Wart Remove 5-FU Ointment

Overview of Wart Remove 5-FU Ointment

Dosage Strength of Wart Remove 5-FU Ointment

Fluorouracil / Salicylic Acid 2.5/17% 5 mL Pump

General Information

Fluorouracil

Fluorouracil (5-FU) is a fluorinated pyrimidine and acts as an antimetabolite antineoplastic agent. It differs from the naturally occurring product, uracil, by the addition of a fluoride at position 5. Fluorouracil is a component of chemotherapy regimens for many solid tumors, including breast, colorectal, gastrointestinal, and head and neck cancers. The clinical pharmacology of 5-FU is complex and the pharmacokinetics are complicated by intra- and inter-patient variability, nonlinear elimination, and erratic bioavailability. The toxicities and efficacy of 5-FU differ depending upon the route of administration of the drug. A meta-analysis of 5-FU studies in the treatment of colorectal cancer found that continuous infusion led to a superior response and overall survival rate with a decreased incidence of severe hematologic toxicity as compared to bolus injection. However, there was an increased incidence of hand-foot syndrome with the continuous infusion as compared to the bolus injection.1 Fluorouracil commonly is given intravenously but is also used topically for malignant keratoses of the skin. Fluorouracil was approved by the FDA in 1962. In October 2000, a new formulation of fluorouracil cream using a microsponge delivery system (Carac™) was FDA-approved. The new delivery system allows for once daily dosing and a sustained release of fluorouracil.

Salicylic Acid

Salicylic acid is a topical keratolytic agent. It is used to remove excess keratin in hyperkeratotic skin disorders such as common and plantar warts, psoriasis, seborrheic dermatitis, calluses, and corns. Salicylic acid also is used to treat acne. Salicylic acid works by causing desquamation of the horny layer of skin. Prolonged or repeated daily use over large areas of skin may result in salicylism, especially in children and patients with renal or hepatic impairment. This drug was approved by the FDA in 1939.23456789

Mechanism of Action

Fluorouracil

Fluorouracil (5-FU) is a pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with RNA synthesis and function. Fluorouracil also has some effects on DNA.

RNA-related effects: Formation of fluorouracil monophosphate (FUMP) occurs through two different pathways. FUMP may be formed as the result of direct transfer of a ribose sugar from phosphoribosylpyrophosphate (PPRP) to 5-FU via orotic acid phosphoribosyltransferase (OPRTase). In the second pathway, a ribose sugar is added to 5-FU by uridine phosphorylase forming fluorouridine (FUrd). FUrd undergoes phosphorylation by uridine kinase to form fluorouracil monophosphate (FUMP). Flurouridine diphosphate (FUDP) and flurouridine triphosphate (FUTP) are formed due to the sequential activity of pyrimidine monophosphate kinase and pyrimidine diphosphate kinase on FUMP. The FUTP is then incorporated into RNA and inhibits RNA activity and synthesis.

DNA-related effects: Fluorouracil can be converted to fluorodeoxyuridine (FdUrd) by thymidine phosphorylase and then fluorodeoxyuridine monophosphate (FdUMP) by thymidine kinase. As a secondary pathway, FdUMP may be formed indirectly by the conversion of FUDP to fluorodeoxyuridine diphosphate (FdUDP) and then to FdUMP. FdUMP forms a tight, but reversible, covalent bond with thymidylate synthase (TS) in the presence of methylenetetrahydrofolate (CH2-THF), a natural reduced folate. Binding of FdUMP to TS inhibits the formation of thymidylate from uracil. Thymidylate is the necessary precursor of thymidine triphosphate (dTTP), one of four deoxyribonucleotides required for synthesis of DNA. Thus, a deficiency of thymidylate leads to depletion of dTTP. Both FdUMP and FdUDP may be converted to fluorodeoxyuridine (FdUTP), which can be incorporated into DNA by DNA polymerase in place of dTTP. When given in combination with leucovorin, the DNA-effects of 5-FU are enhanced through stabilization of the ternary complex of TS, FdUMP, and CH2-THF.

Cytotoxicity: During the first 24 hours after drug exposure, S-phase cytotoxicity is noted, probably due to 5-FU-induced DNA effects. After 24 hours, cytotoxicity occurs primarily in the G1-phase of the cell cycle probably due to incorporation of 5-FU into RNA. The selectivity of 5-FU for rapidly dividing cells is due to the higher concentrations of thymidylate synthase (TS) in dividing cells, up to 20-fold, versus non-proliferating cells.
 
