Chemical formula: C₁₅H₂₂FN₃O₆ Molecular mass: 359.35 g/mol PubChem compound: 60953
Capecitabine interacts in the following cases:
Other than warfarin, no formal interaction studies between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is co-administered with 2C9 substrates (e.g. phenytoin).
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.
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, capecitabine should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use.
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.
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, capecitabine should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use.
The effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).
Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down- regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly.
A combination study with capecitabine and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimen is 3000 mg/m² per day whereas it is only 2000 mg/m² per day when capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.
The MTD of capecitabine was 2000 mg/m² per day when combined with interferon alpha-2a (3 MIU/m² per day) compared to 3000 mg/m² per day when capecitabine was used alone.
There is no data on capecitabine and impact on fertility. The capecitabine pivotal studies included females of childbearing potential and males only if they agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a reasonable period thereafter. In animal studies effects on fertility were observed.
Interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided.
Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.
Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy.
Hypo- or hypercalcaemia has been reported during capecitabine treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia.
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.
Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.
Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.
There are no studies in pregnant women using capecitabine; however, it should be assumed that capecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated during pregnancy.
It is not known whether capecitabine is excreted in human breast milk. No studies have been conducted to assess the impact of capecitabine on milk production or its presence in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. As the potential for harm to the nursing infant is unknown, breast-feeding should be discontinued while receiving treatment with capecitabine and for 2 weeks after the final dose.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, the potential hazard to the foetus must be explained. An effective method of contraception should be used during treatment and for 6 months after the last dose of capecitabine. Based on genetic toxicity findings, male patients with female partners of reproductive potential should use effective contraception during treatment and for 3 months following the last dose of capecitabine.
There is no data on capecitabine and impact on fertility. The capecitabine pivotal studies included females of childbearing potential and males only if they agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a reasonable period thereafter. In animal studies effects on fertility were observed.
Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea.
The overall safety profile of capecitabine is based on data from over 3000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable.
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.
ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine are listed in table 1 for capecitabine given as monotherapy and in table 2 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), very rare (<1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Table 1 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 1. 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 | Angioedema (rare) |
| 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/infarction, 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 erythro- dysaesthesia 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
Table 2 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 1). 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 cannot be excluded.
Table 2. 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 disorder | - | 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 "+", 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.
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/m 2 twice daily on days 1 to 14 every 3 weeks, 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).
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.
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.
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%.
In the instance of exposure to crushed or cut capecitabine tablets, the following adverse drug reactions have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.
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.
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.
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.
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