1.23) |
| ADDITIONAL 6 MONTHS OF FOLLOW UP | |||
| Population | Median Time to Event (Days) | HR (95% CI) | |
| Parameter: Progression-free Survival | |||
| PPP ITT | 154 143 | 166 146 | 1.04 (0.87; 1.24) 0.97 (0.83; 1.14) |
| Parameter: Overall Survival | |||
| PPP ITT | 393 363 | 402 382 | 1.05 (0.88; 1.27) 1.02 (0.86; 1.21) |
*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 Catepen for the first-line treatment of advanced gastric cancer (ML17032). In this trial, 160 patients were randomised to treatment with Catepen (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). Catepen 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 (Catepen + 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 (Catepen + cisplatin) versus 9.3 months (5-FU + cisplatin).
Data from a randomised multicentre, phase III study comparing Catepen to 5-FU and oxaliplatin to cisplatin in patients with advanced gastric cancer supports the use of Catepen 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 Catepen (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 Catepen (625 mg/m2 twice daily continuously).
The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall survival for Catepen- 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 Catepen-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.
Catepen has also been used in combination with oxaliplatin for the treatment of advanced gastric cancer. Studies with Catepen monotherapy indicate that Catepen 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 Catepen replacing 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with Catepen -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 Catepen -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 Catepen -containing regimens are non-inferior to 5-FU-containing regimens.
Breast cancer:
Combination therapy with Catepen and docetaxel in locally advanced or metastatic breast cancer
Data from one multicentre, randomised, controlled phase III clinical trial support the use of Catepen 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 Catepen (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 Catepen + docetaxel combination arm (p=0.0126). Median survival was 442 days (Catepen + docetaxel) vs. 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (Catepen + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the Catepen + docetaxel combination arm (p<0.0001). The median time to progression was 186 days (Catepen + docetaxel) vs. 128 days (docetaxel alone).
Monotherapy with Catepen 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 Catepen 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 Catepen (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 Catepen monotherapy or Catepen in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that patients on Catepen 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
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: L01BC06
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine 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 capecitabine 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 capecitabine 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 capecitabine for the adjuvant treatment of patients with colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with capecitabine (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). Capecitabine 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 capecitabine 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 capecitabine 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, capecitabine 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 capecitabine 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 capecitabine (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 capecitabine in metastatic colorectal cancer
Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials (SO14695; SO14796) support the use of capecitabine for first line treatment of metastatic colorectal cancer. In these trials, 603 patients were randomised to treatment with capecitabine (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% (capecitabine) vs. 16.7% (Mayo regimen); p <0.0002. The median time to progression was 140 days (capecitabine) vs. 144 days (Mayo regimen). Median survival was 392 days (capecitabine) vs. 391 days (Mayo regimen). Currently, no comparative data are available on capecitabine 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 capecitabine 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)
| Treatment | Starting Dose | Schedule | |
| FOLFOX-4 or FOLFOX-4 + Bevacizumab | Oxaliplatin | 85 mg/m2 intravenous 2 hr | Oxaliplatin on Day 1, every 2 weeks Leucovorin on Days 1 and 2, every 2 weeks 5-fluorouracil intravenous bolus/infusion, each on Days 1 and 2, every 2 weeks |
| Leucovorin | 200 mg/m2 intravenous 2 hr | ||
| 5-Fluorouracil | 400 mg/m2 intravenous bolus, followed by 600 mg/ m2 intravenous 22 hr | ||
| Placebo or Bevacizumab | 5 mg/kg intravenous 30-90 mins | Day 1, prior to FOLFOX-4, every 2 weeks | |
| XELOX or XELOX+ Bevacizumab | Oxaliplatin | 130 mg/m2 intravenous 2 hr | Oxaliplatin on Day 1, every 3 weeks capecitabine oral twice daily for 2 weeks (followed by 1 week off- treatment) |
| capecitabine | 1000 mg/m2 oral twice daily | ||
| Placebo or Bevacizumab | 7.5 mg/kg intravenous 30-90 mins | Day 1, prior to XELOX, every 3 weeks | |
| 5-Fluorouracil: intravenous bolus injection immediately after leucovorin | |||
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
| PRIMARY ANALYSIS | |||
| XELOX/ XELOX+P/ XELOX+BV (EPP*: N=967; ITT**: N=1017) | FOLFOX-4/ FOLFOX-4+P /FOLFOX-4+BV (EPP*: N = 937; ITT**: N= 1017) | ||
| Population | Median Time to Event (Days) | HR (97.5% CI) | |
| Parameter: Progression-free Survival | |||
| EPP ITT | 241 244 | 259 259 | 1.05 (0.94; 1.18) 1.04 (0.93; 1.16) |
| Parameter: Overall Survival | |||
| EPP ITT | 577 581 | 549 553 | 0.97 (0.84; 1.14) 0.96 (0.83; 1.12) |
| ADDITIONAL 1 YEAR OF FOLLOW UP | |||
| Population | Median Time to Event (Days) | HR (97.5% CI) | |
| Parameter: Progression-free Survival | |||
| EPP ITT | 242 244 | 259 259 | 1.02 (0.92; 1.14) 1.01 (0.91; 1.12) |
| Parameter: Overall Survival | |||
| EPP ITT | 600 602 | 594 596 | 1.00 (0.88; 1.13) 0.99 (0.88; 1.12) |
*EPP=eligible patient population; **ITT=intent-to-treat population.