Resistance to 5-FU therapy may be due to a variety of mechanisms due to the complex effects of 5-FU. Deletion or decreased activity of various activating enzymes, decreased availability of cofactors (i.e., PRPP), competition with natural substrates (i.e., uracil triphosphate and dTTP), and increased activity of enzymes associated with the catabolism of 5-FU to inactive compounds (i.e., dihydropryrimidine dehydrogenase) may all play a role in the development of chemotherapy resistance.

Salicylic Acid

Salicylic acid exhibits keratolytic action by dissolution of intercellular cement substance causing desquamation of the horny layer of skin.6710

Pharmacokinetics

Fluorouracil

Fluorouracil (5-FU) is administered topically or parenterally. Due to low and inconsistent oral bioavailability, 5-FU is not given orally.  The drug distributes widely throughout the body tissues and crosses the blood-brain barrier to a significant degree. CSF concentrations can be sustained for several hours. Fluorouracil also distributes well into ascites and pleural effusions; delayed elimination from these fluid reservoirs could prolong toxicity. Fluorouracil exhibits nonlinear kinetics. With increasing IV doses of 5-FU, hepatic extraction ratio is decreased, bioavailability and AUC are increased, total-body clearance is decreased, and elimination half-life is increased. Although changes in 5-FU clearance or AUC with increasing 5-FU dose may be linear over a certain dose range, with higher doses the decrease in clearance and increase in AUC may change disproportionately. This nonlinearity probably represents saturation of metabolic processes at higher drug concentrations. A small portion of fluorouracil is converted to active metabolites (FdUMP, FUTP) in the tissues; the rest (85%) is catabolized via dihydropryrimidine dehydrogenase (DPD), the initial rate-limiting step, and other enzymes to the dihydropyrimidine form. DPD is widely distributed through out the body including the liver, gastrointestinal mucosa, and peripheral white blood cells. The liver is the major site of 5-FU catabolism. However, during continuous infusion of 5-FU the clearance of 5-FU exceeds liver blood flow indicating significant extrahepatic metabolism. DPD plays a critical role in determining the amount of 5-FU available for anabolism, and therefore, may in part determine the efficacy and/or toxicity of 5-FU therapy. DPD follows a circadian pattern and exhibits significant interpatient variability in terms of activity. The circadian variation of DPD levels is associated with an inverse circadian pattern in plasma 5-FU patterns. Individuals with low or nonexistent DPD activity experience severe toxicity when treated with conventional doses of 5-FU. It also appears this interpatient variability in DPD activity is responsible for the variable bioavailability following oral administration of 5-FU.11 Following IV administration of fluorouracil, the mean elimination half-life from plasma is 16 minutes (range: 8—20 minutes) and is dose dependent. In contrast to the parent compound, the intracellular nucleotides FdUMP and FUTP have prolonged half-lives. A small amount of unchanged 5-FU and primarily its metabolites are eliminated via the biliary and renal systems. Seven to 20 percent of 5-FU is renally excreted unchanged.12

Route-Specific Pharmacokinetics

Topical Route
After a 12 hour application of 1 g of topical fluorouracil, 5-FU to the head and neck, approximately 6% of the dose was absorbed systemically.13 In a multiple-dose pharmacokinetic study in which 10 patients received the 0.5% topical cream at a dose of 1 g once daily (Carac) and 10 patients received the 5% topical cream (Efudex) at a dose of 1 g twice daily, 3 patients receiving the 0.5% cream and 9 patients receiving the 5% cream had measurable plasma concentrations. However, only 1 patient receiving the 0.5% cream and 6 patients receiving the 5% cream had sufficient data points to calculate mean pharmacokinetic parameters. The Tmax occurred at about 1 hour in both groups. The Cmax for the 0.5% cream (n = 1) was 0.77 ng/mL and AUC was 2.8 ng x hr/mL. The Cmax for the 5% cream (n = 6) was 11.49 +/- 8.24 ng/mL and the AUC was 22.39 +/- 7.89 ng x hr/mL.14 In a study of the 4% topical cream (Tolak, n = 21) in patients with at least 3 actinic keratosis lesions (4 mm or greater in diameter), steady state plasma concentrations were obtained at 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours after the last dose of a 4-week regimen. Eight patients had undetectable plasma concentrations (lower limit of 1 ng/mL) in all plasma samples. In patients with detectable 5-FU concentrations, the highest concentration was generally observed at 1 hour after the administered dose with a mean observed maximum concentration of 3.66 +/- 1.58 ng/mL and a range of 1.11 to 7.35 ng/mL.15

