Capecitabine oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of capecitabine.
Drugs List
Therapeutic Indications
Uses
Advanced gastric carcinoma in combination with platinum-based regimen
First-line monotherapy for metastatic colorectal cancer
Locally advanced breast cancer if more anthracycline therapy is unsuitable
Locally advanced breast cancer where anthracycline therapy has failed
Metastatic breast cancer where anthracycline therapy has failed
Metastatic breast cancer where further anthracycline therapy is unsuitable
Post-surgery adjuvant treatment of colon cancer
Adjuvant treatment of patients following surgery of stage III (Duke's stage C) colon cancer.
First line monotherapy of metastatic colorectal cancer.
First line treatment of advanced gastric cancer in combination with a platinum-based regimen.
Capecitabine in combination with docetaxel is indicated for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
Capecitabine is also indicated 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.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
Monotherapy
Metastatic colorectal cancer, adjuvant treatment following surgery of Stage III (Duke's C) colon cancer and locally advanced or metastatic breast cancer
1250 mg per square metre body surface area, twice daily (morning and evening; equivalent to 2500 mg per square metre total daily dose) for 14 days. Followed by a 7 day rest period.
For adjuvant treatment following surgery of Stage III (Duke's C) colon cancer a total of 8 three week cycles (total duration of course 24 weeks i.e. 6 months) is recommended.
Combination Therapy
Advanced Gastric Cancer
In combination with platinum-based compound the recommended dose of capecitabine is 800 to 1000 mg per square metre administered twice daily for 14 days followed by a 7 day rest period (the first dose should be given on the evening of day 1 the last dose on the morning of day 15) or 625 mg per square metre twice daily when administered continuously.
In combination with irinotecan, the recommended starting dose is 800 mg per square metre administered twice daily (morning and evening; equivalent to 1600 mg per square metre total daily dose) for 14 days followed by a rest period of 7 days when combined with irinotecan 200 mg per square metre on day 1.
The inclusion of bevacizumab in a combination regimen has no effect on the starting dose of capecitabine.
Consult product literature for details of combination treatment regimens.
Premedication to maintain adequate hydration and anti-emesis should be given according to cisplatin dosing information for patient receiving cisplatin in combination with capecitabine.
Premedication with antiemetics should be given according to oxaliplatin dosing information for patients receiving oxaliplatin in combination with capecitabine.
Locally advanced or metastatic breast cancer
1250 mg per square metre body surface area, twice daily (morning and evening; equivalent to 2500 mg per square metre total daily dose) for 14 days. Followed by a 7 day rest period.
Docetaxel should be given at a dose of 75 mg per square metre as a 1 hour intravenous infusion every three weeks.
Pre-medication with an oral corticosteroid such as dexamethasone should be given before docetaxel administration in accordance with the docetaxel Summary of Product Characteristics.
Elderly
No adjustment of the starting dose is needed for capecitabine monotherapy.
When used in combination with docetaxel, a reduction of the standard starting dose of capecitabine to 75% (i.e. 950 mg per square metre twice daily) is recommended in patients of 60 years of age and over. If no toxicity is observed, the dose of capecitabine may be cautiously escalated to the standard adult dose of 1250 mg per square metre twice daily.
Grade 3 or 4 treatment-related adverse events are more frequent in patients of 60 years of age and over, therefore, these patients should be monitored carefully.
Patients with Renal Impairment
Capecitabine is known to be eliminated predominantly in the urine so the following recommendations are made for patients with renal impairment:
Creatinine clearance 30 to 50 ml/minute at baseline:
The incidence of grade 3 or 4 adverse events in this patient group is increased. In these patients, reduction of a 1250 mg per square metre starting dose to 75% (i.e. 950 mg per square metre) is recommended. No dose reduction is required for a starting doses of 1000 mg per square metre.
Additional Dosage Information
Toxicity due to capecitabine may be managed by symptomatic treatment and/or dose modification (dose reduction or treatment interruption). Once a dose reduction has been made it should not be re-escalated during future treatment.
For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes etc, treatment can be continued at the same dose.
Patients should be informed of the need to interrupt treatment immediately if moderate or worse toxicity occurs. Doses that have been omitted are not replaced or restored, the patient should instead resume the planned treatment cycle as though the doses had been received.
Dosage recommendations to manage toxicity:
Capecitabine as monotherapy:
Toxicity graded using the NCIC CTC (National Cancer Institute of Canada Common Toxicity Criteria, version 1.0 revised December 1994) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0, except for hand-foot syndrome and hyperbilirubinaemia.
Grade 2 toxicity
1st appearance, interrupt therapy until resolved to grade 0 or 1, no dose adjustment for next cycle.
2nd appearance, interrupt therapy until resolved to grade 0 or 1, adjust dose to 75% of starting dose.
3rd appearance, interrupt therapy until resolved to grade 0 or 1, adjust dose to 50% of starting dose.
4th appearance, discontinue treatment permanently.
Grade 3 toxicity
1st appearance, interrupt therapy until resolved to grade 0 or 1, adjust dose to 75% of starting dose.