In a randomised, controlled phase III study (CAIRO), the effect of using capecitabine 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 capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 1), and third-line combination of capecitabine (1000 mg/m2 twice daily for 14 days) with oxaliplatin (130 mg/m2 on day 1). Combination treatment consisted of first-line capecitabine (1000 mg/m2 twice daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line capecitabine (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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine (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
| XELOX + bevacizumab
(ITT: N=127) | Modified XELIRI+ bevacizumab
(ITT: N= 120) | Hazard ratio 95% CI P value | |
| Progression-free Survival after 6 months | |||
| ITT 95% CI | 76% 69 - 84% | 84% 77 - 90% | - |
| Median progression free survival | |||
| ITT 95% CI | 10.4 months 9.0 - 12.0 | 12.1 months 10.8 - 13.2 | 0.93 0.82 - 1.07 P=0.30 |
| Median overall survival | |||
| ITT 95% CI | 24.4 months 19.3 - 30.7 | 25.5 months 21.0 - 31.0 | 0.90 0.68 - 1.19 P=0.45 |
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 capecitabine 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
| PRIMARY ANALYSIS | |||
| XELOX (PPP*: N=251; ITT**: N=313) | FOLFOX-4 (PPP*: N = 252; ITT**: N= 314) | ||
| Population | Median Time to Event (Days) | HR (95% CI) | |
| Parameter: Progression-free Survival | |||
| PPP ITT | 154 144 | 168 146 | 1.03 (0.87; 1.24) 0.97 (0.83; 1.14) |
| Parameter: Overall Survival | |||
| PPP ITT | 388 363 | 401 382 | 1.07 (0.88; 1.31) 1.03 (0.87; 1.23) |
| ADDITIONAL 6 MONTHS OF FOLLOW UP | |||
| Population | Median Time to Event (Days) | HR (95% CI) | |
| Parameter: Progression-free Survival | |||
| PPP ITT | 154 143 | 166 146 | 1.04 (0.87; 1.24) 0.97 (0.83; 1.14) |
| Parameter: Overall Survival | |||
| PPP ITT | 393 363 | 402 382 | 1.05 (0.88; 1.27) 1.02 (0.86; 1.21) |
*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 capecitabine for the first-line treatment of advanced gastric cancer (ML17032). In this trial, 160 patients were randomised to treatment with capecitabine (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). Capecitabine 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 (capecitabine + 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 (capecitabine + cisplatin) versus 9.3 months (5-FU + cisplatin).
Data from a randomised multicentre, phase III study comparing capecitabine to 5-FU and oxaliplatin to cisplatin in patients with advanced gastric cancer supports the use of capecitabine 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 capecitabine (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 capecitabine (625 mg/m2 twice daily continuously).
The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall survival for capecitabine- 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 capecitabine-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.
Capecitabine has also been used in combination with oxaliplatin for the treatment of advanced gastric cancer. Studies with capecitabine monotherapy indicate that capecitabine 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 capecitabine replacing 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with capecitabine -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 capecitabine -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 capecitabine -containing regimens are non-inferior to 5-FU-containing regimens.
Breast cancer:
Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer
Data from one multicentre, randomised, controlled phase III clinical trial support the use of capecitabine 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 capecitabine (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 capecitabine + docetaxel combination arm (p=0.0126). Median survival was 442 days (capecitabine + docetaxel) vs. 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (capecitabine + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the capecitabine + docetaxel combination arm (p<0.0001). The median time to progression was 186 days (capecitabine + docetaxel) vs. 128 days (docetaxel alone).
