Xeloda (Capecitabine)

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Capecitabine). A white to off-white crystalline powder. Sparingly soluble in water; soluble in alcohol and in acetonitrile; freely soluble in methyl alcohol. Store in airtight containers at a temperature of 20° to 25°, excursions permitted between 15° and 30°.

Appearance

Tablets: Small, light peach, oblong tablet containing 150 mg of Capecitabine Larger, peach, oblong tablet containing 500 mg of Capecitabine.

Why This Medication is Used

Capecitabine is used to treat breast and colorectal cancer. It may also be used in other types of cancer.

How do you take this Medication: Capecitabine is taken by mouth, twice daily for 14 days, followed by a 1 week (7 day) rest period. Your dose may be a combination of 150 mg and 500 mg tablets. Tablets should be taken after a meal (breakfast and supper) with a full glass of water.

If you miss a dose of this medicine, do not take the missed dose at all and do not double the next one. Instead, go back to your regular dosing schedule and check with your doctor.

Adverse Effects and Precautions

As for Fluorouracil. Diarrhoea (which may be severe), nausea and vomiting, abdominal pain, stomatitis, and palmar-plantar erythrodysesthesia syndrome (erythema and desquamation of hands and feet) occur commonly with capecitabine, and may be dose-limiting. Other common adverse effects include fatigue, asthenia, and anorexia.

Rashes, alopecia, erythema, dryness of the skin, pruritus, skin pigmentation disorders, and nail disorders can occur. Other adverse effects are fever, pain, arthralgia, constipation, dyspepsia, paraesthesia, headache, dizziness, insomnia, hypoor hypercalcaemia, and dehydration. Dermatitis, cardiotoxicity, and bone-marrow depression have all been reported. Hyperbilirubinaemia has occurred. Doses should be reduced in patients with moderate renal impairment and the drug is contra-indicated in those with severe renal or hepatic impairment.

Effects on blood lipids

Severe hypertriglyceridaemia has been reported with oral capecitabine; patients had high baseline triglyceride concentrations at the start of capecitabine. Despite the introduction of lipid-lowering therapy, triglyceride concentrations remained above baseline, and only decreased several weeks after stopping capecitabine.

Effects on the eyes

A report of severe ocular irritation with corneal deposits and impaired visual acuity in 2 patients given capecitabine. Symptoms resolved within several weeks of stopping the drug.

Effects on the heart

Acute ischaemic chest pain has been reported, usually within a few days of starting capecitabine. Symptoms from case reports and incidence in Phase III studies were similar to those in patients given fluorouracil. While symptoms have generally been reported to be reversible, fatal myocardial infarction has occurred. One patient had also had cardiotoxicity with fluorouracil treatment, but others had no apparent risk factors.

Effects on the nervous system

Peripheral neuropathy and encephalopathy have been reported in association with capecitabine use.

Effects on the skin and nails

While hand-foot syndrome appears to be common in patients treated with capecitabine (see Palmar-plantar Erythrodysesthesia Syndrome, below), other skin eruptions have been rarely reported. Onychomadesis (total separation of the nail-bed) and onycholysis have occurred. Pyogenic granuloma has been seen with the use of capecitabine, as has re-pigmentation of chemotherapy-induced vitiligo.

Hypersensitivity

A patient was successfully given fluorouracil by continuous infusion despite previous hypersensitivity to capecitabine. The authors supposed that the hypersensitivity was likely to have been caused by capecitabine or intermediate metabolites, and suggested a lack of cross-sensitivity between capecitabine and fluorouracil.

Pal mar-plantar erythrodysesthesia syndrome

Hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome) has been reported to be common with use of capecitabine given either as monotherapy or as part of combination chemotherapy regimens. The syndrome developed within the first 2 cycles of monotherapy, but within the first 3 cycles in combination therapy, which was attributed to dose modifications of capecitabine in the latter case. Use with docetaxel, and previous chemotherapy-induced stomatitis were found to be significant risk factors for its occurrence.

