FLUOROURACIL AND RELATED AGENTS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2,4-dioxo-5-fluoropyrimidine
2) 5-Fluoro-2,4(1H,3H)-
3) 5-Fluorouracil
4) Fluorouracil
5) pyrimidinedione
6) 5-FU
7) NSC 19893
8) Ro 2-9757
9) CAS 51-21-8

1) Ro 09-1978

1.2.1) MOLECULAR FORMULA
1) CAPECITABINE: C15H22FN3O6
2) FLUOROURACIL: C4H3FN2O2

Available Forms Sources

1) FLUOROURACIL

a) IV: Available as 50 mg/mL in 10 mL or 20 mL vials for intravenous use (Prod Info fluorouracil intravenous injection, 2014)
b) TOPICAL: Available as a 0.5%, 1%, 4%, and 5% cream (Prod Info TOLAK topical cream, 2015; Prod Info Fluorouracil topical cream, 2010; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003) and as a 2% and 5% topical solution (Prod Info Fluorouracil topical solution, 2010).

2) CAPECITABINE

a) Available as 150 mg and 500 mg tablets (Prod Info XELODA(R) oral tablets, 2015).

3) FLOXURIDINE

a) Available as a 500 mg powder for injection to be reconstituted with 5 mL of sterile water (Prod Info floxuridine intra-arterial injection, 2008).

1) FLUOROURACIL

a) IV: The intravenous formulation is indicated in the palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients who are considered incurable by surgery or other means (Prod Info fluorouracil intravenous injection, 2014).
b) TOPICAL: Fluorouracil cream is approved for the treatment of actinic or solar keratosis lesions of the face, ears, and scalp (Prod Info TOLAK topical cream, 2015; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003), as well as for the treatment of superficial basal carcinoma with the 5% strength (Prod Info Fluorouracil topical cream, 2010). The fluorouracil topical solution is used for the treatment of actinic and solar keratoses, as well as for the treatment of superficial basal cell carcinomas in patients with multiple lesions or at difficult treatment sites that could not be treated with other methods (Prod Info Fluorouracil topical solution, 2010).

2) CAPECITABINE

a) Capecitabine is a prodrug of fluorouracil used in the treatment of metastatic breast cancer that is refractory to paclitaxel and anthracycline-containing chemotherapy regimens and as adjuvant therapy in patients with Dukes' C colon cancer and metastatic colorectal cancer(Prod Info XELODA(R) oral tablets, 2015).

3) FLOXURIDINE

a) Floxuridine rapidly catabolizes to fluorouracil when given intra-arterially and is used for the palliative management of gastrointestinal adenocarcinoma that metastasized to the liver in patients who are considered incurable by surgery or other means (Prod Info floxuridine intra-arterial injection, 2008).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Fluorouracil (5-FU) is an antineoplastic used in the management of carcinoma of the esophagus, head and neck, colon, rectum, breast, stomach, and pancreas. Topical fluorouracil is used to treat actinic and solar keratoses. Capecitabine is a prodrug of fluorouracil, used in the treatment of colorectal cancer and metastatic breast cancer refractory to paclitaxel and anthracycline-containing chemotherapy as adjuvant therapy in patients with Dukes' C colon cancer and metastatic colorectal cancer. Floxuridine rapidly catabolizes to fluorouracil when given intra-arterially and is used for the management of gastrointestinal adenocarcinoma that metastasized to the liver.
B) PHARMACOLOGY: 5-Fluorouracil is a fluorinated pyrimidine antimetabolite which undergoes anabolic and catabolic reactions the same as uracil except it is converted to thymidine. 5-Fluorouracil, or fluorouracil, blocks the methylation reaction of deoxyuridylic acid to thymidylic acid and interferes with DNA synthesis and to a lesser extent inhibits the formation of RNA. This creates a thymine deficiency resulting in cell death, especially in cells which grow more rapidly and take up fluorouracil rapidly. Capecitabine is a prodrug and is extensively metabolized to 5-FU.
C) TOXICOLOGY: Fluorouracil effects rapidly dividing cells. In order to produce toxicity, fluorouracil must be metabolized into the compounds 5-fluorodeoxyurideine monophosphate and 5-fluorouracil triphosphate. Dihydropyrimidine dehydrogenase is an enzyme used in the initial and rate-limiting step of pyrimidine (and 5-FU) catabolism. In rare cases, an inherited deficiency of dipyrimidine dehydrogenase activity has led to severe toxicity (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) following therapeutic doses of 5-FU.
D) EPIDEMIOLOGY: Overdose of 5-FU is typically due to a medication error (ie, malfunction or incorrect programming of the intravenous pump) and is rare, but can be fatal, if it occurs.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: COMMON: Early symptoms include anorexia, stomatitis, esophagopharyngitis, diarrhea, nausea and vomiting. SEVERE: Major toxic effects result from myelosuppression. Clinical effects include palmar-plantar erythrodysesthesia, leukopenia, thrombocytopenia, and anemia.
2) LESS COMMON: Other potentially severe events: neurologic toxicity (ie, mental status changes, ataxia and neuropathy), cardiogenic shock, and gastrointestinal bleeding and perforation can develop. There have been infrequent reports of hepatotoxicity, ileitis, rhabdomyolysis, pulmonary edema, hypokalemia, and seizures.
3) CAPECITABINE: Dose-limiting toxicities with therapy can include gastrointestinal effects (ie, nausea, vomiting, diarrhea, abdominal pain), fatigue, dizziness, thrombocytopenia, and palmar-plantar erythrodysesthesia.

F) WITH POISONING/EXPOSURE

1) OVERDOSE: Effects are expected to be an extension of adverse effects reported with therapeutic use and may include: severe nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (ie, thrombocytopenia, leukopenia, agranulocytosis, sepsis).

0.2.3)

A) WITH THERAPEUTIC USE

1) Tachycardia and hypotension have been reported with therapeutic use of 5-FU. Fever has occurred during capecitabine clinical trials.

0.2.4)

A) WITH THERAPEUTIC USE

1) Visual disturbances and lacrimation may occur.

0.2.20)

A) Capecitabine is classified as FDA pregnancy category D. Fluorouracil topical is classified as FDA pregnancy category X; however, the injection is classified as FDA pregnancy category D. Fluorouracil has been linked with human birth defects when used at therapeutic doses during pregnancy, however conflicting data indicate a lack of birth defects in some studies. Fluorouracil and capecitabine are known to be teratogenic in animals. No information is available on the passage of fluorouracil or capecitabine into breast milk; however, due to concerns for serious adverse effects in the infant mothers should not breastfeed while receiving these drugs. Fluorouracil causes degenerative effects in the male reproductive system for rats and mice, and female fertility impairment and developmental delay of embryos in rats.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for fluorouracil or capecitabine in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) Capecitabine, the oral prodrug of fluorouracil, is converted to fluorouracil in vivo. Overdose of capecitabine is expected to produce the same effects as overdose with the parenteral form of fluorouracil. See PARENTERAL EXPOSURE for further information.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Early symptoms are likely nausea and vomiting. Treat persistent nausea and vomiting with several antiemetics of different classes. Treat mild mucositis with bland oral rinses with saline or bicarbonate. For moderate symptoms, consider adding an oral anesthetics (lidocaine, benzocaine or diphenhydramine). Treat patients with uncomplicated mild to moderate diarrhea (Grade 1 or 2) without signs of infection with loperamide. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.

B) MANAGEMENT OF SEVERE TOXICITY

1) ANTIDOTE: Uridine triacetate , a prodrug of uridine, has been granted orphan-drug status by the FDA as an antidote to treat fluorouracil poisoning. To obtain uridine triacetate, healthcare professionals can contact the Wellstat Therapeutics 24 hours/day, 7 days/week by calling the severe adverse event hotline: (443)-831-5626. In adults, it is administered at a dose of 10 g every 6 hours for 20 doses. Treat severe mucositis with oral anesthetics and systemic analgesics (eg, morphine) and consider topical or systemic antibiotics if infection is suspected. Use sialagogues (eg, bethanechol) for severe salivary gland dysfunction. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Treat patients presenting with progressive and uncontrolled diarrhea with octreotide, IV fluids, electrolyte replacement, and antibiotics. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.

C) DECONTAMINATION

1) PREHOSPITAL: Ingestion: Activated charcoal should be used if exposure is via oral tablets of capecitabine. Fluorouracil is a parenteral product and prehospital decontamination would not be beneficial. Wash exposed skin with soap and water.
2) HOSPITAL: Ingestion: Activated charcoal should be used if exposure is via oral tablets of capecitabine (prodrug of fluorouracil). GI decontamination is not indicated for parenteral fluorouracil overdose. Wash exposed skin with soap and water.

D) ANTIDOTE

1) As of May 2009, uridine triacetate (formerly known as vistonuridine), a prodrug of uridine, has been granted orphan-drug status by the FDA as an antidote in the treatment of fluorouracil poisoning. In adults, it is administered at a dose of 10 g every 6 hours for 20 doses. To obtain uridine triacetate, healthcare professionals can contact the Wellstat Therapeutics 24 hours/day, 7 days/week by calling the severe adverse event hotline: (443)-831-5626.

E) NAUSEA AND VOMITING

1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).

F) DIARRHEA

1) Treat patients with uncomplicated mild to moderate diarrhea (Grade 1 or 2) without signs of infection with loperamide 2 mg every 4 hours for 24 hours. Treat patients presenting with progressive and uncontrolled diarrhea with octreotide 100 mcg to 150 mcg SC or IV (25 to 50 mcg/hr), IV fluids, electrolyte replacement, and antibiotics.

G) STOMATITIS/MUCOSITIS

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a fluorouracil overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

H) MYELOSUPPRESSION

1) Leukopenia accompanies every course of therapy with fluorouracil with peak effects at 7 to 14 days postexposure. Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.

I) NEUTROPENIA

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

J) FEBRILE NEUTROPENIA

1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

K) EXTRAVASATION INJURY

1) Fluorouracil has been classified as an irritant by one source and another classifies it as a neutral agent. If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Another source recommended warm/heat compresses for local reaction. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.