Other Route(s)

Regional Administration Following hepatic artery infusion (HAI) of 5-FU, 19—51% of the infused dose was cleared during first-pass hepatic metabolism. Systemic exposure of 5-FU following HAI has been reported to be 12—52% that of after IV administration; systemic exposure increases with increasing 5-FU doses. 5-FU may be given by the intraperitoneal route. The advantage of regional administration is that low molecular weight products, such as 5-FU, are absorbed primarily through the portal circulation, passing through the liver before reaching the systemic circulation.

Special Populations

Hepatic Impairment Fluorouracil has been administered to patients with hepatic insufficiency without dose reduction; however, dose reduction may be prudent in patients with serum bilirubin > 5 mg/dl and poor performance status.

Renal Impairment Patients with renal insufficiency and normal activity of DPD do not require 5-FU dosage adjustments.

Salicylic Acid

Following topical application, percutaneous absorption of salicylic acid does occur; however, systemic exposure is considered negligible with normal prescription use. Roughly 10% of applied salicylates can remain in the skin after dermal application; however, acute toxicity via dermal exposure is rarely seen for salicylic acid. Salicylism has occurred using high concentrations of salicylic acid on widespread areas of hyperkeratotic skin, but cases resulting from topically applied salicylic acid cosmetic or acne products have not been reported.16

Contraindications/Precautions

Fluorouracil

Fluorouracil, 5-FU is contraindicated in patients with known hypersensitivity to the drug, or any product components. With the topical products, the potential for a delayed hypersensitivity reaction to fluorouracil exists and patch testing to prove hypersensitivity may be inconclusive.
Fluorouracil Injection, USP therapy is contraindicated for patients with bone marrow suppression and those with potentially serious infection. Severe hematological toxicity including bone marrow suppression can occur. Patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy are at risk of increased bone marrow suppression. Fluorouracil may potentiate the effects of radiation therapy. During systemic therapy the hematologic status of the patient should be closely monitored. Pretreatment white blood cell (WBC) and platelet counts should be above institutional limits. A WBC with differential should be assessed before each dose. Fluorouracil, 5-FU should be discontinued at the first visible sign of leukopenia (WBC less than 3500/mm3), a rapidly falling white blood count, or thrombocytopenia (platelet count below 100,000/mm3). Patients with an active infection should be treated prior to receiving 5-FU; the dose may need to be reduced or therapy discontinued in patients who develop serious infections. Patients with varicella-zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of previous infections following administration of chemotherapy. Patients should immediately report any symptoms of severe bone marrow suppression such as fever, sore throat, or abnormal bleeding.17

Fluorouracil, 5-FU systemic therapy is contraindicated for use in patient with malnutrition. Severe gastrointestinal (GI) toxicities, including bleeding (GI bleeding) may occur during treatment.17 Systemic fluorouracil, 5-FU, therapy should be delayed and dosage adjustments may be necessary in patients with stomatitis, intractable vomiting, severe, watery diarrhea, GI bleeding or ulceration, or bleeding from any other site.