The only effective management is treatment interruption and dose modification Supportive measures to reduce pain and discomfort and prevent secondary infection are important. General recommended strategies include submersion of hands and feet in cold water, wound care, and avoidance of extreme temperature changes, tight-fitting clothing, or skin friction. Emollient creams may be of benefit for both prophylaxis and treatment. Other strategies that have been proposed include the use of amifostine, topical or systemic corticosteroids, and nicotine patches; however, use of these drugs for capecitabine-induced hand-foot syndrome remains unproven.

While pyridoxine cannot be recommended for prophylaxis, some consider it a reasonable choice for treatment, since benefit has been reported with its use with topical emollients. Concurrent treatment with celecoxib has been reported to reduce the incidence of hand-foot syndrome induced by capecitabine. For reference to the use of vitamin E to alleviate hand-foot syndrome caused by capecitabine and docetaxel, see Chemotherapy-induced Toxicity, under Uses of Vitamin E.

As a result of capecitabine-induced hand-foot syndrome, fingerprint misidentification has been reported.

Tumour lysis syndrome

A fatal case of tumour lysis syndrome has been reported after the use of capecitabine.

Interactions

As for Fluorouracil. Altered coagulation parameters and bleeding have occurred in patients on warfarin or phenprocoumon given capecitabine. Increased phenytoin plasma concentrations and symptoms of toxicity during use with capecitabine have been reported. Capecitabine must not be given with sorivudine or its analogues as fatal fluoropyrimidine toxicity may occur (see also Antivirals, under Interactions of Fluorouracil).

Antacids containing aluminium or magnesium hydroxides cause a small increase in capecitabine plasma concentration. The maximum tolerated dose of capecitabine is reduced when it is given with either folinic acid or interferon alfa.

Pharmacokinetics

Capecitabine is readily absorbed from the gastrointestinal tract, with peak plasma concentrations occurring at about 1.5 hours. Food reduces the rate and extent of absorption. Plasma protein binding of capecitabine is less than 60%. Capecitabine is hydrolysed in the liver to 5′-deoxy-5-fluorocytidine (5′-DFCR), which is then converted to 5′-deoxy-5-fluorouridine (5′-DFUR; doxifluridine) and subsequently to 5-fluorour-acil in body tissues. 5-Fluorouracil is further metabolised, as discussed on site. About 3% of a dose of capecitabine is excreted in the urine unchanged.

Uses and Administration

Capecitabine is a prodrug that is converted to fluorouracil in body tissues. It is given orally for the treatment of metastatic colorectal cancer and is also used for the adjuvant treatment of patients after surgery for Dukes C colon cancer. Capecitabine is given with docetaxel for the treatment of locally advanced or metastatic breast cancer after failure of anthracycline-containing chemotherapy. It may be given as monotherapy after failure of taxanes and anthracycline-containing regimens for patients with breast cancer and for whom further anthracycline-containing therapy is not indicated.

Capecitabine with lapatinib is used for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress human epidermal receptor type 2 (HER2). Capecitabine is also used with a platinum-based regimen for the first-line treatment of gastric cancer.

For monotherapy in colon, colorectal, or in breast cancer, the recommended initial oral dose is 1.25 g/m given twice daily; doses are given for 14 days, followed by a 7-day rest period. Adjuvant treatment for colon cancer is recommended for a total of 6 months. For combination therapy in breast cancer, when given with docetaxel, capecitabine is given in the same dose as listed above; docetaxel is given at 75 mg/m as a 1-hour intravenous infusion every 3 weeks. However, when used with lapatinib tosilate, a different regimen is used, see Uses and Administration, under Lapatinib Tosilate.