2nd appearance, interrupt therapy until resolved to grade 0 or 1, adjust dose to 50% of starting dose.
3rd appearance, discontinue treatment permanently.
Grade 4 toxicity
1st appearance, discontinue permanently or if the physician considers it is in the patient's best interest to continue, interrupt therapy until resolved to grade 0 or 1, adjust dose to 50% of starting dose.
2nd appearance, discontinue treatment permanently.
Capecitabine in 3 week cycle with other agents
Dose modifications for toxicity when capecitabine used in combination with other products should be made according to adjustments for capecitabine monotherapy for capecitabine and according to appropriate prescribing information for other product(s).
At the beginning of a treatment cycle, if treatment delay for either drug is indicated, administration of both should be delayed until the requirements for starting both drugs are met.
During treatment cycle if toxicity occurs which is not related to capecitabine, capecitabine should be continued and the other agent discontinued according to appropriate prescribing information. If the other agent has to be permanently discontinued capecitabine treatment may be resumed when requirements for restarting capecitabine have been met.
Capecitabine used continuously in combination with other agents
Dose modifications for toxicity when capecitabine is used continuously in combination with other agents should be made according to adjustments for capecitabine monotherapy for capecitabine and according to appropriate prescribing information for other product(s).
Management of specific toxicities
Dehydration
Dehydration should be prevented or corrected at onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. If grade 2 or higher dehydration occurs, capecitabine treatment should be discontinued immediately and the dehydration corrected. Treatment should not be restarted until the patient is hydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be those for the precipitating adverse event, in accordance with the guidelines above.
Diarrhoea
Diarrhoea has been observed in 50% of patients. Careful monitoring with fluid and electrolyte replacement is recommended if dehydration occurs. Anti-diarrhoeal treatments such as loperamide may be used.
Grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools.
Grade 3 diarrhoea is defined as an increase of 7 to 9 stools/day or incontinence and malabsorption.
Grade 4 diarrhoea is defined as an increase of 10 or more stools/day or grossly bloody diarrhoea or the need for parenteral support.
Immediately interrupt the administration of capecitabine if grade 2, 3 or 4 diarrhoea occurs until the event resolves or decreases in intensity to grade 1.
After grade 3 or 4 diarrhoea, subsequent doses of capecitabine should be decreased or discontinue treatment permanently (especially with grade 4).
Hand-foot syndrome (palmar-plantar erythrodysaesthesia)
Grade 1 defined as numbness, dysaesthesia/paraesthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patients normal activities.
Grade 2 defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living.
Grade 3 defined as moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that cause the patient to be unable to work or perform activities of daily living.
Interrupt the administration of capecitabine if grade 2 or 3 palmar-plantar erythrodysaesthesia occurs until the event resolves or decreases in intensity to grade 1.
Subsequent doses of capecitabine should be decreased after grade 3 palmar-plantar erythrodysaesthesia.
When used in combination with cisplatin, it is not recommended to use pyridoxine (vitamin B6) for symptomatic or prophylactic treatment of palmar-plantar erythrodysaesthesia as it may decrease the efficacy of cisplatin.
Haematological toxicities
Capecitabine treatment may continue throughout a grade 3 neutropenic episode. However, the patient should be closely monitored and administration of capecitabine should be interrupted if any grade 2 clinical event (e.g. diarrhoea, stomatitis, fever) coincides with the grade 3 neutropenic episode.
Following interruption, capecitabine should only be re-administered when the neutrophil count is greater than or equal to 1.5 x 10 to the power 9/L.
Contraindications
Children under 18 years
Neutrophil count below 1.5 x 10 to the power of 9 / L
Platelet count below 100 x 10 to the power of 9/ L
Breastfeeding
Complete dihydropyrimidine dehydrogenase deficiency
Long QT syndrome
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Severe hepatic impairment
Severe leucopenia
Severe neutropenia
Severe thrombocytopenia
Torsade de pointes
Precautions and Warnings
Family history of long QT syndrome
Females of childbearing potential
Patients over 60 years
Central nervous system disorder
Dehydration
Diabetes mellitus
Electrolyte imbalance
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of angina
History of cardiac arrhythmias
History of cardiac disorder
History of eye disorder
History of torsade de pointes
Hypercalcaemia
Hypocalcaemia
Lactose intolerance
Partial dihydropyrimidine dehydrogenase deficiency
Peripheral neuropathy
Renal impairment
Correct dehydration before commencing therapy
Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Concurrent radiotherapy may increase risk of serious adverse effects
DPD deficiency phenotype/genotype testing is recommended prior to treatment
Treatment to be initiated and supervised by a specialist
Some formulations contain lactose
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Consider monitoring ECG in patients at risk of QT prolongation
Limited data in hepatic impairment: monitor patient closely
Monitor ophthalmic function
Monitor patients receiving concurrent anticoagulants
Monitor plasma calcium
Monitor serum electrolytes
Monitor toxicity - discontinue or modify dose if necessary
Persistent diarrhoea - monitor patient; reduce dose or discontinue therapy
Advise patient to seek medical advice if severe skin reaction occurs
Advise patient to seek medical help if diarrhoea/emesis/neutropenia occur
Treatment may need modifying if diarrhoea and stomatitis occur
Consider suspending treatment for any grade 2 or worse toxicity
Discontinue if severe hypersensitivity reactions occur
Discontinue permanently if severe skin reaction occurs
If dehydration occurs, discontinue treatment until patient has recovered
Interrupt therapy if elevations in bilirubin of > 3 x ULN occur
Interrupt therapy if neutrophil count <1.0x10 to the power 9/L
Interrupt therapy if treatment-related elevations in ALT,AST (>2.5 x ULN)
Interrupt therapy/reduce dose if palmar-plantar erythrodysaesthesia occurs
Suspend therapy if platelet count falls below 75,000 per cubic mm
Female: Contraception required during and for 6 months after treatment
Male: Contraception required during and for 3 months after treatment
Breastfeeding: Do not breastfeed during & for 2 weeks after treatment
Advise patients on the risk of neutropenia and the significance of fever
Pregnancy and Lactation
Pregnancy
Capecitabine is contraindicated during pregnancy.