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency (familial pyrimidinemia), should not receive systemic or topical fluorouracil, 5-FU, therapy. Dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of 5-FU and deficiency of this enzyme leads to elevated concentrations of 5-FU due to decreased clearance. Administration of 5-FU to individuals with DPD deficiency can lead to enhanced and severe 5-FU toxicity including abdominal pain, diarrhea, vomiting, fever, chills, stomatitis, and neurotoxicity. Some of these patients have been rechallenged with lower doses of 5-FU and experienced recurrent and progressive toxicity and increased morbidity. Fluorouracil Injection, USP should be used with extreme caution in poor risk patients with impaired renal function, as these patients may be more at risk for toxicity. Patients with renal impairment and exhibiting low activity of DPD concurrently may also experience severe toxicity following 5-FU therapy and may require 5-FU dosage reduction; patients with renal impairment but without DPD deficiency do not appear to require dosage reduction in 5-FU therapy on the basis of renal impairment alone.17 Only 1 case of serious systemic toxicity associated with DPD deficiency during the topical administration of 5-FU has been observed in a patient using the 5% cream. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. It is unknown whether patients with profound DPD deficiency would develop systemic toxicity with lower concentrations of topical 5-FU.141819
Fluorouracil Injection, USP should be used with extreme caution in poor risk patients with impaired hepatic function, as these patients may be more at risk for toxicity.17 Patients with hepatic disease, especially biliary tract disease or jaundice may have decreased detoxification and elimination of systemic fluorouracil, 5-FU. Avoid the use of 5-FU in patients with a serum bilirubin exceeding 5 mg/dL.20
Use care to avoid accidental exposure to fluorouracil, 5-FU, injection during preparation, handling, and administration. The use of protective gowns, gloves, and goggles is recommended. Following skin or ocular exposure to the injection, skin and eyes should be thoroughly rinsed.1217 If 5-FU cream or topical solution is applied with non-protected fingers, the hands should be washed immediately afterward. Use care to avoid accidental exposure of skin areas not being treated to fluorouracil, 5-FU topical products. Wash hands after topical application to the skin. Topical 5-FU preparations should not be applied on the eyelids or directly into the eyes, nose, or mouth or other mucous membranes because irritation may occur.1413151819

There is a possibility of increased absorption of topical fluorouracil, 5-FU, through skin abrasion, skin ulceration, or an area of inflammation. Application of topical fluorouracil, 5-FU to mucous membranes may cause local inflammation and ulceration and should be avoided. Skin occlusion with resultant hydration has been shown to increase the absorption of some topical preparations. If any occlusive dressing is used during topical 5-FU treatment of basal cell carcinoma, there may be an increase in the severity of inflammatory reactions in the adjacent skin. A gauze dressing may be applied for cosmetic reasons without increased inflammation.1413151819
Sunlight (UV) exposure or exposure to other forms of ultraviolet light (e.g., tanning beds) should be limited during and immediately following treatment with topical fluorouracil, 5-FU, preparations. The intensity of local reactions may be increased with exposure to sunlight. Patients treated with systemic 5-FU therapy may also experience increased sensitivity to sunlight. It is recommended that these patients wear protective clothing and sunscreen when outside during and following therapy.1413151819
Fluorouracil, 5-FU, when given topically or systemically, may cause harm to the fetus if administered to a woman during pregnancy. Topical 5-FU is contraindicated during pregnancy (FDA pregnancy risk category X).141819 Systemic 5-FU is classified as FDA pregnancy risk category D and should only be used during pregnancy if the benefit justifies the potential risks.12 5-FU has been shown to cause teratogenic effects in animals, but adequate and well-controlled studies in pregnant women have not been performed. One birth defect (cleft lip and palate) has been reported in the newborn of a patient using fluorouracil as recommended. Miscarriages and birth defects (ventricular septal defects) have been reported when topical 5-FU was applied to mucous membranes during pregnancy. Multiple birth defects have been reported in a fetus of a patient treated with intravenous 5-FU. Females of childbearing age should be advised to avoid becoming pregnant while receiving or using the drug due to the potential risk to the fetus. If a woman becomes pregnant while receiving topical or systemic 5-FU therapy, she should be apprised of the potential risk to the fetus.

It is uncertain whether fluorouracil, 5-FU, is distributed into breast milk. According to the manufacturer, due to the inhibition of DNA, RNA, and protein synthesis by fluorouracil, mothers should not nurse while receiving this drug. A decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.1214

Intrathecal administration of fluorouracil, 5-FU, is not recommended because of severe neurotoxicity associated with intrathecal exposure to 5-FU.
Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy with systemic fluorouracil, 5-FU is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.21

The myelosuppressive effects of systemic fluorouracil, 5-FU, can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

The safety and efficacy of fluorouracil, 5-FU, therapy have not been established in children.