Monotherapy with capecitabine 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 capecitabine 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 capecitabine (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 capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that patients on capecitabine 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 Catepen have been evaluated over a dose range of 502-3514 mg/m2/day. The parameters of Catepen, 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. Catepen 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, Catepen is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of Catepen 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 (Cmax in µg/ml) for Catepen, 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 (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-∞ 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 Catepen, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.
Biotransformation
Catepen 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 Catepen 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 Catepen 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 Catepen.
Elimination
The elimination half-life (t1/2 in hours) of Catepen, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Catepen and its metabolites are predominantly excreted in urine; 95.5% of administered Catepen 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 Catepen on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by Catepen on the pharmacokinetics of docetaxel or paclitaxel (Cmax 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 Catepen 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 Catepen 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 Catepen twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for Catepen than Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax 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).
The pharmacokinetics of capecitabine have been evaluated over a dose range of 502-3514 mg/m2/day. The parameters of capecitabine, 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. Capecitabine 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, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of capecitabine 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 (Cmax in µg/ml) for capecitabine, 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 (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-∞ 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 capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.
Biotransformation
Capecitabine 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 capecitabine 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 capecitabine 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 capecitabine.
Elimination
The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine 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 capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax 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 capecitabine 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 capecitabine 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 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax 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).
AbsorptionFollowing oral administration of 1255 mg/m2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean C and AUC decreased by 60% and 35%, respectively. The Cmax and AUC0-8 of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours.
The pharmacokinetics of Catepen and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2 /day. Over this range, the pharmacokinetics of Catepen and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.
DistributionPlasma protein binding of capecitabine and its metabolites is less than 60% and is not concentrationdependent. Capecitabine was primarily bound to human albumin (approximately 35%). Catepen has a low potential for pharmacokinetic interactions related to plasma protein binding.
Bioactivation And MetabolismCapecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of Catepen 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
Metabolic Pathway of capecitabine to 5-FU
The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureidopropionase cleaves FUPA to a-fluoro-β-alanine (FBAL) which is cleared in the urine.
In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
ExcretionCapecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal 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 as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.
Effect Of Age, Gender, And Race On The Pharmacokinetics Of CapecitabineA population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Catepen at 1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL.
Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
Effect Of Hepatic InsufficiencyCatepen has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m2 dose of Catepen. Both AUC0-8 and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-8 and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Catepen is administered. The effect of severe hepatic dysfunction on Catepen is not known.
Effect Of Renal InsufficiencyFollowing oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients.
Effect Of Capecitabine On The Pharmacokinetics Of WarfarinIn four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%.
Effect Of Antacids On The Pharmacokinetics Of CapecitabineWhen Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Catepen (1250 mg/m2 , n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of Catepen.
Effect Of Capecitabine On The Pharmacokinetics Of Docetaxel And Vice VersaA Phase 1 study evaluated the effect of Catepen on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of Catepen was conducted in 26 patients with solid tumors. Catepen was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'- DFUR.
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 Catepen is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration might be potentially fatal. If grade 2 (or higher) dehydration occurs, Catepen 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 Catepen should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of Catepen should be decreased. When Catepen 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 Catepen 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 Catepen.
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 Catepen 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 Catepen 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 Catepen. Patients receiving concomitant Catepen 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, Catepen use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen, 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
Catepen can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Catepen 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.
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 capecitabine is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration might be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabine 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 capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine 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 Catepen.
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 capecitabine.
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 capecitabine 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 capecitabine 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 capecitabine. Patients receiving concomitant capecitabine 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, capecitabine use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of capecitabine 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 capecitabine 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 Catepen. 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 Catepen 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 capecitabine, 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
Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Capecitabine 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.
WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS GeneralPatients receiving therapy with Catepen should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
CoagulopathyPatients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.
DiarrheaCatepen can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received Catepen monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of =10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of Catepen should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Standard antidiarrheal treatments (eg, loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
CardiotoxicityThe cardiotoxicity observed with Catepen includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
Dihydropyrimidine Dehydrogenase DeficiencyBased on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Catepen (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by Catepen.
Withhold or permanently discontinue Catepen based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Catepen dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.
