capecitabine (Rx)

Varies with carcinoma type

10%

Diarrhea

Nausea

Anemia

Lymphopenia

Hand and foot syndrome

Edema

Fatigue

Fever

Headache

Pain

Paresthesia

Alopecia

Dermatitis

Abdominal pain

Anorexia

Appetite decreased

Constipation

Dyspepsia

Stomatitis

Vomiting

Neutropenia

Thrombocytopenia

Dyspnea

Bilirubin increased

Eye irritation

1-10%

Chest pain

Dermatitis

Pruritus

Rash

Dizziness

Headache

Weakness

Dehydration

Dry mouth

Dyspepsia

Taste disturbance

Back pain

Postmarketing reports

Toxic leukoencephalopathy

Contraindications

Hypersensitivity to capecitabine or fluorouracil (5-FU)

Severe renal impairment (CrCl <30 mL/min)

Cautions

May result in bleeding, death; monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly

Diarrhea may be severe; interrupt capecitabine treatment immediately until diarrhea resolves or decreases to grade 1; recommend standard antidiarrheal treatments

May cause cardiomyopathy and acute decreases in LVEF

Increased risk of severe or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase (DPD) activity; withhold or permanently discontinue capecitabine in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity; no capecitabine dose has been proven safe in patients with absent DPD activity

Interrupt capecitabine treatment until dehydration is corrected; potential risk of acute renal failure secondary to dehydration; monitor and correct dehydration

Can cause fetal harm; advise women of the potential risk to the fetus

Based on animal studies, therapy may impair fertility in females and males of reproductive potential

Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), reported; discontinue therapy in patients who experience a severe mucocutaneous reaction during treatment; capecitabine may induce hand-and-foot syndrome; interrupt capecitabine treatment until hand-and-foot syndrome event resolves or decreases in intensity; persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints

If hypervilirubinemia occurs, interrupt therapy immediately until it resolves or decreases in intensity

Do not treat patients with neutrophil counts <1.5 x 10^9;/L or thrombocyte counts <100 x 10^9;/L; if grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for 6 months after last therapeutic dose
• Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after last therapeutic dose

Pregnancy

Based on findings in animal reproduction studies and its mechanism of action, therapy can cause fetal harm when administered to a pregnant; limited available human data are not sufficient to inform drug-associated risk during pregnancy

In animal reproduction studies, therapy in pregnant animals during period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times, respectively, the exposure (AUC) in patients

Pregnancy testing is recommended for females of reproductive potential prior to initiating therapy

Lactation

There is no information regarding presence in human milk, or effects on milk production or breast-fed infant; drug metabolites were present in milk of lactating mice; because of potential for serious adverse reactions from exposure in breast-fed infants, advise women not to breastfeed during therapy and for 2 weeks after final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Half-life: 0.75 hr

Peak Plasma Time: 1.5 hr

Protein Bound: <60%

Metabolism: hepatic

Metabolites: 5'-DFUR

Excretion: urine (95%)

Dialyzable: yes

Pharmacogenomics

Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates >80% of 5FU standard doses and the 5FU prodrug capecitabine

Contraindicated in patients with DPD deficiency; causes severe toxicity with conventional doses (ie, grade III/IV toxicity and potentially fatal neutropenia, mucositis, and diarrhea)

Because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted

Genetic testing laboratories

• The following companies currently offer testing for DPYD*2A mutations
• EntroGen (http://www.entrogen.com)
• Myriad (http://www.myriadtests.com)
• LabCorp (http://www.labcorp.com)
• Molecular Diagnostics Laboratories (http://www.mdl-labs.com)

Mechanism of Action

Converted to 5-FU by thymidine phosphorylase in neoplastic tissue