Use of capecitabine during pregnancy is contraindicated by the manufacturer.
Animal studies have shown teratogenic effects. Human data is limited and such a potential risk cannot be ruled out.
Lactation
Capecitabine is contraindicated during breastfeeding.
Use of capecitabine when breastfeeding is contraindicated by the manufacturer.
Animal data reports significant levels of capecitabine in the breast milk, however presence in human breast milk is unknown. Breastfeeding should be discontinued during treatment and for 6 weeks after final dose.
Counselling
Advise patients to seek medical attention if they develop an adverse reaction, particularly if diarrhoea is significant/bloody, they develop jaundice, a severe skin reaction or signs of neutropenia such as a sore throat, fever or an influenza like illness.
Tablets should be swallowed with water and taken with food or within 30 minutes after a meal.
Side Effects
Alopecia
Altered liver function tests
Anaemia
Angina
Anorexia
Anxiety
Aphasia
Arrhythmias
Ascites
Asthenia
Asthma
Ataxia
Atrial fibrillation
Bone marrow depression
Bradycardia
Cardiac failure
Cardiogenic shock
Colitis
Confusion
Cough
Dehydration
Depression
Deterioration of renal function in pre-existing renal disease
Diabetes mellitus
Diplopia
Dizziness
Dry mouth
Dry skin
Dysgeusia
Dysphagia
Dysphonia
Dyspnoea
Ear pain
Electrolyte disturbances
Encephalopathy
Epistaxis
Fatigue
Gastro-intestinal haemorrhage
Gastro-intestinal symptoms
Haematological disorders
Haemoptysis
Headache
Hydronephrosis
Hyperbilirubinaemia
Hyperpigmentation of skin
Hypersensitivity reactions
Hypertriglyceridaemia
Impaired memory
Increase in creatinine
Infections
Influenza-like syndrome
Insomnia
Intestinal obstruction
Jaundice
Lacrimal gland disorder
Leucopenia
Lipoma
Lower respiratory tract infection
Malaise
Musculoskeletal disturbances
Myocardial infarction
Nail disorders
Neuralgia
Neutropenia
Oedema
Pain
Palmar-plantar erythrodysaesthesia
Paraesthesia
Peripheral neuropathy
Photosensitivity
Pneumothorax
Prolongation of QT interval
Pulmonary embolism
Pyrexia
Radiation recall dermatitis
Reduced libido
Reduced visual acuity
Rhinorrhoea
Rigors
Rise in body temperature
Skin reactions
Stevens-Johnson syndrome
Stomatitis
Syncope
Thrombocytopenia
Thrombophlebitis
Thrombosis
Torsades de pointes
Toxic epidermal necrolysis
Tremor
Urinary abnormalities
Vaginal haemorrhage
Vascular disorders
Ventricular fibrillation
Vertigo
Weight loss
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: December 2019
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
HPRA Safety Notice - 5-Fluorouracil (i.v.), capecitabine and tegafur containing products: Pre-treatment testing to identify DPD-deficient patients at increased risk of severe toxicity Available at: https://www.hpra.ie/homepage/medicines/safety-notices/item?t=/important-safety-information-from-marketing-authorisation-holders-of-products-containing-5-fluorouracil-(i.v.)-capecitabine-and-tegafur-as-approved-by-the-hpra&id=809e0d26-9782-6eee-9b55-ff00008c97d0
Last accessed: 26 October 2020
Joint Formulary Committee. British National Formulary. 66th ed. London: BMJ Group and Pharmaceutical Press; 2013. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on [January 20, 2014]].
Summary of Product Characteristics: Capecitabine. Accord Healthcare Limited. Revised October 2019.
Summary of Product Characteristics: Capecitabine. Dr. Reddys Laboratories (UK) Ltd. Revised July 2019.
Summary of Product Characteristics: Xeloda. Roche Products Limited. Revised June 2019.
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