Salicylic Acid

Salicylic acid preparations are contraindicated in patients who have previously exhibited salicylate hypersensitivity.6 7 10

Topical salicylic acid preparations in concentrations greater than 6% are contraindicated in patients with diabetes mellitus and other conditions of poor blood circulation such as peripheral vascular disease. Do not use these preparations on moles, birthmarks, warts with hair growing from them, genital warts, or warts on the face or mucous membranes.422 5

Prolonged use of salicylic acid over large areas, especially in children and patients with renal impairment or hepatic disease may increase the risk for development of salicylism. In such patients, limit the treated area and closely monitor the patient for signs of salicylate toxicity such as nausea, vomiting, dizziness, loss of hearing, tinnitus, lethargy, hyperpnoea, diarrhea, and psychic disturbances. When the potential for toxicity is present, advise patients not to apply occlusive dressings, clothing or other occlusive topical products such as petrolatum-based ointments to prevent excessive systemic exposure to salicylic acid. Concomitant use of other drugs which may contribute to elevated serum salicylate levels (e.g., oral aspirin and other salicylate containing medications, such as sports injury creams) should be avoided. Discontinue use of salicylic acid if salicylic acid toxicity occurs and treat appropriately.6 7 10

The potential for Reye's syndrome should be considered with administration of salicylic acid products in children and adolescents with varicella or influenza.6 7 10

Avoid accidental exposure of salicylic acid products to the eyes, lips, mucus membranes and inflamed or broken skin as increased absorption may occur. If unintended mucus membrane or ocular exposure occurs, thoroughly rinse affected areas with water.6 7 10

Pregnancy

Fluorouracil

Fluorouracil, 5-FU, when given topically or systemically, may cause harm to the fetus if administered to a woman during pregnancy. Topical 5-FU is contraindicated during pregnancy (FDA pregnancy risk category X).141819 Systemic 5-FU is classified as FDA pregnancy risk category D and should only be used during pregnancy if the benefit justifies the potential risks.12 5-FU has been shown to cause teratogenic effects in animals, but adequate and well-controlled studies in pregnant women have not been performed. One birth defect (cleft lip and palate) has been reported in the newborn of a patient using fluorouracil as recommended. Miscarriages and birth defects (ventricular septal defects) have been reported when topical 5-FU was applied to mucous membranes during pregnancy. Multiple birth defects have been reported in a fetus of a patient treated with intravenous 5-FU. Females of childbearing age should be advised to avoid becoming pregnant while receiving or using the drug due to the potential risk to the fetus. If a woman becomes pregnant while receiving topical or systemic 5-FU therapy, she should be apprised of the potential risk to the fetus.

Salicylic Acid

There are no adequate and well-controlled studies in pregnant women. Salicylic acid products should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.6 7 10 8 9

Breastfeeding

Fluorouracil

It is uncertain whether fluorouracil, 5-FU, is distributed into breast milk. According to the manufacturer, due to the inhibition of DNA, RNA, and protein synthesis by fluorouracil, mothers should not nurse while receiving this drug. A decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.1214

Salicylic Acid

It is not known whether topically applied salicylic acid is excreted into breast milk. According to the manufacturer, salicylic acid should not be used during breast-feeding. However, if the drug is used by nursing mothers, care should be taken to avoid application to the skin of the breast during lactation; oral ingestion by the infant could be harmful.6 7 10 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Adverse Reactions/Side Effects

Fluorouracil

Miscellaneous adverse events reported with fluorouracil cream include allergies (0 to 2.3%) as well as post-marketing reports of chronic lymphocytic leukemia and non-melanoma skin cancer.1415

Bleeding and epistaxis have been reported with IV fluorouracil use. Discontinue IV fluorouracil in patients who develop bleeding from any site.17

Medicinal taste (dysgeusia) and stomatitis have been reported infrequently in patients treated with fluorouracil solution or cream.1315 Stomatitis and esophagitis/pharyngitis (including oral ulceration and sloughing), diarrhea, anorexia, nausea, and vomiting occurred commonly with IV fluorouracil therapy; gastrointestinal (GI) ulceration (peptic ulcer) and GI bleeding were also reported. Discontinue IV fluorouracil in patients who develop stomatitis, esophagopharyngitis, intractable vomiting, diarrhea, GI ulceration, or GI bleeding.17 Antiemetics, such as metoclopramide or phenothiazines, are often effective in alleviating GI symptoms. Diarrhea and stomatitis are more common with constant infusions than with bolus therapy; however both may be dose limiting regardless of administration. Concurrent leucovorin therapy can increase severity of fluorouracil-induced diarrhea and stomatitis. Life-threatening and sometimes fatal enterocolitis, dehydration, and diarrhea have occurred when high-dose fluorouracil is given in combination with leucovorin, especially in elderly patients. Octreotide has been reported to be useful in the treatment of severe fluorouracil-induced diarrhea.