L) INTRATHECAL INJECTION

1) No clinical reports of intrathecal injection with fluorouracil are available. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative-free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

M) ENHANCED ELIMINATION

1) Dialysis may be of benefit in overdoses with capecitabine (prodrug of fluorouracil) in reducing the amount of 5'-DFUR, a low molecular weight metabolite of the parent compound. Dialysis is unlikely to be of benefit in the overdose of intravenous fluorouracil due to large volume of distribution. Circulating levels of fluorouracil are undetectable within 3 hours of injection.

N) PATENT DISPOSITION

1) HOME CRITERIA: Patients who have had a known overdose of fluorouracil MUST seek medical attention so the antidote can be administered as soon as possible. Only patients who have been exposed to therapeutic doses and have mild symptoms of toxicity (ie, Grade 1 uncomplicated diarrhea or Grade 1 nausea/vomiting) may be managed at home under the supervision of their oncologist. Patients with new or worsening symptoms must seek medical attention.
2) ADMISSION CRITERIA: Admit patients with known overdose. Patients who have received therapeutic doses and are hemodynamically unstable, require IV fluids and electrolyte replacement secondary to progressive, complicated chemotherapy induced diarrhea or treatment resistent nausea or vomiting, and/or patients who are at a severe risk of infection must be admitted to the hospital for supportive care.
3) CONSULT CRITERIA: Consult a medical toxicologist or oncologist in cases where management of chemotherapy adverse events or toxicity is uncertain.
4) TRANSFER CRITERIA: Patients with large overdose or profound neutropenia may benefit from transfer to an oncology treatment or bone marrow transplant center.

O) PITFALLS

1) Therapeutic doses of fluorouracil have been known to produce profound toxicity and even death. Patients presenting with symptoms of 5-FU toxicity may not have been exposed to an overdose, but the adverse effects of the medication may be life threatening. Early symptoms of overdose may not be evident and may result in lack of perception by the patient and healthcare staff regarding the life-threatening nature of the incident.

P) PHARMACOKINETICS

1) Fluorouracil is rapidly absorbed following IV administration and distributes into tumor, intestinal mucosa, bone marrow, liver, and other tissues throughout the body, including crossing the blood brain barrier and cerebrospinal fluid. Within 6 hours of administration, 7% to 20% of the total dose of fluorouracil is excreted unchanged in the urine, with 90% of this percentage excreted within the first hour. The remaining dose is metabolized in the liver. Volume of distribution is 25 L/kg and protein binding is approximately 10%. Catabolic metabolism produces inactive metabolites of urea and alpha-fluoro-beta-alanine which are excreted in the urine 3 to 4 hours after administration, and CO2 which is mostly excreted via exhalation. The mean half-life of elimination from plasma is approximately 16 minutes, with a range of 8 to 20 minutes and is dose dependent. No intact drug can be detected within the plasma 3 hours after IV administration. CAPECITABINE: Capecitabine is the oral prodrug of fluorouracil and is biologically activated in vivo by cytidine deaminase to produce 5'-deoxy-5-fluorouridine (5'-DFUR). Thymidine phosphorylase hydrolyzes 5'-DFUR to 5-FU (fluorouracil). Increase in capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. Increases in AUC of fluorouracil were greater than proportional to the increase in dose, measuring 34% higher on day 14 of therapy than on day 1.

Q) DIFFERENTIAL DIAGNOSIS

1) Patients on chemotherapy should always be evaluated for serious infection. Patients presenting with bloody stools and significant GI symptoms should be evaluated for ulceration and bleeding and subsequent coagulopathy.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Tachycardia and hypotension have been reported with therapeutic use of 5-FU. Fever has occurred during capecitabine clinical trials.

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever was reported in 7% to 28% of the cancer patients (n=2004) involved in various clinical trials for capecitabine (Prod Info XELODA(R) oral tablets, 2009a).
2) Fever occurred in 4 of 12 patients who participated in a capecitabine clinical trial at a dose of 1657 mg/m(2)/day (Budman et al, 1998).

3.3.4)

A) WITH THERAPEUTIC USE

1) HYPOTENSION

3.3.5)

A) WITH THERAPEUTIC USE

1) TACHYCARDIA

a) Tachycardia has been noted in some patients experiencing chest pain (Carpenter, 1972).

Heent

3.4.1)

A) WITH THERAPEUTIC USE

1) Visual disturbances and lacrimation may occur.

3.4.3)

A) WITH THERAPEUTIC USE

1) VISUAL DISTURBANCES have been reported with therapeutic doses (Dorr & Fritz, 1980).
2) Extreme LACRIMATION may occur with therapeutic doses (Dorr & Fritz, 1980).
3) Ocular contact with 5-FU may produce stinging or burning with blurred vision. No permanent ocular injury has been reported (Curran & Luce, 1989).
4) Ocular lesions consisting of bilateral conjunctival ulcers and ulcerative blepharitis leading to ankyloblepharon were associated with systemic 5-FU treatment in a 59-year-old man with metastatic adenocarcinoma of the stomach (Insler & Helm, 1987).
5) OPTIC NEUROPATHY

a) Reversible OPTIC NEUROPATHY was associated with 5-FU therapy in a 51-year-old woman (Adams et al, 1984).
b) CASE REPORT: A 72-year-old woman experienced progressive vision loss after receiving one year of intravenous 5-FU therapy (a total of 12 courses). Ophthalmological examination showed bilateral swelling of the optic disc and diminished vision of both eyes. Despite discontinuation of 5-FU therapy and administration of corticosteroids, vitamin B, and acetylsalicylic acid, the visual defects persisted. It was determined that the patient had a dihydropyrimidine dehydrogenase deficiency, thereby increasing the patient's risk for developing unusual and/or severe 5-FU toxicity (Delval & Klastersky, 2002).

3.4.6)

A) WITH THERAPEUTIC USE

1) CASE REPORT: Mouth soreness and pharyngeal erythema occurred in a 55-year-old woman 2 days after receiving one cycle of 5-fluorouracil and levofolinic acid chemotherapy for treatment of stage III sigmoid carcinoma. The dosage regimen was 425 mg/m(2) of 5-fluorouracil and 10 mg/m(2) of levofolinic acid administered on days 1 to 5 of a 28 day cycle. Despite treatment with analgesic mouthwashes, the mouth soreness progressed to severe mucosal ulcerations resulting in complete aphagia (Diaz et al, 2004).

Cardiovascular

3.5.2)

A) CHEST PAIN

1) WITH THERAPEUTIC USE

a) 5-FLUOROURACIL

1) Severe chest pain and ischemia have been reported with therapeutic use of 5-FU (Cianci et al, 2003; Godfraind, 1984; Lestuzzi et al, 2001; Underwood et al, 1983; Dent & McColl, 1975; Ensley et al, 1989; Freeman & Costanza, 1988; McLachlan et al, 1994). Coronary vasospasm has been suggested as a possible mechanism (Lestuzzi et al, 2001; Kleiman et al, 1987; Burger & Mannino, 1987) and may lead to cardiogenic shock in some cases (Godfraind, 1984).
2) Cianci et al (2003) reported the use of prophylactic options in three patients with 5-fluorouracil-associated cardiotoxicity. In one patient, the echocardiogram showed a reduction in inferior and posterolateral contractility and an altered left ventricle diastolic release with an ejection fraction of 56%. 5-FU doses for two patients were reduced by 10% to 20%. In addition, they were given prophylactic transepidermal nitroglycerin. In the third patient, the 5-FU administration modality was changed; the bolus schedule was modified to a weekly schedule, without prophylactic therapy. These patients no longer complained of anginal pain (Cianci et al, 2003).
3) CASE REPORT: An 83-year-old man with colon cancer developed severe chest pain while receiving a continuous IV infusion of high dose 5-fluorouracil (5-FU) 1000 mg/m(2)/day for 3 days (cumulative dose received 1679 mg/m(2)). An ECG revealed ST segment elevation in leads I, aVL, and V4-6, with reciprocal ST segment depression with a tall T wave in leads V1-2. Troponin-I and creatine kinase (CK-MB) levels were within normal limits; however, an echocardiogram demonstrated severe hypokinesia of the left ventricle wall. The patient's chest pain and ECG changes resolved following an IV infusion of nitroglycerin and cessation of 5-FU therapy. An angiography revealed significant stenosis in the proximal left circumflex coronary artery, requiring placement of a stent. Eight hours later, the patient's chest pain and ECG changes recurred despite continued cessation of 5-FU therapy. Repeat angiography indicated a widely patent stent, and the chest pain and ECG changes resolved with sublingual administration of nifedipine. A repeat echocardiography showed normal left ventricular systolic function and the patient was discharged without recurrence of chest pain (Kim et al, 2012).

b) CAPECITABINE

1) Cardiotoxicity has been reported with therapeutic use of capecitabine (Bertolini et al, 2001).
2) CASE REPORT: A 43-year-old woman with metastatic cancer of the sigmoid colon and minimal cardiac risk factors experienced several episodes of chest pain at rest 5 days after starting capecitabine (1000 mg/m(2) twice a day for 2 weeks on and then 1 week off). ECG revealed ST elevation in all the chest and limb leads. Her symptoms resolved with a nitrate infusion (Papadopoulos & Wilson, 2008).
3) CASE REPORT: A 39-year-old man with advanced gastric cancer (peritoneal carcinosis) developed acute cardiotoxicity 4 days after starting capecitabine 2000 mg/m(2)/day. He experienced retrosternal pain at rest with palpitation and diaphoresis, lasting for about 30 minutes. ECG revealed normal sinus rhythm at 67/min (80/min 4 hours later), along with a normal P wave, A-V conduction and QRS complex, but ST segment elevation with an inverted T wave. Normal cardiac markers were observed. He recovered following the use of transdermal nitroglycerin and verapamil (Bertolini et al, 2001).

B) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Tachycardia has been noted in some patients experiencing chest pain (Carpenter, 1972).

C) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) ST elevation, inverted T waves, and tall, peaked T waves have been reported during chest pain episodes (Papadopoulos & Wilson, 2008; Cianci et al, 2003; Lestuzzi et al, 2001; Bertolini et al, 2001; Sanani et al, 1981).

D) CARDIAC ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Lactate dehydrogenase was elevated in one patient (Pottage et al, 1978).
b) A transient rise in aspartate transaminase and creatine phosphokinase was noted in one patient, but no rise in hydroxybutyrate dehydrogenase was reported (Stevenson et al, 1977).

E) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypotension has been reported with therapeutic doses (Dorr & Fritz, 1980) and has been associated with severe left ventricular dysfunction, a manifestation of cardiotoxicity (David et al, 2000; Jakubowski & Kemeny, 1988).
b) CASE REPORT: A 48-year-old man with no history of heart disease developed an episode of acute reversible cardiogenic shock associated with the first continuous infusion of 5-FU (total dose 3750 mg). Symptoms and signs (ie, substernal chest pain, nausea, diaphoresis, sinus tachycardia of 120 beats/min, nonspecific ST-T ECG changes, and refractory hypotension of 80/58 mmHg requiring dopamine and norepinephrine) improved after the continuous infusion of 5-FU was discontinued (McKendall et al, 1989).
c) CASE REPORT: A 68-year-old man with no history of ischemic heart disease and a 50-pack year history of smoking developed sudden cardiogenic shock and died. No autopsy was performed (Ensley et al, 1989).

F) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) Myocardial infarction has been reported with therapeutic doses of 5-FU (Ensley et al, 1989).

G) CARDIAC ARREST

1) WITH THERAPEUTIC USE

a) Cardiac arrest has been reported during infusion of 5-FU (Millward et al, 1988).
b) CASE REPORT: A 78-year-old woman with advanced squamous cell carcinoma received a continuous infusion of 5-FU 1 g/m(2)/day on days 1 through 4. On day 5, the patient had a cardiorespiratory arrest. The ECG showed ventricular fibrillation. The patient was resuscitated with no subsequent evidence of a myocardial infarction (McLachlan et al, 1994).
c) CASE REPORT: A fatal cardiac arrest was reported following continuous administration of 5-FU, even after the patient had already experienced cardiac reactions to the initial administration of the 5-FU. One theory is that the cardiac reactions may be a cumulative effect, ultimately resulting in death following the second to the fourth dose of 5-FU (Hannaford, 1994).
d) CASE REPORT: A 70-year-old man developed sudden cardiac arrest from ventricular fibrillation after taking 5-FU (725 mg [400 mg/m2] IV bolus with IV infusion of 4400 mg [2400 mg/m2] over 46 hours), irinotecan, and leucovorin for 9 months. An ECG after cardiopulmonary resuscitation and defibrillation showed widespread 5 mm ST segment elevation in the anterior leads. Angiography revealed normal coronary arteries, and it was suspected that his cardiac arrest was secondary to myocardial infarction from 5-FU induced vasospasm. Despite supportive therapy, he remained in a deep coma. He died 3 days later when life support was withdrawn. The possible late-onset of severe cardiotoxicity from 5-FU therapy may have been responsible for the patient's sudden cardiac arrest (Wijesinghe, 2007).

H) AVASCULAR NECROSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Massive myocardial necrosis developed in a 71-year-old diabetic man, 13 days after beginning 5-FU therapy, 1000 mg/m(2) continuous infusion daily for 5 days. The patient's creatinine kinase enzyme levels ranged from 4000 Units/L to 5000 Units/L. Despite vasopressor therapy, the patient died within a week (Sadoff, 1998).

I) DEAD - SUDDEN DEATH

1) WITH THERAPEUTIC USE

a) CASE REPORT: Sudden death occurred in a 44-year-old man 4 days after beginning 5-FU therapy, 1440 mg (20 mg/kg) daily intraperitoneally, as a chemotherapeutic agent to treat a peritoneal tumor. The patient had no prior history of cardiac disease and the autopsy showed no residual tumor, nor pulmonary or air embolus, no atheromata in the coronary arteries, and there was no evidence of a myocardial infarction (El-Attar et al, 1999).
b) CASE REPORT: A 70-year-old man developed a sudden cardiac arrest from ventricular fibrillation after taking 5-FU (725 mg [400 mg/m2] IV bolus with IV infusion of 4400 mg [2400 mg/m2] over 46 hours), irinotecan, and leucovorin for 9 months. An ECG after cardiopulmonary resuscitation and defibrillation showed widespread 5 mm ST segment elevation in the anterior leads. Despite supportive therapy and an urgent primary angioplasty, he remained in a deep coma. He died 3 days later when life support was withdrawn. The possible late-onset of severe cardiotoxicity from 5-FU therapy may have been responsible for the patient's sudden cardiac arrest (Wijesinghe, 2007).

J) HEART FAILURE

1) WITH THERAPEUTIC USE

a) Severe cardiac failure was reported in two patients following treatment with fluorouracil. The ECG of both patients showed sinus tachycardia, with one patient also exhibiting non-specific ST and T wave changes. A transesophageal echocardiography revealed left ventricular dysfunction in both patients. One patient spontaneously recovered following cessation of fluorouracil therapy, while the other patient required treatment with an intra-aortic balloon pump in addition to pressors and inotropic agents (David et al, 2000; Kuropkat et al, 1999).
b) LACK OF ADVERSE EFFECT

1) During episodes of chest pain, while on therapeutic doses of 5-fluorouracil, cardiac enzymes remained normal (Sanani et al, 1981).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) Pulmonary edema without chest pain was a manifestation of reversible heart failure secondary to 5-fluorouracil (Chaudary et al, 1988).

B) LACK OF EFFECT

1) WITH POISONING/EXPOSURE

a) No adverse effects were noted in 6 individuals following inhalation of fluorouracil during a truck fire (Curran & Luce, 1989).

Neurologic

3.7.2)

A) CEREBELLAR DISORDER

1) WITH THERAPEUTIC USE

a) Acute cerebellar syndrome is a form of neurotoxicity associated with use of 5-FU. Onset ranges from initial exposure to several doses and sometimes several courses of 5-fluorouracil therapy. Symptomatology may consist of somnolence, mental confusion, cerebellar ataxia, oculomotor disturbances, and slurred speech (Pirzada et al, 2000; Bixenman et al, 1977).
b) CAPECITABINE: A 65-year-old man with adenocarcinoma of the cecum developed cerebellar ataxia 6 days after receiving capecitabine 1250 mg/m(2) by mouth twice daily. He presented with a wide-based ataxic gait, inability to maintain heel-to-toe walking, and bilateral nystagmus, accompanied by altered finger-to-nose testing. All laboratory tests were normal. Following the discontinuation of capecitabine, his symptoms resolved completely over the next 24 hours (Renouf & Gill, 2006).
c) CAPECITABINE: A 56-year-old woman with metastatic breast cancer developed truncal ataxia after receiving 11 cycles of capecitabine 1000 mg/m(2) twice daily plus lapatinib 1250 mg/day. No other etiology for her symptoms could be determined, and complete neurologic recovery was achieved a few days after discontinuing the capecitabine and lapatinib (Mukesh & Murray, 2008).

B) NEUROPATHY

1) WITH THERAPEUTIC USE

a) Neurotoxicity may develop in individuals with dihydropyrimidine dehydrogenase deficiency. In one patient with this enzyme deficiency, 89% of the administered dose was excreted unchanged in the urine with a prolonged plasma elimination half-life of 159 minutes (Diasio et al, 1988).

C) SECONDARY PERIPHERAL NEUROPATHY

1) WITH THERAPEUTIC USE

a) Peripheral neuropathy was reported in 2 patients who received fluorouracil as part of a chemotherapeutic regimen to treat adenocarcinoma. The neuropathy resolved following discontinuation of the 5-FU (Stein et al, 1998).

D) PARESTHESIA

1) WITH THERAPEUTIC USE

a) Paresthesia occurred in 21% of the breast cancer patients (n=162) who were involved in a Phase 2 clinical trial for capecitabine (Prod Info XELODA(R) oral tablets, 2009a).

E) FATIGUE

1) WITH THERAPEUTIC USE

a) Six patients involved in a capecitabine clinical trial, developed fatigue after ingestion of capecitabine at 1657 mg/m(2)/day (Budman et al, 1998).
b) Fatigue occurred in 41% of the breast cancer patients (n=162) who participated in a Phase 2 clinical trial for capecitabine. Approximately 8% of those patients experienced moderate fatigue (Grade 3) (Prod Info XELODA(R) oral tablets, 2009a).

F) DIZZINESS

1) WITH THERAPEUTIC USE

a) Vertigo/dizziness, as a dose-limiting toxicity, occurred in colorectal cancer patients following capecitabine ingestions of 1657 mg/m(2)/day. The onset of vertigo occurred 36 days after beginning capecitabine therapy and lasted for 7 days (Budman et al, 1998).

G) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 73-year-old man experienced generalized tonic-clonic seizures, as well as confusion, ataxia, and oculomotor disturbances, following treatment with a continuous intravenous infusion of fluorouracil, 1500 mg daily for 4 days (Pirzada et al, 2000).

H) APHASIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Aphasia with cerebellar ataxia and dysdiadochokinesia was reported in a 38-year-old woman 5 days after beginning her sixth cycle of chemotherapy, which included a continuous infusion of fluorouracil 1600 mg daily for 5 days and cisplatin 160 mg on day 1 every 3 weeks. At the time of her aphasia, a brain scan, lumbar puncture, and MRI of the head were within normal limits. Four weeks after cessation of the chemotherapy, the patient's condition improved (Bofill et al, 2000).