Dehydration And Renal FailureDehydration has been observed and may cause acute renal failure which can be fatal. Patients with preexisting compromised renal function or who are receiving concomitant Catepen with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Catepen is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Catepen 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 should be applied for the precipitating adverse event as necessary.
Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2.
PregnancyCatepen may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Catepen, the patient should be apprised of the potential hazard to the fetus.
Mucocutaneous And Dermatologic ToxicitySevere mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Catepen. Catepen should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Catepen treatment.
Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving Catepen monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or 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. If grade 2 or 3 hand-and-foot syndrome occurs, administration of Catepen should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of Catepen should be decreased.
HyperbilirubinemiaIn 875 patients with either metastatic breast or colorectal cancer who received at least one dose of Catepen 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
In the 596 patients treated with Catepen as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of Catepen monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with Catepen. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
In 251 patients with metastatic breast cancer who received a combination of Catepen and docetaxel, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2% (n=5).
If drug-related grade 3 to 4 elevations in bilirubin occur, administration of Catepen should be immediately interrupted until the hyperbilirubinemia decreases to =3.0 × ULN.
HematologicIn 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of Catepen in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.
Patients with baseline neutrophil counts of <1.5 × 10 /L and/or thrombocyte counts of <100 × 10 /L should not be treated with Catepen. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with Catepen should be interrupted.
Geriatric PatientsPatients =80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received Catepen monotherapy, 62% of the 21 patients =80 years of age treated with Catepen experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with Catepen in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-andfoot syndrome.
Among the 67 patients =60 years of age receiving Catepen in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.
In 995 patients receiving Catepen as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients =65 years of age treated with Catepen experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients =65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for Catepen compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.
Hepatic InsufficiencyPatients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when Catepen is administered. The effect of severe hepatic dysfunction on the disposition of Catepen is not known.
Combination With Other DrugsUse of Catepen in combination with irinotecan has not been adequately studied.
Patient Counseling InformationInformation for Patients (see FDA-approved Patient Labeling)
Patients and patients' caregivers should be informed of the expected adverse effects of Catepen, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary. As described below, patients taking Catepen should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Catepen treatment See FDA-approved patient labeling (Patient Information).
Dihydropyrimidine Dehydrogenase DeficiencyPatients should be advised to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Catepen (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).
DiarrheaPatients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to stop taking Catepen and to call their physician immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.
DehydrationPatients experiencing grade 2 or higher dehydration should be instructed to stop taking Catepen immediately and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.
NauseaPatients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Catepen immediately. Initiation of symptomatic treatment is recommended.
VomitingPatients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Catepen immediately. Initiation of symptomatic treatment is recommended.
Hand-And-Foot SyndromePatients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking Catepen immediately. Initiation of symptomatic treatment is recommended.
StomatitisPatients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Catepen immediately and to call their physician. Initiation of symptomatic treatment is recommended.
Fever And NeutropeniaPatients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician immediately.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityAdequate studies investigating the carcinogenic potential of Catepen have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
Impairment Of FertilityIn studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2 /day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.
Use In Specific Populations Pregnancy Category DCatepen can cause fetal harm when administered to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose.
There are no adequate and well controlled studies of Catepen in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Catepen, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with Catepen.
Nursing MothersLactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseThe safety and effectiveness of Catepen in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to Catepen was similar.
The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dosefinding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.
The second trial was conducted in 34 additional pediatric patients with newly diagnosed nondisseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.
There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.
The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence =40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).
Geriatric UsePhysicians should pay particular attention to monitoring the adverse effects of Catepen in the elderly.
Hepatic InsufficiencyExercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Catepen. The effect of severe hepatic dysfunction on Catepen is not known.
Renal InsufficiencyPatients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-DFUR, and FBAL than in those with normal renal function.
Catepen has minor or moderate influence on the ability to drive and use machines. Catepen may cause dizziness, fatigue and nausea.
Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea.
Catepen 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 Catepen 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 Catepen 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 Catepen 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 Catepen. 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 Catepen plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the Catepen 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 Catepen 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 Catepen plus docetaxel combination.