Leukocytosis has been reported in patients treated with fluorouracil solution or cream; pancytopenia, eosinophilia, thrombocytopenia, and toxic granulation have also occurred infrequently.1315 Leukopenia occurred commonly with IV fluorouracil therapy; pancytopenia, thrombocytopenia, agranulocytosis, and anemia were also reported. White blood cell (WBC) count nadirs typically occur between day 9 and 20 following treatment, with recovery by day 30. WBC counts with differential are recommended prior to each IV dose. Discontinue IV fluorouracil in patients who develop leukopenia (WBC < 3500/mm3), a rapidly falling WBC count, thrombocytopenia (platelets < 100,000/mm3) or bleeding from any site.17

Palmar-plantar erythrodysesthesia (hand and foot syndrome) has been reported with IV fluorouracil therapy. Symptoms gradually resolve over 5 to 7 days after fluorouracil is discontinued; use of pyridoxine may ameliorate this adverse event.17 Prolonged fluorouracil infusions are more commonly associated with this syndrome than bolus injections. With high-dose continuous infusions, this toxicity can be dose-limiting.

Headache was reported in 3.1% of patients treated with fluorouracil 0.5% cream (n = 257) compared with 2.4% of patients who received vehicle alone (n = 127) in a pooled analysis from 2 phase III studies.14 Acute cerebellar syndrome, nystagmus, and headache have been reported with IV fluorouracil therapy. Acute cerebellar syndrome may persist after discontinuing therapy.17

Ocular irritation was reported in 3.4 to 5.9% of patients treated with fluorouracil cream. Symptoms of ocular irritation were burning, watering (lacrimation), sensitivity, stinging (ocular pain) and ocular pruritus. Conjunctival reaction (conjunctivitis), corneal reaction, and lacrimation have been reported infrequently in patients treated with fluorouracil solution or cream.141315 Lacrimal duct stenosis, visual changes, lacrimation, and photophobia have been reported with IV fluorouracil therapy.17
Myocardial ischemia and angina have been reported with IV fluorouracil therapy.17 Cardiotoxicity due to systemic fluorouracil, 5-FU, therapy has been reported. Reported toxicities include angina, arrhythmias including ventricular tachycardia, cardiogenic shock, chest pain (unspecified), coronary vasospasm, electrocardiographic changes, myocardial infarction, palpitations, and sudden death. In general patients who have developed chest pain following 5-FU did so within several hours of receiving the third or fourth dose of drug. Rechallenge with 5-FU is usually associated with recurrence of the chest pain, which usually resolves, but has been associated with more serious sequelae. Cardiac catheterization reveals normal coronary arteries in these patients. It is believed that fluorouracil causes vasospastic angina. Asymptomatic ST-T wave changes have been seen in up to 65% of monitored patients, which suggests cardiac ischemia. Continuous infusions of 5-FU, especially high doses, have been associated with an increased incidence of cardiac effects; although, cardiotoxicity may occur after bolus injections as well. The chest pain responds to nitrates, calcium-channel blockers, or beta-blockers similar to other forms of angina. Thromboembolism, including pulmonary embolism, has also been reported with 5-FU therapy.

In two trials sponsored by the National Cancer Institute for initial treatment of metastatic colorectal cancer, an imbalance in the number of deaths occurring within 60 days of the initiation of treatment was associated with irinotecan, leucovorin, and 5-fluorouracil (5-FU) treatment as compared to 5-FU and leucovorin (Trial C89803) or oxaliplatin, 5-FU, and leucovorin therapy (Study N9741). In study N9741 of patients with advanced disease, 12/14 deaths associated with irinotecan, 5-FU, and leucovorin had several characteristics in common: dehydration (resulting from diarrhea, nausea, and vomiting), neutropenia, and sepsis (alone or in combination with shock), leading to death. Thirteen deaths occurred during the first 6-week cycle or immediately afterward. In the surgical adjuvant study (Trial C89803), 14 deaths in the group assigned to receive irinotecan, 5-FU, and leucovorin included pulmonary embolism (3 patients), sepsis (3), aspiration (3), myocardial infarction (1), dehydration and neutropenia (1), stroke (1), bowel ischemia or infarct or both (1), and one unknown. Dose modifications to these trials have been made in an attempt to decrease toxicity. Close monitoring of patients receiving the combination of irinotecan, 5-FU, and leucovorin is warranted.23