I) CEREBROVASCULAR ACCIDENT

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 42-year-old man developed aphasia, drowsiness, and right hemiplegia during a combination chemotherapy, cisplatin 100 mg/m(2) and fluorouracil 1000 mg/m(2). Although the initial neuroimaging studies were normal, subsequent studies revealed a severe brain infarction in the right medial cerebral artery. Segmental cerebral artery vasospasm was suggested as a possible mechanism. The authors suggested that vascular ischemia should be considered as the cause of sudden development of focal neurologic dysfunction in a patient receiving fluorouracil and cisplatin (Serrano-Castro & Aguilar-Castillo, 2001).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting are common with therapeutic doses (Prod Info XELODA(R) oral tablets, 2009a; Bocci et al, 2002; Smith et al, 1983; Baselt, 2000).
b) Nausea and vomiting occurred as a dose-limiting toxicity in colorectal cancer patients involved in a capecitabine clinical trial after ingesting capecitabine, 1657 mg/m(2)/day for 41 to 46 days. The duration of the nausea and vomiting was 4 to 11 days (Budman et al, 1998).
c) During a Phase 2 capecitabine trial with breast cancer patients (n=162), nausea and vomiting occurred in 53% and 37% of the patients, respectively. The dose administered was 2510 mg/m(2)/day for 2 weeks followed by a 1 week rest period (Prod Info XELODA(R) oral tablets, 2009a).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting should be anticipated in overdose (Prod Info Fluorouracil IV injection, 2008; Prod Info XELODA(R) oral tablets, 2009a).

B) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE

1) WITH THERAPEUTIC USE

a) Stomatitis is often a dose-limiting adverse reaction of therapeutic 5-FU (Prod Info Fluorouracil IV injection, 2008). It may be a sign of severe impending bone marrow toxicity (Dorr & Fritz, 1980).
b) The earliest adverse reactions to fluorouracil are anorexia and nausea. These are followed shortly after by stomatitis and diarrhea. Stomatitis may be preceded by a sensation of dryness, followed by erythema and formation of a white, patchy membrane that develops into ulceration and necrosis (Bocci et al, 2002; HSDB , 2001).
c) Stomatitis was reported in 4 patients who ingested capecitabine 1657 mg/m(2)/day (Budman et al, 1998).
d) The manufacturer reported that stomatitis occurred in 22% to 67% of cancer patients (n=2004) involved in various capecitabine clinical trials. The dose administered was 2510 mg/m(2)/day for 2 weeks followed by a 1 week rest period (Prod Info XELODA(R) oral tablets, 2009a).

C) DIARRHEA

1) WITH THERAPEUTIC USE

a) Chemotherapy induced diarrhea occurs frequently with 5-fluoruracil. When combined with other forms of chemotherapy, incidence rates can increase to 50% to 80% (Maroun et al, 2007). Definitions of the National Cancer Institute Grades of Diarrhea are listed below:

1) GRADE 1: Increase of less than 4 stools a day or increase in loose, watery colostomy output.
2) GRADE 2: Increase of 4 to 6 stools a day or nocturnal stools, moderate cramping, but not interfering with activities of daily living. Patients with colostomy will have an increase in loose, watery colostomy output, but it will not interfere with daily activities.
3) GRADE 3: Severe cramping with an increase of greater than 7 stools per day or incontinence that is interfering with activities of daily living. Patients with colostomy will have a severe increase in loose watery stools that will interfere with daily activities. Patients may also need parenteral support for dehydration.
4) GRADE 4: Patients may have grossly bloody stools and severe cramping. Physiological consequences or hemodynamic collapse require hospitalization or intensive care for patients with or without a colostomy.

b) Moderate to severe diarrhea was reported as a dose-limiting toxicity in patients involved in a capecitabine clinical trial after long-term capecitabine ingestions at doses of 1657 mg/m(2)/day. Onset of symptoms occurred from 31 to 47 days after beginning capecitabine therapy, and the duration of diarrhea lasted from 3 to 19 days (Budman et al, 1998).
c) Diarrhea developed in 47% to 67% of cancer patients (n=2004) involved in various clinical trials for capecitabine. Approximately 12% to 14% of those patients experienced moderate to severe diarrhea (Prod Info XELODA(R) oral tablets, 2009a).
d) A 52-year-old woman developed grade 4 diarrhea and stomatitis, as well as grade 3 vomiting, neutropenia, and dermatitis, 9 days after beginning her first cycle of chemotherapy, consisting of 5-FU, 370 mg/m(2)/day for 5 days, and leucovorin, 100 mg/m(2)/day for 5 days. It was determined that the patient was partially dihydropyrimidine dehydrogenase deficient, which may have contributed to the severe toxicity that she experienced following receipt of a single cycle of 5-FU therapy (Bocci et al, 2002).

D) GASTROINTESTINAL NECROSIS

1) WITH THERAPEUTIC USE

a) Mucosal necrosis and erosion has been reported with 5-FU use. The mechanism behind this adverse event is thought to arise from early changes of loss of nuclear polarity, nuclear pyknosis, karyorrhexis and apoptosis of mucosal cells. Further progression proceeds to the crypts and results in necrosis and erosion (Gordon, 2010).

E) PEPTIC ULCER

1) WITH THERAPEUTIC USE

a) Gastrointestinal (GI) ulceration or perforation with GI bleeding has been reported with therapeutic doses (Dorr & Fritz, 1980; Narsete et al, 1977; Gordon, 2010).

F) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) Paralytic ileus has been reported in serious overdoses (Dorr & Fritz, 1980).

G) ILEITIS

1) WITH THERAPEUTIC USE

a) Intraarterial (hepatic) or intravenous administration of therapeutic doses of 5-FUDR may result in extensive or segmental ileitis with diarrhea and abdominal pain; this is confirmed radiologically and resolves after discontinuation of 5-FUDR therapy (Kelvin et al, 1986).

H) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain developed following long-term ingestion (22 to 42 days) of capecitabine in colorectal cancer patients. The abdominal pain was considered a dose-limiting toxicity at doses of 1657 mg/m(2)/day (Budman et al, 1998).
b) Abdominal pain was reported in 23% of the cancer patients (n=2004) participating in various capecitabine clinical trials (Prod Info XELODA(R) oral tablets, 2005).
c) Acute abdominal pain and diarrhea were reported in several patients, with colorectal carcinoma, following treatment with 5-fluorouracil and leucovorin. Laparotomy, colonoscopy, and an abdominal CT scan revealed small bowel damage, including perforation with necrosis and ileitis, in all patients. The patients recovered following supportive treatment and cessation of fluorouracil therapy (Fata et al, 1999).

I) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) Anorexia was reported in 16% of the cancer patients (n=2004) involved in various capecitabine clinical trials. The dose administered was 2510 mg/m(2)/day for 2 weeks followed by a 1 week rest period (Prod Info XELODA(R) oral tablets, 2005).
b) Following capecitabine ingestions of 1657 mg/m(2)/day, 5 of 12 patients experienced anorexia (Budman et al, 1998).

J) ENTEROCOLITIS

1) WITH THERAPEUTIC USE

a) Necrotizing enterocolitis has been reported following capecitabine administration (Prod Info XELODA(R) oral tablets, 2009a).
b) CASE REPORT: A 39-year-old woman, with Pseudomyxoma peritonei, underwent surgical intervention with subsequent administration of hyperthermic intraperitoneal chemotherapy with Mitomycin 12.5 mg/m(2) for 90 minutes, followed by 5-FU intraperitoneally 650 mg/m(2)/day for 5 days. Fourteen days post-surgery (approximately 8 days after completing 5-FU therapy), she developed neutropenic sepsis and persistent severe rectal bleeding suspected to be related to 5-FU therapy. A CT scan demonstrated diffuse enterocolitis and laboratory data revealed platelet count of 140 x 10(9)/L and an INR of 2.9. Although her lab values normalized following transfusions of cryoprecipitate, platelets, fresh frozen plasma, and packed red cells over a 10-day period, gastrointestinal bleeding persisted with a nasogastric (NG) tube output of up to 1.5 liters, despite supportive therapy with proton pump inhibitor infusion. Gastroscopy and sigmoidoscopy revealed severe mucosal ulceration and erosions with large amounts of blood. Because of severe refractory enterocolitis, high-dose sucralfate was then initiated (2 g four times daily via NG and rectal tube for 2 weeks). Within 2 days of starting sucralfate therapy, the patient's rectal bleeding stopped and, within 3 days, the output from her NG tube was bilious and non-bloody. The patient was eventually discharged on oral sucralfate. At her 1-year follow-up, the patient was in remission with no evidence of residual gastrointestinal toxicity (Toh et al, 2015).

Hepatic

3.9.2)

A) CHOLESTASIS

1) WITH THERAPEUTIC USE

a) Cholestasis has been reported with 5-FU use (Tapalaga, 1982).

B) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) Infusion of therapeutic doses of FUDR into the hepatic artery may result in:

1) Cholecystitis (Pietrafitta et al, 1986; Lafon et al, 1985);
2) Sclerosing cholangitis (Pettavel et al, 1986; Shea et al, 1986);
3) Hepatitis with portal triad fibrosis (Doria et al, 1986);
4) Biliary sclerosis (Shea et al, 1986; Bolton & Bowen, 1986);
5) And fatal liver cirrhosis (Pettavel et al, 1986).

C) HYPERBILIRUBINEMIA

1) WITH THERAPEUTIC USE

a) Moderate (grade 3) to severe (grade 4) hyperbilirubinemia occurred in 15.2% and 3.9%, respectively, of 875 cancer patients who received at least one dose of capecitabine 2510 mg/m(2)/day for 2 weeks followed by a 1 week rest period for metastatic breast or colorectal cancer (Prod Info XELODA(R) oral tablets, 2009a).

D) HEPATIC FAILURE

1) WITH THERAPEUTIC USE

a) Hepatic failure with massive ascites and esophageal varices was reported following long-term tegafur therapy. Liver biopsies, performed at 6, 18, and 34 months following withdrawal of tegafur, revealed gradual improvement of pathological hepatic changes (Matsumoto et al, 1998).

Genitourinary

3.10.2)

A) KIDNEY DISEASE

1) WITH THERAPEUTIC USE

a) A 68-year-old woman with ovarian cancer receiving 500 mg/day of 5-fluorouracil developed drug-induced nephropathy as evidenced by serum creatine of 1.1 mg/dl, hematuria, proteinuria, and oligoria, after a total dose of 1500 mg (3 days of treatment) (Joh, 1986).