In combination therapy in colorectal or gastric cancer, the recommended initial oral dose of capecitabine is 0.8 to 1 g/m twice daily for 14 days, followed by a 7-day rest period. Alternatively, capecitabine 625 mg/m twice daily is given continuously. Capecitabine tablets should be swallowed with water within 30 minutes after a meal. Doses should be modified in subsequent cycles according to toxicity. Capecitabine doses should be reduced in patients with renal impairment (see below). Capecitabine is also under investigation in the treatment of other malignancies.

Administration in renal impairment

Renal impairment increases systemic exposure to 5′-deoxy-5-fluorouridine, a metabolite of capecitabine. An increase in the severity of adverse effects appears to correlate with decreased renal function and increased exposure to this metabolite.

Licensed product information suggests the following dosage adjustments based on creatinine clearance (CC):

• mild renal impairment, CC 51 to 80 mL/minute: no dosage adjustment necessary
• moderate renal impairment, CC 30 to 50 mL/minute: when the starting dose is 1.25 g/m twice daily, a dose reduction of 25%, to about 950 mg/m twice daily is recommended; however, when the starting dose is 1 g/m twice daily, no dose reduction is required
• severe renal impairment, CC below 30 mL/minute: capecitabine is contra-indicated.

Precautions

Capecitabine may interact with other medications (such as warfarin and phenytoin). Make sure your doctor and pharmacist have a complete list of the medications (including herbal and over-the-counter medication) that you are taking.

Capecitabine may make you more sensitive to sunlight. Use a sunscreen with SPF of at least 15. Wear a hat and cover exposed skin while you are receiving this medication.

Store away from heat, light, and moisture.

Keep out of reach of children.

This chemotherapy should not be used if you are pregnant or breast-feeding. It is important to discuss birth control with your doctor. If you are a male taking this medication, birth control should also be used by female partners. NOTE: If you are taking this medication for breast cancer, a reliable barrier form of contraception (e.g. spermicidal jelly and condom or diaphragm) should be used. Birth control pills are not recommended.

It is important to tell your doctor if you have chickenpox (or have recently been exposed to someone who has had chickenpox), shingles, kidney disease or liver disease. Any of these conditions could affect therapy with this medication.

Due to increased risk of infection check with your doctor before having any vaccinations. Check with your doctor, before any surgery or dental work.

Do not take ASA without your doctor’s knowledge and consent.

> If a doctor has advised you to take ASA to prevent heart disease or stroke, please discuss this with your oncologist (cancer doctor) before starting treatment.

> Do not use ASA (aspirin, acetylsalicylic acid) for headache, fever, or occasional aches and pains; use acetaminophen (Tylenol) instead. Many non-prescription medications contain ASA; always ask your pharmacist’s advice when choosing a product.

For more information on this medication, please call your doctor, pharmacist or nurse.

Preparations

The United States Pharmacopeia 31, 2008: Capecitabine Tablets.

Proprietary Preparations

Argentina: Apecitab ; Categor; Xeloda;

Australia: Xeloda;

Austria; Xeloda;

Belgium: Xeloda;

Brazil: Xeloda;

Canada: Xeloda;

Chile: Xeloda;

Czech Republic: Xeloda;

Denmark: Xeloda;

Finland: Xeloda;

France: Xeloda;

Germany; Xeloda;

Greece: Xeloda;

Hong Kong; Xeloda;

Hungary: Xeloda;

Indonesia: Xeloda;

Israel: Xeloda;

Italy: Xeloda;

Japan: Xeloda;

Malaysia: Xeloda;

Mexico: Xeloda;

Netherlands: Xeloda;

Norway: Xeloda;

New Zealand: Xeloda;

Philippines: Xeloda;

Poland: Xeloda;

Portugal: Xeloda;

Russia: Xeloda;

South Africa: Xeloda;

Singapore; Xeloda;

Spain: Xeloda;

Sweden: Xeloda;

Switzerland: Xeloda;

Thailand: Xeloda;

Turkey: Xeloda;

United Kingdom (UK): Xeloda;

United States of America (US and USA): Xeloda;

Venezuela: Xeloda