Catepen Accord dose calculations
Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of Catepen of 1250 mg/m2.
|
| Dose level 1250 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body surface area (m2) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of Catepen of 1000 mg/m2
|
| Dose level 1000 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body surface area (m2) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
Posology adjustments during treatment
General
Toxicity due to Catepen 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 Catepen should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Catepen omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:
Catepen Accord 150 mg and 500mg film-coated tablets
Table 3 Catepen dose reduction schedule (3-weekly cycle or continuous treatment).
| Toxicity grades* | Dose changes within a treatment cycle | Dose adjustment for next cycle/dose (% of starting dose) |
| - Grade 1 | Maintain dose level | Maintain dose level |
| - Grade 2 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 100% |
| -2nd appearance | 75% | |
| -3rd appearance | 50% | |
| -4th appearance | Discontinue treatment permanently | Not applicable |
| - Grade 3 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 75% |
| -2nd appearance | 50% | |
| -3rd appearance | Discontinue treatment permanently | Not applicable |
| - Grade 4 | ||
| -1st appearance | Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 | 50% |
| -2nd appearance | Discontinue permanently | Not applicable |
Catepen Accord 300 mg film-coated tablets
Table 4 Catepen dose reduction shedule(3-weeklycycle or continuous treatment).
|
| Dose level 1250 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body Surface Area (m2 ) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
*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 Catepen. 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 Catepen should be interrupted.
Dose modifications for toxicity when Catepen is used as a 3 weekly cycle in combination with other medicinal products
Dose modifications for toxicity when Catepen is used as a 3 weekly cycle in combination with other medicinal products should be made according to Table 3 above for Catepen 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 Catepen 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 Catepen, Catepen 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, Catepen treatment can be resumed when the requirements for restarting Catepen are met.
This advice is applicable to all indications and to all special populations.
Dose modifications for toxicity when Catepen is used continuously in combination with other medicinal products
Dose modifications for toxicity when Catepen is used continuously in combination with other medicinal products should be made according to Table 3 above for Catepen 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
Catepen 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, Catepen 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 Catepen 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 Catepen 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 Catepen to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in patients >60 years of age treated with a reduced Catepen starting dose in combination with docetaxel, the dose of Catepen may be cautiously escalated to 1250 mg/m2 twice daily.
Paediatric population
There is no relevant use of Catepen in the paediatric population in the indications colon, colorectal, gastric and breast cancer.
Method of administration
Catepen Accord tablets should be swallowed with water within 30 minutes after a meal.
Catepen 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 Catepen 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 capecitabine 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 capecitabine 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 capecitabine. 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 capecitabine plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the capecitabine 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 capecitabine 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 capecitabine plus docetaxel combination.
Catepen dose calculations
Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of capecitabine of 1250 mg/m2.
|
| Dose level 1250 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body surface area (m2) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of Capecitabine of 1000 mg/m2
|
| Dose level 1000 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body surface area (m2) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
Posology adjustments during treatment
General
Toxicity due to capecitabine 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 capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:
Catepen 150 mg and 500mg film-coated tablets
Table 3 Capecitabine dose reduction schedule (3-weekly cycle or continuous treatment).
| Toxicity grades* | Dose changes within a treatment cycle | Dose adjustment for next cycle/dose (% of starting dose) |
| - Grade 1 | Maintain dose level | Maintain dose level |
| - Grade 2 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 100% |
| -2nd appearance | 75% | |
| -3rd appearance | 50% | |
| -4th appearance | Discontinue treatment permanently | Not applicable |
| - Grade 3 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 75% |
| -2nd appearance | 50% | |
| -3rd appearance | Discontinue treatment permanently | Not applicable |
| - Grade 4 | ||
| -1st appearance | Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 | 50% |
| -2nd appearance | Discontinue permanently | Not applicable |
Catepen 300 mg film-coated tablets
Table 4 Capecitabine dose reduction shedule(3-weeklycycle or continuous treatment).
|
| Dose level 1250 mg/m2 (twice daily) | |||||
|
| Full dose
1250 mg/m2 | Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening) | Reduced dose (75%)
950 mg/m2 | Reduced dose (50%)
625 mg/m2 | ||
| Body Surface Area (m2 ) | Dose per administration (mg) | 150 mg | 300 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 | - | 1 | 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 | - | 1 | 4 | 1800 | 1150 |
| 1.93 - 2.06 | 2500 | - | - | 5 | 1950 | 1300 |
| 2.07 - 2.18 | 2650 | 1 | - | 5 | 2000 | 1300 |
| >2.19 | 2800 | - | 1 | 5 | 2150 | 1450 |
*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 capecitabine. 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 capecitabine should be interrupted.