Hematologic

3.13.2)

A) MYELOSUPPRESSION

1) WITH THERAPEUTIC USE

a) Bone marrow depression is a delayed toxicity to 5-FU therapy. Peak effects may be noted from 9 to 14 days postexposure depending on cell type. Leukopenia and agranulocytopenia may occur with therapeutic doses.

1) The nadir for granulocytes is 9 to 14 days. Thrombocytopenia may occur with a nadir of 7 to 14 days (Dorr & Fritz, 1980). Bone marrow depression is considered a dose-limiting toxicity. Although uncommon, the maximum depression may be delayed for as long as 20 days. Counts usually return to normal within 30 days (Prod Info Fluorouracil IV injection, 2008).

B) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 54-year-old woman developed acute immune hemolytic anemia associated with her fifth injection of 5-FU. A similar episode was reproduced during a controlled challenge with 5-FU (Sandvei et al, 1987).

C) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Neutropenia occurred in 26% of breast cancer patients (n=162) who participated in a Phase 2 clinical trial for capecitabine (Prod Info XELODA(R) oral tablets, 2009a).

D) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) SUMMARY: Thrombocytopenia can develop with therapeutic use; therapy should be stopped with platelet counts of less than 100,000 (Prod Info Fluorouracil IV injection, 2008)
b) Grade 3 thrombocytopenia was the dose limiting toxicity in a patient with pancreatic cancer receiving capecitabine 1657 mg/m(2)/day (Budman et al, 1998).

3.13.3)

A) ANIMAL STUDIES

1) PORPHYRIA

a) In animal porphyria models, 5-FU has shown the capacity to induce porphyrinogens (Cochon et al, 1997).

Dermatologic

3.14.2)

A) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia has been reported as a delayed toxicity of therapeutic doses of 5-FU (Dorr & Fritz, 1980).
b) CASE REPORT: Extensive alopecia occurred in a 55-year-old woman, with stage III sigmoid carcinoma, who received one course of 5-FU therapy, 425 mg/m(2) on days 1 to 5 of a 28 day cycle (Diaz et al, 2004).

B) DISCOLORATION OF SKIN

1) WITH THERAPEUTIC USE

a) Hyperpigmentation may occur on the face, hands, nail beds, and other body areas (Dorr & Fritz, 1980; Baran & Laugier, 1985).

C) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY

1) WITH THERAPEUTIC USE

a) Palmar-plantar erythrodysesthesia syndrome (hand-and-foot syndrome) occurred in 54% to 63% of cancer patients (n=2004) involved in various capecitabine clinical trials. Approximately 11% to 24% of those patients experienced moderate effects (Grade 3) (Prod Info XELODA(R) oral tablets, 2009a).
b) Prodromal tingling progressing to tender, erythematous, swollen, desquamative eruptions of the palms and soles is limited to patients receiving prolonged infusion of fluorouracil at doses of 300 mg/m(2)/day or greater. This rash improves with discontinuation of chemotherapy (Feldman & Ajani, 1985; Lo et al, 1999).
c) Budman et al (1998) reported that 8 of 12 patients experienced palmar-plantar erythrodysesthesia syndrome (grade 3 severity in 1 patient) following long-term ingestion of capecitabine at a dose of 1657 mg/m(2)/day. The onset of symptoms (grade 3) of palmar-plantar erythrodysesthesia syndrome occurred 62 days after beginning capecitabine therapy with effects lasting 3 days (Budman et al, 1998).
d) In another study, at least one episode of hand-and-foot syndrome (HFS) occurred in 28 patients (68.3%; n=41). Grades 1, 2, and 3 occurred in 5, 20, and 3 patients, respectively. Within the first two cycles, the first or the most severe episode of HFS occurred in 92.9% and 67.9% of the patients, respectively (Abushullaih et al, 2002).

D) ERUPTION

1) WITH THERAPEUTIC USE

a) Rapidly resolving skin irritation or skin discoloration requiring 2 weeks to resolve has been reported in 2 cases of accidental 5-FU contact with hands or fingers. All other exposures were associated with no adverse effects (Curran & Luce, 1989).
b) Skin irritation was reported in humans using the Standard Draize Test (RTECS , 2001).

E) SEBORRHEA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 65-year-old man with squamous cell carcinoma of the tongue base extending to the epiglottis developed severe exacerbation of a pre-existing seborrheic dermatitis 24 hours after receiving 5-FU 1000 mg/m(2) via continuous infusion daily for 5 days. This patient did not have actinic keratoses, exposure to sunlight, or a history of prior use of topical 5-FU (Vukelja et al, 1989).

F) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Allergic contact dermatitis has been reported with use of 5-fluorouracil topical ointment (Tennstedt & Lachapelle, 1987).

G) PHOTOSENSITIVITY

1) WITH THERAPEUTIC USE

a) Photosensitization from ultraviolet light has been reported with 5-FU (Umstead et al, 1991).

H) DERMATITIS

1) WITH THERAPEUTIC USE

a) Dermatitis occurred in 8% to 37% of the cancer patients (n=1009) who participated in various clinical trials for capecitabine. The dose administered was 2510 mg/m(2)/day for 2 weeks followed by a 1 week rest period (Prod Info XELODA(R) oral tablets, 2009a).

I) ERYTHEMA MULTIFORME

1) WITH THERAPEUTIC USE

a) Two patients developed erythema multiforme within 2 weeks after beginning 5-FU chemotherapy. In one patient, the rash was also associated with the development of palmar-plantar erythrodysaesthesia. The rash resolved spontaneously within 2 weeks after cessation of 5-FU therapy, however restarting therapy resulted in the recurrence of the lesions. Again, the lesions resolved spontaneously following cessation of 5-FU therapy (Lo et al, 1999).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH THERAPEUTIC USE

a) Rhabdomyolysis may occur following chronic topical exposure to 5-FU in propylene glycol based solution (Schmied & Levy, 1986).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) A severe contact hypersensitivity reaction has been reported with a topical fluorouracil preparation (Sevadjian, 1985).

B) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 62-year-old woman developed diaphoresis, cutaneomucosal pallor with acral cyanosis, and bronchospasm beginning 15 minutes after the first injection of 5-FU. She subsequently developed erythrodermia and papule formation in the area of application of an intradermal injection of diluted 5-FU during a controlled challenge (Milla Santos & Sanchiz Medina, 1986).
b) CASE REPORT: A 58-year-old man developed edema of the lips, tongue, eyes, legs, and face following an infusion of 5-FU during his 6th course of chemotherapy (Spidhar, 1986).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL MALFORMATIONS

1) One birth defect (cleft lip and palate) was reported in the newborn of a patient using topical fluorouracil (Efudex(R)) as recommended. One birth defect (ventricular septal defect) and cases of miscarriage were reported when Efudex(R) was applied to mucous membrane areas (Prod Info EFUDEX(R) topical cream, topical solution, 2005).
2) Although data are scanty, fluorouracil has been linked with human birth defects when used at therapeutic doses during pregnancy. Multiple defects were seen in one aborted fetus, which was also exposed to 5 rad ionizing radiation, a known human teratogen (Briggs et al, 1994). In addition, fluorouracil has been shown in women to cause toxic effects on the newborn, and specific developmental abnormalities in the newborn's musculoskeletal system (RTECS , 2001).
3) There is a report of a human pregnancy where the mother received fluorouracil 600 mg IV 5 times weekly at 11 to 12 fetal weeks. Imperforate anus; radial aplasia; esophageal aplasia; and hypoplasia of the duodenum, lung, and aorta were present in the infant (Shepard, 1995).

B) LACK OF EFFECT

1) Twin neonates exposed to 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) from week 13 of gestation through delivery were born with no evidence of teratogenicity or intrauterine growth retardation and remained developmentally normal at their 2-year follow up. A 26-year-old woman diagnosed with metastatic colorectal cancer in week 10 of pregnancy received 10 courses of a full-dose biweekly modified FOLFOX-6 regimen (oxaliplatin 85 mg/m(2) 2-hour infusion with leucovorin 400 mg/m(2), then 5-FU 400 mg/m(2) bolus and 5-FU 2400 mg/m(2) 46-hour infusion). The last FOLFOX exposure occurred 15 days before delivery at 33 weeks via cesarean section; the fraternal twins both had birth weights of about 2200 g and had one-minute Apgar scores of 10 (Jeppesen & Osterlind, 2011).
2) An apparently normal infant was delivered to a women who had received fluorouracil along with cyclophosphamide, doxorubicin, and methotrexate during pregnancy (Briggs et al, 1994).
3) Vaginal fluorouracil administered topically during pregnancy (up to 16 weeks gestation; doses of 1 to 2.5 grams) did not result in abnormalities in the infants delivered (Van Le et al, 1991; Odom et al, 1990).
4) In two large studies, no increased risk for birth defects was apparent for women treated with fluorouracil either during or as long as 10 years prior to pregnancy. In follow-up, 80% of the children born to these women developed normally (Song et al, 1988).

