Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Brivudine must not be administered concomitantly with capecitabine. Fatal cases have been reported following this drug interaction. There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of capecitabine (see section 4.3 and 4.5).
In the event of accidental administration of brivudine to patients being treated with capecitabine, effective measures should be taken to reduce the toxicity of capecitabine.
Immediate admission to hospital is recommended. All measures should be initiated to prevent systemic infections and dehydration.
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.
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 (see section 4.2).
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 products. 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 (see section 4.2).
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 Kapetral.
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 (See section 4.8).
Hypo-or hypercalcaemia has been reported during capecitabine treatment. Caution must be exercised in patients with pre-existing hypo-or hypercalcaemia (see section 4.8).
Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy (see section 4.8).
Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.
In a drug 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 (see section 4.5).
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.
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 (see section 4.2 and 4.3).
DPD activity is rate limiting in the catabolism of 5-fluorouracil (see Section 5.2). Patients with DPD deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.
DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.
Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with Kapetral (see section 4.3).
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.
Phenotype and/or genotype testing prior to the initiation of treatment with Kapetral is recommended despite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should be given to applicable clinical guidelines.
Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.
The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic activity. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.
Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g.
combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause complete or near complete absence of DPD enzymatic activity.
Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated with fluoropyrimidines.
The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G.
Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) are considered virtually absent in populations of African (-American) or Asian origin.
For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil (U) in plasma is recommended.
Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥16 ng/ml and <150 ng/ml should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥150 ng/ml should be considered indicative of complete DPD deficiency and associated with a risk for life-threatening or fatal fluoropyrimidine toxicity.
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.
Kapetral can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Kapetral should be permanently discontinued in patients who experience a severe skin reaction during treatment.
Kapetral tablets should not be crushed or cut. In case of exposure of either patient or caregiver to crushed or cut Kapetral tablets adverse drug reactions could occur (see Section 4.8).
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Interaction studies have only been performed in adults.
A clinically significant interaction between brivudine and fluroropyrimidines (e.g. capecitabine, 5-Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with capecitabine (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy.
Treatment with brivudine can be started 24 hours after the last dose of capecitabine.
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). See also interaction with coumarin-derivative anticoagulants below, and section 4.4.
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 anti-coagulant dose adjusted accordingly.
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.
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 effect of an aluminum 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).
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.
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.
The MTD of capecitabine alone using the intermittent regimen is 3000 mg/m² per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m² per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.
No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.
There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.
In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food. Administration with food decreases the rate of capecitabine absorption (see section 5.2).
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 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.
There is no data on Kapetral and impact on fertility. The Kapetral 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 (see section 5.3).
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. See section 5.1 for details of major studies, including study designs and major efficacy results.
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 4 for capecitabine given as a monotherapy and in Table 5 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, <1/10), uncommon (≥1/1,000, <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 4 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 4. 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, haryngitis, Oral candidiasis, Influenza, astroenteritis, Fungal infection, Infection, Tooth abscess | |
| Neoplasm benign, malignant and unspecified | - | - | Lipoma | |
| Blood and lymphatic system disorders | - | Neutropenia, Anaemia | Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leucopenia, 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, Paresthesia, 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 | - | Hyperbilirubinaemia, 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) (see section 4.4.) |
| Musculoskeletal 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 (see section 4.4)
Table 5 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 4). 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 5. 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 | |
| ,b>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/m² 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 diarrhea: 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 diarrhea: 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%.
Exposure to crushed or cut capecitabine tablets
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 diarrhea 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 diarrhea 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) (see section 5.2). 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 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 the national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy/phs.
Not applicable.
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