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal products
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal products should be made according to Table 3 above for capecitabine 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 capecitabine 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 capecitabine, capecitabine 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, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.
This advice is applicable to all indications and to all special populations.
Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products
Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products should be made according to Table 3 above for capecitabine 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
Capecitabine 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, Catepen should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use (see also section “Elderly†below).
Elderly
During capecitabine 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 capecitabine 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 capecitabine to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in patients >60 years of age treated with a reduced capecitabine starting dose in combination with docetaxel, the dose of capecitabine may be cautiously escalated to 1250 mg/m2 twice daily.
Paediatric population
There is no relevant use of capecitabine in the paediatric population in the indications colon, colorectal, gastric and breast cancer.
Method of administration
Catepen tablets should be swallowed with water within 30 minutes after a meal.
Catepen tablets should be swallowed whole with water within 30 minutes after a meal. Do not crush or cut Catepen tablets. Catepen dose is calculated according to body surface area.
Standard Starting Dose Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)The recommended dose of Catepen is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).
Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [ie, Catepen 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3- week cycles for a total of 8 cycles (24 weeks)].
Table 1 Catepen Dose Calculation According to Body Surface Area
| Dose Level 1250 mg/m2 Twice a Day | Number of Tablets to be Taken at Each Dose (Morning and Evening) | ||
| Surface Area (m2) | Total Daily Dose* (mg) | 150 mg | 500 mg |
| = 1.25 | 3000 | 0 | 3 |
| 1.26-1.37 | 3300 | 1 | 3 |
| 1.38-1.51 | 3600 | 2 | 3 |
| 1.52-1.65 | 4000 | 0 | 4 |
| 1.66-1.77 | 4300 | 1 | 4 |
| 1.78-1.91 | 4600 | 2 | 4 |
| 1.92-2.05 | 5000 | 0 | 5 |
| 2.06-2.17 | 5300 | 1 | 5 |
| = 2.18 | 5600 | 2 | 5 |
| *Total Daily Dose divided by 2 to allow equal morning and evening doses |
In combination with docetaxel, the recommended dose of Catepen is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the Catepen plus docetaxel combination. Table 1 displays the total daily dose of Catepen by body surface area and the number of tablets to be taken at each dose.
Dose Management Guidelines GeneralCatepen dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of Catepen should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to Catepen administration may be managed by symptomatic treatment, dose interruptions and adjustment of Catepen dose. Once the dose has been reduced, it should not be increased at a later time. Doses of Catepen omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with Catepen.
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)Catepen dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.
Table 2 Recommended Dose Modifications of Catepen
| Toxicity NCIC Grades* | During a Course of Therapy | Dose Adjustment for Next Treatment (% of starting dose) |
| Grade 1 | Maintain dose level | Maintain dose level |
| Grade 2 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 100% |
| -2nd appearance | 75% | |
| -3rd appearance | 50% | |
| -4th appearance | Discontinue treatment permanently | - |
| Grade 3 | ||
| -1st appearance | Interrupt until resolved to grade 0-1 | 75% |
| -2nd appearance | 50% | |
| -3rd appearance | Discontinue treatment permanently | - |
| Grade 4 | ||
| -1st appearance | Discontinue permanently OR If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 | 50% |
| *National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome. |
Dose modifications of Catepen for toxicity should be made according to Table 2 above for Catepen. At the beginning of a treatment cycle, if a treatment delay is indicated for either Catepen or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
The dose reduction schedule for docetaxel when used in combination with Catepen for the treatment of metastatic breast cancer is shown in Table 3.
Table 3 Docetaxel Dose Reduction Schedule in Combination with Catepen
| Toxicity NCIC Grades* | Grade 2 | Grade 3 | Grade 4 |
| 1st appearance | Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m2 docetaxel | Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m22 of docetaxel. | Discontinue treatment with docetaxel |
| 2nd appearance | Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. | Discontinue treatment with docetaxel | - |
| 3rd appearance | Discontinue treatment with docetaxel | - | - |
| *National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome. |
No adjustment to the starting dose of Catepen is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the Catepen starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both Catepen monotherapy and Catepen in combination use with docetaxel.
Cockroft and Gault Equation:
| Males: | (weight in kg) x (140 – age) |
| (72) x serum creatinine (mg/100 mL) | |
| Females: | (0.85) x (above value) |
Physicians should exercise caution in monitoring the effects of Catepen in the elderly. Insufficient data are available to provide a dosage recommendation.
No special requirements.