C) ANIMAL STUDIES

1) MICE: Capecitabine caused cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, dilation of cerebral ventricles, and embryo death in mice when doses of 198 mg/kg/day were given during organogenesis. The 5’-DFUR AUC values were about 0.2 times the corresponding values for patients using a recommended daily dose (Prod Info XELODA(R) oral tablets, 2009).
2) MONKEYS: Fluorouracil was not teratogenic when given IM in divided doses of 40 mg/kg between days 20 and 24 of gestation to monkeys, but abortions resulted with doses higher than 40 mg/kg (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005). Capecitabine caused fetal death when pregnant monkeys were given 90 mg/kg/day during organogenesis. The 5’-DFUR AUC values were about 0.6 times the corresponding values for patients using a recommended daily dose (Prod Info XELODA(R) oral tablets, 2009).
3) RATS: Fluorouracil was teratogenic in rats, inducing cleft palate and hindlimb defects, when injected subQ at doses up to 40 mg/kg on day 14 of gestation (Shuey et al, 1994). Inhibition of thymidylate synthetase appeared to be a key step in this effect (Shuey et al, 1995).
4) RODENTS: Fluorouracil was teratogenic in laboratory animals, causing cleft palates, skeletal defects, and deformed appendages, paws and tails. Maximum teratogenicity was observed with single intraperitoneal doses of 10 to 40 mg/kg on day 10 or 12 of gestation in mice, intraperitoneal doses of 12 to 37 mg/kg given between days 9 and 12 of gestation in rats, and IM doses of 3 to 9 mg given between days 8 and 11 of gestation in hamsters. The doses were 1 to 3 times the maximum recommended human therapeutic dose (Prod Info Fluorouracil IV injection, 2008; Prod Info fluorouracil 5% topical cream, 2008).
5) RODENTS: In the rat, mouse, and hamster, fetotoxicity and specific developmental abnormalities in the musculoskeletal system and craniofacial area (including nose and tongue) were observed with fluorouracil. Specifically, in the rat, a change in litter size, fetal death, developmental abnormalities in the gastrointestinal system and a change in homeostasis occurred. In the mouse, cytological changes (including somatic cell genetic material), fetal death, change in litter size, and changes in the newborn's viability index, live birth index, and growth statistics occurred. Also in the mouse, specific developmental abnormalities of the eye and ear occurred. A change in homeostasis also occurred in hamster studies (RTECS , 2001).

3.20.3)

A) FLUOROURACIL

1) A case report describes the use of irinotecan/fluorouracil/leucovorin (FOLFIRI regimen) in a 33-year-old pregnant woman with adenocarcinoma of the transverse colon. The patient was initiated on chemotherapy according to the FOLFIRI regimen at gestational week 23. Fetal growth and morphology were normal with no major defects or abnormalities detected. Chemotherapy was well tolerated with cycles repeated every 2 weeks. The patient was restaged at gestational week 29 after 3 cycles of chemotherapy. An abdominal MRI revealed progression of the hepatic and peripancreatic lesions. Chemotherapy was discontinued at gestational week 30 and the patient was admitted to surgery due to a perforated bowel. The patient underwent a cesarean section and transverse colon resection. The male infant weighed 1070 g at birth and had a reported Apgar score of 4 and 7 for the first and fifth minute, respectively. The infant was admitted to neonatal pathology due to prematurity and intrauterine growth restriction. After 48 hours the infant was extubated. After an additional 48 hours in continuous positive airway pressure, the infant resumed spontaneous breathing. After 28 days, the infant was transferred for stabilization where he was hospitalized for the first 70 days of life. Upon followup at 13-months of age, the infant was observed to be within normal limits and satisfactory in weight and physical and neurological development. The mother received treatment with a modified regimen consisting of oxaliplatin, fluorouracil, and leucovorin. Chemotherapy was discontinued after 4 cycles due to disease progression and going forward the patient received supportive care only (Cirillo et al, 2012).

B) PREGNANCY CATEGORY

1) The manufacturer has classified capecitabine as FDA pregnancy category D (Prod Info XELODA(R) oral tablets, 2009)
2) The manufacturer has classified topical fluorouracil as FDA pregnancy category X; however, the injection is classified as FDA pregnancy category D (Prod Info EFUDEX(R) topical cream, topical solution, 2005; Prod Info Fluorouracil IV injection, 2008).

C) CYANOSIS/JERKING EXTREMITIES

1) Cyanosis and jerking extremities were seen in a newborn who had been exposed to fluorouracil during the last trimester (Briggs et al, 1994).

D) ANIMAL STUDIES

1) MONKEYS: In monkeys, fluorouracil maternal doses higher than 40 mg/kg resulted in abortion of all embryos exposed (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005; Prod Info fluorouracil 5% topical cream, 2008).
2) RATS: Fluorouracil crosses the placenta and enters the fetal circulation in rats, resulting in increased resorptions and embryolethality (Prod Info Fluorouracil IV injection, 2008).
3) RODENTS: In female rats who ingested fluorouracil prior to mating, toxic maternal effects in the ovaries, fallopian tubes, uterus, cervix, and vagina were observed. Postimplantation mortality and abortion occurred in mice given fluorouracil while pregnant. Postimplantation mortality also occurred in hamsters given fluorouracil while pregnant (RTECS , 2001).
4) RODENTS: In the rat, mouse, and hamster, fetotoxicity and specific developmental abnormalities in the musculoskeletal system and craniofacial area (including nose and tongue) were observed with fluorouracil. Specifically, in the rat, a change in litter size, fetal death, developmental abnormalities in the gastrointestinal system and a change in homeostasis occurred. In the mouse, cytological changes (including somatic cell genetic material), fetal death, change in litter size, and changes in the newborn's viability index, live birth index and growth statistics occurred. Also in the mouse, specific developmental abnormalities of the eye and ear occurred. A change in homeostasis also occurred in hamster studies (RTECS , 2001).

3.20.4)

A) BREAST MILK

1) There is no information available on the passage of fluorouracil or capecitabine into breast milk. Fluorouracil inhibits DNA, RNA, and protein synthesis, which could cause serious adverse reactions in the infant. Mothers should not breastfeed while receiving these drugs (Prod Info XELODA(R) oral tablets, 2009; Prod Info Fluorouracil IV injection, 2008). Topical application of fluorouracil 100 mg produced systemic absorption of approximately 5 mg to 6 mg. Due to the potential risk of serious adverse events to a nursing infant, a decision regarding the use of topical fluorouracil in a nursing mother should be made, taking into account the importance of the medication to the mother (Prod Info fluorouracil 5% topical cream, 2008).
2) MILK, HUMAN: A 36-year-old breastfeeding female diagnosed with rectal cancer had undetectable levels of 5-fluorouracil in milk samples obtained prior to, during, and up to 10 days following 5-fluorouracil administration. The patient discontinued breastfeeding and continued to pump breast milk twice daily during the 5-fluorouracil-based chemoradiotherapy 200 mg/m(2)/day IV. Despite plasma concentrations between 11.14 and 114.95 micromolar, in 33 milk samples evaluated using high performance liquid chromatography (limit of detection 0.5 micromolar), the levels of 5-fluorouracil in milk were undetectable at any time during or following 5-fluorouracil administration (Peccatori et al, 2012).

3.20.5)

A) ANIMAL STUDIES

1) FEMALE RABBITS: In a limited study, fluorouracil as a single 25 mg/kg dose or 5 daily doses of 5 mg/kg had no effect on ovulation and implantation in female rabbits, and only a limited effect in producing zygote destruction (Prod Info Fluorouracil IV injection, 2008).
2) FEMALE RATS: Intraperitoneal fluorouracil at weekly doses of 25 or 50 mg/kg for 3 weeks during the preovulatory phases of oogenesis caused a significant reduction in the incidence of fertile matings, a delay in the development of preimplantation and postimplantation embryos, and an increased incidence of preimplantation lethality and chromosomal anomalies in the embryos of female rats (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005).
3) MALE MICE: Fluorouracil did not produce abnormalities at oral doses of up to 80 mg/kg/day in a strain of mouse that is sensitive to the induction of sperm head abnormalities after exposure to chemical mutagens and carcinogens (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005). Single doses of IV and intraperitoneal fluorouracil at 500 mg/kg killed differentiated spermatogonia and spermatocytes in mice; doses of 50 mg/kg produced abnormalities in spermatids (Prod Info EFUDEX(R) topical cream, topical solution, 2005).
4) MALE RATS: Intraperitoneal fluorouracil doses of 125 or 250 mg/kg induced chromosomal aberrations and changes in chromosomal organization of spermatogonia in male rats. Transient infertility occurred after spermatogonial differentiation was inhibited (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005).
5) MALE RODENTS: Toxic paternal effects such as changes in the epididymis, sperm duct, prostate, seminal vesicle, cowper's gland, and accessory glands occurred in male rats who ingested fluorouracil prior to mating. Observed paternal effects in mouse studies consisted of a change in spermatogenesis and a change in sperm morphology (RTECS , 2001).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS51-21-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: 5-Fluorouracil
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for fluorouracil or capecitabine in humans.

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, the manufacturer does not report any carcinogenic potential for fluorouracil or capecitabine in humans (Prod Info Fluorouracil IV injection, 2008; Prod Info XELODA(R) oral tablets, 2009).

3.21.4)

A) TUMORS

1) Fluorouracil was positive in 3 in vitro cell neoplastic transformation assays. Morphologically transformed cells created tumors after inoculation in immunosuppressed syngeneic mice in the C3H/10T one-half clone 8 mouse embryo cell system (Prod Info EFUDEX(R) topical cream, topical solution, 2005).

B) LACK OF EFFECT

1) No evidence of carcinogenicity was found when oral fluorouracil was given to rats for 52 weeks at doses of 0.01, 0.3, 1, or 3 mg per rat 5 days per week. Male rats were given 33 mg/kg of IV fluorouracil once a week for 52 weeks, followed by observation for the remainder of their lifetime, with no evidence of carcinogenicity. No effect on the incidence of lung adenomas was noted in female mice after 16 weeks of IV fluorouracil in doses of 1 mg once a week (Prod Info Fluorouracil IV injection, 2008).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor daily CBC with differential to detect bone marrow depression. Leukopenia accompanies every course of therapy with fluorouracil. Nadirs in circulating white blood cells are typically reached between the 9th and 14th day after therapy, maximal depression may be seen as late as 20 days after therapy. By day 30, WBC should return to normal range. Patients with overdose of fluorouracil should be hematologically monitored for a minimum of 4 weeks after exposure. Monitor patient for signs of bleeding.
B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
C) Monitor vital signs and mental status.
D) Closely monitor electrolytes, renal function, and hepatic enzymes.
E) Initiate continuous ECG monitoring in cases of severe overdose.