Injection site reaction has been associated with IV fluorouracil administration. An erythematous eruption overlying the veins on both arms has been reported in several patients after IV fluorouracil. No superficial phlebitis or extravasation were observed.24 Vein discoloration following fluorouracil administration has been reported. The veins remain patent but show darkening of the skin immediately over the vein.17

Dermatologic reaction to the topical products were the most commonly reported. These included erythema (89.4 to 99%), scaling / xerosis (69 to 95%), crusting (87%), pruritus (85%), stinging / burning (60 to 87%), edema (14.1 to 69%), skin erosion (24.7 to 68%), pain (30.6 to 62.2%), application site reaction (91.8 to 96.5%), skin irritation (0 to 2.4%), allergic contact dermatitis, scarring, rash (unspecified), skin ulcer, inflammation, telangiectasia, alopecia, blistering, skin hyperpigmentation, bullous pemphigoid, ichthyosis, suppuration, swelling, soreness, tenderness, urticaria, and photosensitivity. These adverse events generally increased over the treatment period and diminished to baseline levels weeks after treatment cessation.14132515 Alopecia and dermatitis has occurred with IV fluorouracil therapy; the dermatitis typically is a reversible pruritic maculopapular rash on the extremities or the trunk. Other dermatologic adverse events reported with IV fluorouracil include xerosis, fissuring, photosensitivity (observed as erythema or skin hyperpigmentation), and nail discoloration.17 Patients should wear a sunscreen with SPF 15 or greater and should cover exposed skin when outside after fluorouracil treatment. Sunlight may worsen other dermatologic reactions (i.e., rash) to fluorouracil.

Cleft lip/palate was reported in a newborn whose mother used topical fluorouracil as recommended. Additionally, cases of spontaneous fetal abortion (miscarriage) and teratogenesis (specifically, ventricular septal defect) have been reported when fluorouracil was applied to mucous membranes during pregnancy. Multiple birth defects were reported in a fetus of a patient who received IV fluorouracil.13

Emotional upset, insomnia, and irritability occurred infrequently in patients treated with fluorouracil solution or cream.1315 Disorientation, confusion, and euphoria have been reported with IV fluorouracil therapy.17

Nasal irritation has been reported infrequently in patients treated with fluorouracil 2% or 5% solution or 5% cream.13

Infection (e.g., common cold virus (0 to 4.7%), sinusitis (0 to 4.7%) was reported in patients treated with fluorouracil 0.5% cream; however, the incidence of infection was not greater in the fluorouracil arm compared with the vehicle alone arm.14 Herpes simplex viral infection occurred infrequently in patients treated with fluorouracil solution or cream.1315

Generalized allergic reactions including anaphylactoid reactions have been reported with IV fluorouracil therapy.17

Thrombo-phlebitis has been reported with IV fluorouracil use.17
 

Salicylic Acid

Prolonged and repeated daily use over large areas, especially in children and patients with significant renal or hepatic impairment increases the potential for development of salicylism. 6710

Topical application of salicylic acid is generally well tolerated, but may result in skin irritation including transient stinging, burning, or pruritus. Excessive erythema, peeling of the skin, and scaling may also occur, particularly if used on open skin lesions. Advise patients to discontinue use and consult a physician if excessive burning, stinging, or peeling occurs.6 7 10

Topical over-the-counter (OTC) acne products, including salicylic acid, have been associated with rare but serious and potentially life-threatening hypersensitivity reactions. These reactions may occur within minutes to a day or longer after use of the product. Instruct patients to stop using topical acne products if they experience signs of anaphylactoid reactions such as throat tightness; difficulty breathing; feeling faint; or swelling of the eyes, face, lips, or tongue. The product should also be discontinued in patients who develop urticaria or pruritus. Based on the information reported to the FDA, it is uncertain whether the reactions are caused by the active ingredients benzoyl peroxide or salicylic acid, the inactive ingredients or a combination of both. When initiating therapy with an OTC topical acne product, advise patients to apply a small amount to one or two small affected areas for 3 days and monitor for signs of a hypersensitivity reaction. If no discomfort occurs, the instructions on the Drug Facts label may be followed.26