4.1.2)

A) MONITORING

1) Blood counts (CBC) need to be followed closely several weeks postexposure to 5-fluorouracil to monitor for delayed bone marrow depression.

a) Monitor daily CBC with differential to detect bone marrow depression. Leukopenia accompanies every course of therapy with fluorouracil. Nadirs in circulating white blood cells are typically reached between the 9th and 14th day after therapy, maximal depression may be seen as late as 20 days after therapy. By day 30, WBC should return to normal range. Patients with overdose of fluorouracil should be hematologically monitored for a minimum of 4 weeks after exposure (Prod Info Fluorouracil IV injection, 2008).

2) Monitor electrolytes in patients with vomiting and diarrhea. Fluid and electrolyte replacement should be administered as needed.
3) Hypokalemia has been reported in up to 20% of patients (11 of 54) receiving capecitabine therapy with no vomiting or diarrhea etiology. The authors speculate capecitabine may impair potassium reabsorption in the kidney, resulting in hypokalemia (Saif et al, 2007).
4) Monitor renal function and hepatic enzymes after overdose.

Methods

1) 5-fluorouracil and its metabolites can be analyzed by HPLC and GC-MS methods (Aubert et al, 1981) 1982; (Lakings et al, 1978; Diasio & Harris, 1989).
2) In one study, HPLC was used to determine 5-fluorouracil and its three metabolites plasma levels (5-fluorouridine (5-Furd), 5-fluoro-2'-deoxyuridine (5-Fdurd), 5-fluoro-5,6-dihydro-uracil (5-FuH2), in 18 cancer patients treated with 5-Fu (400 mg/m(2) IV bolus) and folinic acid (100 mg/m(2) IV). The limit of quantitation for 5-Fu, 5-Fdurd, and 5-FuH2 were 0.5 mcg/mL, 3 mcg/mL, and 1 mcg/mL, respectively. Although 5-Furd and 5-Fdurd were detected in only 8 patients, levels of 5-FU and 5-FuH2 were obtained in all the patients (Casale et al, 2002).
3) In one study (n=80), HPLC-UV method was found to be a simple, rapid, and cost-effective way for identifying cancer patients at risk of toxicity with 5-FU or capecitabine, by determining uracil to dihydrouracil (U/UH2) ratios (as a surrogate marker of dihydropyrimidine dehydrogenase [DPD] activity) and 5-FU concentrations. The limit of quantitation was 5 mcg/mL. Impaired DPD activity was detected in 57 of 80 toxic patients (71%) and 4 of 5 patients (80%) with a fatal outcome (Ciccolini et al, 2006).

Treatment

Life Support

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) Admit patients with known overdose. Patients who have received therapeutic doses and are hemodynamically unstable, require IV fluids and electrolyte replacement secondary to progressive, complicated chemotherapy induced diarrhea or treatment resistent nausea or vomiting, and/or patients who are at a severe risk of infection must be admitted to the hospital for supportive care.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) Patients who have had a known overdose of fluorouracil MUST seek medical attention so the antidote can be administered as soon as possible. Only patients who have been exposed to therapeutic doses and have mild symptoms of toxicity (ie, Grade 1 uncomplicated diarrhea or Grade 1 nausea/vomiting) may be managed at home under the supervision of their oncologist. Patients with new or worsening symptoms must seek medical attention.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult a medical toxicologist or oncologist in cases where management of chemotherapy adverse events or toxicity is uncertain.

6.3.2.4) PATIENT TRANSFER/PARENTERAL

A) Patients with profound neutropenia or large overdose may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital activated charcoal should be administered if possible after capecitabine overdose.
B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) Administer activated charcoal after capecitabine overdose.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) GENERAL TREATMENT

1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) INITIAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

B) DISPOSAL GUIDELINES

1) LABELING: Cytotoxic waste should be regarded as HAZARDOUS or TOXIC waste. It must be handled differently from other trash and should be clearly labeled "HAZARDOUS CHEMICAL WASTE - DISPOSE OF PROPERLY" (Anon, 1990).
2) CONTAINER: Cytotoxic waste may be placed in a leakproof, puncture resistant container which is then placed in disposable wire-tie or sealable 4-mil-thick polyethylene or 2-mil-thick propylethylene bags. These bags should be colored so as to be easily distinguishable from other trash bags, and labeled with a "Cytotoxic Hazard" label (Jeffrey LP, Anderson RW & Fortner CL et al, 1984; Anon, 1986).
3) SPILL PROCEDURE: Spills should be cleaned up immediately by a person trained in such procedures and wearing appropriate protective clothing (commercial spill kits are available) (Anon, 1990). The area of the spill should be marked so that while cleanup is occurring someone in the area is not accidentally contaminated. Broken glass should be carefully removed possibly by using a scoop. A broom or mop is not advised due to the risk of further contamination of the environment.
4) DISPOSAL: Cytotoxic waste may be disposed of at an EPA permitted hazardous waste incinerator, an EPA permitted hazardous waste burial site, or by a licensed hazardous waste disposal company and in accordance with all applicable state, federal, and local regulations (Anon, 1990; Jeffrey LP, Anderson RW & Fortner CL et al, 1984).

C) SMALL SPILL CLEANUP

1) SUMMARY: Small spills (less than 5 milliliters or 5 grams) should be cleaned immediately by personnel wearing double surgical latex gloves, disposable gown, a face shield or splash goggles and a dust/mist respirator mask (Anon, 1986; Chasse & Gaudet, 1992; Peters, 1995).

a) CLEAN UP PROCEDURE: Liquids should be adsorbed with gauze pads; solids should be wiped up with wet absorbent gauze (Anon, 1986).
b) DECONTAMINATION: The spill area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
c) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).

D) LARGE SPILL CLEANUP

1) SUMMARY: Large spills (greater than 5 milliliters or 5 grams) should be covered immediately with absorbent sheets or spill control pads to reduce the spread. If a powder was spilled use a damp cloth or towel (Anon, 1986).

a) SECURE AREA: Restrict access to the spill area and take precautions to minimize the generation of aerosols (Anon, 1986).
b) PERSONNEL PROTECTION: Protective clothing should be worn as with the small spill with the addition of a respirator or breathing apparatus when there is an airborne contamination danger (Anon, 1986).
c) DECONTAMINATION: The area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
d) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).

E) PERSONNEL PROTECTION

1) PROTECTIVE CLOTHING: A double layer of disposable surgical latex gloves, protective disposable gowns (non-permeable, made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs) with cuff tucked into glove, eye protection (splash goggles), breathing apparatus, in ventilated cabinets when there is airborne contamination danger (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a; Anon, 1986).
2) DECONTAMINATION/CLOTHING: Laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. DISPOSAL: The appropriate procedure for the disposal of these materials should be determined by the institution (or as required by state or local regulation or disposal contractor) (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a).

Enhanced Elimination

Abstracts

Case Reports

1) INTRAVENOUS

a) A 43-year-old woman with a history of nasopharyngeal cancer received 5250 mg of fluorouracil intravenously over a period of 4 hours due to a pump error, instead of a period of 4 days as prescribed. Three days after the incident, the patient presented to her clinic with nausea, vomiting and discomfort in her throat and a WBC of 10.6 and a platelet count of 388. The patient was admitted to the hospital the next day to be given hydration, ondansetron, dexamethasone and metoclopramide for her nausea and vomiting. Relevant CBC counts at admission included WBC 9.4, platelets 259. Over the course of a week, the patient's condition continued to deteriorate with the patient developing increased pain in her mouth, nausea with occasional emesis and diarrhea. Ten days after the overdose, the patient became tachycardic, developed bright green emesis with occasional bright red blood, a WBC 0.1, platelets 83, and a presumed collapsed or fluid-filled bowel that could not be recognized on X-ray. The patient was admitted to intensive care the next day (day 11 after overdose) and was placed on aggressive therapy including intubation, IV antibiotics, filgrastim, antifungals, electrolyte replacement. CBC counts upon ICU admission were WBC 0.2, platelets 13. Approximately 3 weeks after the incident, the patient was removed from life support and expired due to multi-organ failure (ISMP Canada, 2007).

2) ORAL

a) A 42-year-old renal transplant patient reportedly rejecting the transplant was treated with cyclophosphamide, methylprednisolone sodium succinate, and azathioprine. Rejection continued and several organisms were cultured from a suspected pulmonary infection. Treatment consisted of amphotericin B and multiple antibiotics. Flucytosine was to be added at a dose of 1 g orally every 6 hours. 5-fluorouracil was administered in error for a total dose of 4 g prior to discovery. The patient was hemodialyzed, but her condition continued to deteriorate with severe leukopenia, thrombocytopenia, and progressive pulmonary problems. Granulocyte transfusions were given, but death ensued 16 days post 5-FU administration (Prod Info, 1980).

3) DERMAL

a) A patient was prescribed topical application of 1.25% 5-fluorouracil in propylene glycol to nails for psoriasis. At 14 weeks of therapy routine laboratory screening was performed. Elevated total creatinine phosphokinase (1366 Units/L), MB fraction (34 Units/L), glutamic oxaloacetic transaminase (94 Units/L), and lactic dehydrogenase (468 Units/L due to isoenzyme) were reported. ECG, renal function tests, and blood tests were normal. Elevated total creatinine phosphokinase (1366 Units/L), MB fraction (34 Units/L), glutamic oxaloacetic transaminase (94 Units/L), and lactic dehydrogenase (468 Units/L due to isoenzyme) were reported. ECG, renal function tests, and blood tests were normal. Rhabdomyolysis was the reported cause of the elevated enzymes. The propylene glycol was postulated to enhance 5-FU dermal absorption (Schmied & Levy, 1986).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) CAPECITABINE

1) The recommended dose for chemotherapy is 2500 mg/m(2) orally daily in 2 divided doses for 2 weeks, followed by 1 week off, and repeated in 3-week cycles. Capecitabine is given as monotherapy and in combination with other chemotherapy agents (Prod Info XELODA(R) oral tablets, 2015).

B) FLUOROURACIL

1) INTRAVENOUS

a) The recommended dose for chemotherapy is 6 to 12 mg/kg IV daily on a specified schedule for 8 days, and repeated in 30-day cycles; dose should NOT exceed 800 mg/day. An alternative schedule, following the initial course of therapy, is a single maintenance dose of 10 to 15 mg/kg/wk; dose should NOT exceed 1 g/wk. Fluorouracil is given as monotherapy and in combination with other chemotherapy agents (Prod Info fluorouracil intravenous injection, 2014).

2) TOPICAL

a) ACTINIC KERATOSIS: The recommended dose is topical application of solution or cream to affected area once or twice daily for 2 to 4 weeks. Complete healing may not be apparent for 1 to 2 months following cessation of therapy (Prod Info TOLAK topical cream, 2015; Prod Info Fluorouracil topical cream, 2010; Prod Info Fluorouracil topical solution, 2010; Prod Info fluorouracil 5% topical cream, 2008; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003).
b) BASAL CELL CARCINOMA: The recommended dose is topical application of 5% solution or 5% cream to affected area twice daily for at least 3 to 6 weeks; therapy may be required for up to 12 weeks (Prod Info Fluorouracil topical solution, 2010; Prod Info fluorouracil 5% topical cream, 2008).

C) FLOXURIDINE

1) The recommended dose is 0.1 to 0.6 mg/kg/day by continuous arterial infusion; higher dose ranges of 0.4 mg to 0.6 mg are usually used for hepatic artery infusion because the drug is metabolized by the liver, reducing the potential for systemic toxicity (Prod Info floxuridine intra-arterial injection, 2008).

7.2.2)

A) CAPECITABINE

1) Safety and effectiveness have not been established (Prod Info XELODA(R) oral tablets, 2015).

B) FLUOROURACIL

1) Safety and effectiveness have not been established (Prod Info TOLAK topical cream, 2015; Prod Info fluorouracil intravenous injection, 2014; Prod Info Fluorouracil topical cream, 2010; Prod Info Fluorouracil topical solution, 2010; Prod Info fluorouracil 5% topical cream, 2008; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003).

C) FLOXURIDINE

1) Safety and effectiveness have not been established. (Prod Info floxuridine intra-arterial injection, 2008)

Minimum Lethal Exposure

1) Death has been reported in a patient who received as little as 1000 mg of fluorouracil(Von Borstel et al, 2009).
2) In a review of 33 patients with inadvertent fluorouracil overdoses not treated with uridine triacetate, 29 patients died (Bamat, Tremmel, and O'Neil, 2010). Patients who died received doses ranging from 1000 mg to 27200 mg of fluorouracil. The 4 patients who recovered received doses ranging from 3588 mg to 7651 mg.
3) Severe toxicity and some deaths have been reported at 5-fluorouracil doses of 20 to 25 mg/kg (Dorr & Fritz, 1980).
4) CASE REPORT: A 55-year-old woman, with stage III sigmoid carcinoma, developed severe mucosal ulcerations, alopecia, palmar-plantar desquamation, and severe pancytopenia 9 days after receiving the first cycle of 5-fluorouracil and levofolinic acid combination chemotherapy, 425 mg/m(2) and 10 mg/m(2), respectively, given on days 1 to 5 of a 28-day cycle. She developed gram negative sepsis, multiorgan system failure, and died 15 days after the completion of the first cycle of chemotherapy. It was suspected that she may have had dihydropyrimidine dehydrogenase deficiency (Diaz et al, 2004).

Maximum Tolerated Exposure

1) INTRAVENOUS: 10 grams over 36 hours (Bamat, Tremmel, and O'Neil, 2010).
2) ORAL - 6 grams (Prod Info, 1980)
3) CONTINUOUS INTRAVENOUS INFUSION - 450 mg/m(2)/day (Spicer et al, 1988)

1) Uridine triacetate appears to be an effective and lifesaving antidote. All patients treated to date with uridine triacetate following 5-FU overdose have recovered completely (more than 35 patients who received 5-FU doses ranging from 2,100 mg to 10,000 mg). Patients did not develop the anticipated gastrointestinal and hematologic toxicities following 5-FU overdose. Uridine triacetate was found to be effective after exposure to a range of doses of 5-FU; the highest dose for which a patient recovered was 10,000 mg of 5-FU infused over 3 hours. Two other patients recovered fully after receiving uridine triacetate following 5-FU doses of 8960 mg over 3 hours and 5000 mg over 17 minutes, respectively (Bamat, Tremmel, and O'Neil, 2010).
2) CASE REPORT: A 55-year-old, 77.9 kg man with colon cancer inadvertently received an overdose of 5-FU due to an infusion error and was treated with uridine triacetate about 18 hours after exposure. He was premedicated with ondansetron and received uridine triacetate 11 g every 6 hours orally for a total of 20 doses. He developed no clinical symptoms and his laboratory studies remained normal (McEvilly et al, 2011).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) Steady state plasma concentration of 5-FU administered by continuous infusion for 5 days increased from 3.37 to 7.49 micromolar with dose increased from 1.25 to 2.25 g/m(2)/day (Erlichman et al, 1986).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: 5-Fluorouracil

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) References: RTECS, 1990

1) LD50- (INTRAMUSCULAR)RAT:

a) 240 mg/kg

2) LD50- (INTRAPERITONEAL)RAT:

a) 70 mg/kg
b) 100 mg/kg

3) LD50- (ORAL)RAT:

a) 230 mg/kg
b) 115 mg/kg

4) LD50- (SUBCUTANEOUS)RAT:

a) 169 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

1) 5-fluorouracil is therefore considered to be cell-cycle phase specific for the S-phase (Dorr & Fritz, 1980).

Toxicologic Mechanism

1) As of May 2009, uridine triacetate (formerly known as vistonuridine), a prodrug of uridine, had been granted orphan-drug status by the FDA as an antidote in the treatment of fluorouracil poisoning. To obtain uridine triacetate, healthcare professionals can contact the Wellstat Therapeutics 24 hours/day, 7 days/week by calling the severe adverse event (SAE) hotline: (443)-831-5626.

Physicochemical

Physical Characteristics

Ph

Molecular Weight

1) 359.35 (Prod Info XELODA(R) oral tablets, 2015)

1) 130.08 (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005)

Animal Toxicology

Clinical Effects

11.1.3)

A) Uncontrollable seizures, vomiting, diarrhea, tremors, ataxia, lethargy, cardiac dysrhythmias, and respiratory depression were reported in dogs who ingested 5-Fluorouracil (5-FU), resulting in death or euthanasia despite aggressive decontamination and intensive supportive treatment (Albretson, 2001; (Dorman et al, 1990).
B) Out of 72 cases of 5-FU toxicosis reported to the ASPCA Animal Poison Control Center (APCC) between 1989 and 1998, 35 dogs died and 11 dogs were euthanized, with the onset of signs and symptoms occurring within 30 minutes to 5 hours after ingestion and death occurring as quickly as 7 hours after ingestion (Albretson, 2001).
C) If dogs survive for more than 4 to 7 days after 5-FU ingestion, myelosuppression is possible, manifested by leukopenia, depression, and hyperthermia, but is a rare occurrence. White blood cell counts as low as 750/microliter have been reported (normal white blood cell counts are 5,000 to 14,000/microliter) (Albretson, 2001).

1) CASE REPORT - A 6-year-old female Siberian Husky presented with generalized ataxia with facial tremors and persistent gagging 12 to 24 hours after ingesting approximately 25% of a tube of 5% 5-fluorouracil topical cream (estimated dose of 32 mg/kg). Initial laboratory analysis showed mild leukopenia and mild thrombocytopenia, both of which progressively worsened over the next 7 days. On day 8, examination of bone marrow aspirate showed bone marrow aplasia and, on day 9, pancytopenia was evident. With supportive care, the dog gradually recovered, with complete resolution of the myelosuppression by day 25 (Fry & Forman, 2004).

Treatment

11.2.1)

A) ANIMAL POISON CONTROL CENTERS

1) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
2) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
3) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

Range Of Toxicity

11.3.2)

A) DOG

1) The ASPCA APCC determined that the lowest toxic dose in dogs following 5-FU ingestion was 8.6 milligrams/kilogram (Albretson, 2001).

11.3.4)

11.3.4.1) TOXICITY VALUES

A) DOG

1) According to the ASPCA APCC, the lowest lethal dose of 5-FU in dogs is estimated to be 20 milligrams/kilogram (Albretson, 2001).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) ANIMAL POISON CONTROL CENTERS

11.4.3)

11.4.3.4) PHARMACOLOGIC INTERVENTION

A) SEIZURES

1) DOGS - 5-Fluorouracil seizures in dogs have been successfully controlled using pentobarbital sodium (3 to 15 milligrams/kilogram IV slowly to effect), phenobarbital (3 to 30 milligrams/kilogram IV slowly to effect), isoflurane, and propofol (4 to 6 milligrams/kilogram IV or 0.6 milligram/kilogram/minute continuous rate IV infusion) (Albretson, 2001). Seizures and tremors are RARELY controlled with diazepam.

B) BONE MARROW SUPPRESSION

1) DOGS - Filgrastim (G-CSF) has been given at a dose of 4.2 to 6 micrograms/kilogram subcutaneously once daily for 1 to 3 days with no adverse effects in dogs who develop bone marrow suppression following 5-FU ingestion (Albretson, 2001).

C) GASTROINTESTINAL PROTECTION

1) DOGS - If the dog is not vomiting, administer sucralfate (In large dogs, 1 gram orally three times daily; in small dogs, 0.5 gram orally three times daily) or misoprostol (2 to 5 micrograms/kilogram orally three to four times daily)(Albretson, 2001).

D) VOMITING

1) DOGS - In cases of protracted vomiting, metoclopramide may be used at doses of 0.1 to 0.3 milligram/kilogram IV or orally three times daily. Animals should be monitored closely for the development of extrapyramidal reactions (Albretson, 2001).

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

Pharmacology Toxicology

1) It is speculated that interference of the normal Krebs cycle mechanisms of cellular energy production by fluorocitrate, a metabolite of 5-fluorouracil, may be the cause of cerebellar ataxia and convulsions in dogs following ingestion of 5-fluorouracil (Albretson, 2001).

References

General Bibliography

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