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

• 1. No authors listed. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol 1998;16:301-308.
• 2. Compound W (salicylic acid 17%) package insert. Tarrytown, NY: Prestige Brands; 2013 Mar.
• 3. Compound W gel (salicylic acid 17% gel) package insert. Tarrytown, NY: Prestige Brands; 2013 April.
• 4. a. b. Hydrisalic gel (salicylic acid 17%) package insert. Farmingdale, NY: Pedinol Pharmacal Inc.; 2011 Nov.
• 5. a. b. Virasal (salicylic acid 27.5%) package insert. Vernon Hills, IL: Elorac, Inc.; 2011 Jan.
• 6. a. b. c. d. e. f. g. h. i. j. Salex 6% (salicylic acid) cream and lotion package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2019 Jan.
• 7. a. b. c. d. e. f. g. h. i. j. Salacyn 6% (salicylic acid 6%) cream or lotion package insert. Miami, Fl: Stratus Pharmaceuticals Inc.; 2010 Nov..
• 8. a. b. Salitech (salicylic acid 5% lotion) package insert. Peoria, AZ: Solutech Pharmaceuticals; 2016 Dec.
• 9. a. b. Salisol (salicylic acid 23% topical solution) package insert. Peoria, AZ: Solutech Pharmaceuticals; 2016 Dec.
• 10. a. b. c. d. e. f. g. h. i. Salvax 6% foam (salicylic acid) package insert. Newtown, PA: Quinnova Pharmaceuticals, Inc.; 2009 Apr.
• 11. Diasio RB. Oral administration of fluorouracil: A new approach utilizing modulators of dihydropyrimidine dehydrogenase activity. Cancer Therapeutics 1999;2:97-106.
• 12. a. b. c. d. e. f. Adrucil (fluorouracil injection) package insert. Irvine, CA: Teva Parenteral Medicines, Inc.; 2007 July.
• 13. a. b. c. d. e. f. g. h. i. j. k. l. Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC, 2016 Feb.
• 14. a. b. c. d. e. f. g. h. i. j. k. l. m. n. Carac (fluorouracil) cream package insert. Bridgewater, NJ: Dermik Laboratories; 2009 Aug.
• 15. a. b. c. d. e. f. g. h. i. j. k. Tolak (fluorouracil) 4% topical cream package insert. Sanford, FL: Hill Dermaceuticals, Inc.; 2015 Sep.
• 16. Cosmetic Ingredient Review Expert Panel. Safety assessment of Salicylic Acid, Butyloctyl Salicylate, Calcium Salicylate, C12-15 Alkyl Salicylate, Capryloyl Salicylic Acid, Hexyldodecyl Salicylate, Isocetyl Salicylate, Isodecyl Salicylate, Magnesium Salicylate, MEA-Salicylate, Ethylhexyl Salicylate, Potassium Salicylate, Methyl Salicylate, Myristyl Salicylate, Sodium Salicylate, TEA-Salicylate, and Tridecyl Salicylate. Int J Toxicol 2003;22 (Suppl 3):1-108. Review.
• 17. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. Fluorouracil injection package insert. New York, NY: Pfizer Labs; 2012 Aug.
• 18. a. b. c. d. e. f. Topical fluorouracil 5% cream package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.
• 19. a. b. c. d. e. f. Topical fluorouracil 2% or 5% solution package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.
• 20. Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33(1):50-67.
• 21. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60(2):1-64.
• 22. Curad mediplast (salicylic acid 40%) package insert. Mundelein, IL: Medline Industries, Inc.; 2013 Feb.
• 23. Sargent DJ, Niedzwiecki D, O’Connell MJ, et al. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001;345:144-145.
• 24. Pujol RM, Rocamora V, Lopez-Poussa A, et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol 1998;39:839-42.
• 25. Fluoroplex (fluorouracil) cream package insert. West Chester, PA: Aqua Pharmaceuticals; 2012 Mar.
• 26. Food and Drug Administration MedWatch. Over-The-Counter Topical Acne Products: Drug Safety Communication - Rare But Serious Hypersensitivity Reactions. Retrieved June 25, 2014. Available on the World Wide Web http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm402722.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery