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  • CLASSES

    Pyrimidine Analogs
    Topical Antimetabolites

    BOXED WARNING

    Requires a specialized care setting, requires an experienced clinician

    Systemic therapy with fluorouracil, 5-FU therapy requires an experienced clinician. Fluorouracil, 5-FU injection should be given only by or under the supervision of a qualified clinician who is experienced in cancer chemotherapy and intra-arterial therapy and is well versed in the use of potent antimetabolites and the potential for adverse reactions due to these effects. Systemic administration of fluorouracil, 5-FU requires a specialized care setting and patients should be hospitalized at least during the initial course of therapy because of the possibility of severe toxic reactions.

    DEA CLASS

    Rx

    DESCRIPTION

    Antimetabolite antineoplastic agent; fluorinated pyrimidine antineoplastic agent; toxicities and efficacy of 5-FU differ depending upon the route of administration; used for breast, colorectal, gastrointestinal, and head and neck cancers; used topically for malignant keratoses.

    COMMON BRAND NAMES

    Adrucil, Carac, Efudex, Fluoroplex, Tolak

    HOW SUPPLIED

    Adrucil/Fluorouracil Intravenous Inj Sol: 1mL, 50mg
    Carac/Efudex/Fluoroplex/Fluorouracil/Tolak Topical Cream: 0.5%, 1%, 4%, 5%
    Efudex/Fluorouracil Topical Sol: 2%, 5%

    DOSAGE & INDICATIONS

    For the treatment of colorectal cancer.
    NOTE: Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    NOTE: Fluorouracil has been given in a large number of different dosages and schedules. The correct dose of fluorouracil will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.
    For the adjuvant treatment of colon cancer in combination with leucovorin (Roswell Park)†.
    Intravenous dosage
    Adults

    500 mg/m2 IV bolus on day 1; 1 hour prior to administering 5-FU bolus, give leucovorin 500 mg/m2 IV over 2 hours. Repeat weekly on days 1, 8, 15, 22, 29, and 36 every 8 weeks for 4 to 6 cycles. In a randomized clinical trial, patients with stage II or III colon cancer post-curative resection received treatment with weekly 5-FU either in combination with high dose leucovorin (Roswell Park regimen; n = 981), low dose leucovorin (Mayo Clinic regimen; n = 984), or levamisole (n = 871). There were no clinically significant differences in 10-year overall survival (OS) (52% vs. 52% vs. 50%) or 10-year disease-free survival (DFS) (47% vs. 49% vs. 45%). Grade 3 or 4 toxicities were reported in 40.3% of patients treated with Roswell Park, 55.6% of those who received the Mayo Clinic regimen, and 44.4% of patients treated with levamisole plus 5-FU. In a separate clinical trial, patients randomized to receive adjuvant treatment with the Roswell Park regimen (n = 519) had improved 3-year DFS (73% vs. 64%; p = 0.0004) and 3-year OS (84% vs. 77%; p = 0.003) compared with those treated with MOF (lomustine, vincristine, 5-FU) (n = 522).

    For adjuvant treatment of high-risk stage II or stage III rectal cancer in combination with radiation therapy.
    Intravenous dosage
    Adults

    500 mg/m2 IV bolus daily for 5 days on days 1 and 36 beginning 22 to 70 days after surgery; radiation therapy for 6 weeks is begun on day 64 after initiation of 5-FU therapy. 5-FU 225 mg/m2/day IV continuous infusion is given throughout radiation therapy. Then, 5-FU 450 mg/m2 IV bolus daily for 5 days beginning 1 month after radiation (i.e., days 134 to 138) and repeated in 4 weeks (i.e., days 169 to 173). As compared to patients who received bolus injection 5-FU during radiation therapy (5-FU 350 mg/m2/day IV bolus on days 1 to 5; 400 mg/m2 IV bolus on days 36 to 40; 300 mg/m2 IV bolus on days 134 to 138; and 350 mg/m2 IV bolus on days 169 to 173 with radiation therapy beginning on day 64), patients receiving the continuous infusion during radiation therapy had a statistically significant improvement in relapse-free and overall survival rates.

    For the treatment of metastatic colorectal cancer in combination with irinotecan and leucovorin, with or without bevacizumab (FOLFIRI with or without bevacizumab)†.
    NOTE: Both bevacizumab and irinotecan are FDA approved for the treatment of metastatic colorectal cancer in combination with leucovorin and 5-FU.
    NOTE: Outside of a clinical trial, irinotecan should only be given in combination with weekly 5-FU/leucovorin bolus regimens or continuous infusion 5-FU/leucovorin as listed below. Use of irinotecan in combination with 5-FU/leucovorin regimens administered for 4 to 5 consecutive days every 4 weeks are not recommended due to an increased risk of toxicity, including death; use of these regimens should be limited to controlled clinical trials.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2/day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 hours) for cycles 1 and 2. If there is no toxicity greater than grade 1, the 5-FU infusion dose may be increased to 3,000 mg/m2 for all subsequent cycles. Prior to 5-FU bolus on day 1, administer irinotecan 180 mg/m2 IV over 90 minutes, administered concomitantly but in separate bags with leucovorin 400 mg/m2 IV over 2 hours. If bevacizumab is included, give bevacizumab 5 mg/kg IV over 30 to 90 minutes every 2 weeks on day 1, concurrently with irinotecan. Repeat this 2-day regimen every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, randomized, phase 3 clinical trial, patients with previously untreated metastatic colorectal cancer (mCRC) who received FOLFIRI (n = 144) had improved progression-free survival (PFS) (7.6 months vs. 5.9 months; HR 1.51; p = 0.004) and overall survival (OS) (23.1 months vs. 17.6 months; p = 0.09) compared with those treated with modified IFL (mIFL; n = 141); overall response rate (ORR) was 47.2% vs. 43.3%, respectively. Patients treated with bevacizumab plus FOLFIRI had PFS of 11.2 months vs. 8.3 months (p = 0.28) and OS of 28 months vs. 19.2 months (HR 1.79; p = 0.037) compared with bevacizumab plus mIFL. Compared with FOLFOX6, PFS was 8.5 months vs. 8 months (p = 0.26) when FOLFIRI was used as first-line therapy for mCRC and 2.5 months vs. 4.2 months (p = 0.003) as second-line therapy compared with FOLFOX6; OS was 21.5 months for patients treated with first-line FOLFIRI and 20.6 months for patients who received FOLFOX6. Another dosing schedule of FOLFIRI shown to improve ORR (35% vs. 22%), time to progression (TTP) (6.7 months vs. 4.4 months) and OS (17.4 months vs. 14.1 months; p < 0.05) compared with 5-FU/leucovorin is irinotecan 180 mg/m2 IV over 90 minutes followed by leucovorin 200 mg/m2 IV over 2 hours, and then 5-FU 400 mg/m2 IV bolus and 600 mg/m2 CIV over 22 hours; leucovorin and 5-FU (bolus and CIV) are repeated on day 2. Repeat every 2 weeks until disease progression or unacceptable toxicity.

    For the treatment of advanced colorectal cancer in combination with leucovorin (LV) and oxaliplatin with or without bevacizumab (FOLFOX4 with or without bevacizumab)†.
    NOTE: Bevacizumab is FDA approved for the treatment of metastatic colorectal cancer in combination with 5-FU based chemotherapy and oxaliplatin is FDA approved for advanced colorectal cancer in combination with infusional 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus over 2 to 4 minutes, followed by 5-FU 600 mg/m2 continuous IV infusion (CIV) over 22 hours on day 1. Prior to 5-FU bolus on day 1, administer oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV (both over 120 minutes via Y-site). If giving FOLFOX4 plus bevacizumab, administer bevacizumab 10 mg/kg IV over 30 to 90 minutes prior to chemotherapy on day 1. On day 2, repeat leucovorin 200 mg/m2 IV over 2 hours followed by 5-FU 400 mg/m2 IV bolus, then 5-FU 600 mg/m2 CIV over 22 hours. The order of administration is (bevacizumab) followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for 5-FU and leucovorin need not be changed. In a multicenter, randomized, open-label clinical trial, previously untreated patients with advanced colorectal cancer who received FOLFOX4 (n = 267) had improved median overall survival compared with irinotecan plus 5FU/LV (IFL; n = 264) (19.4 months vs. 14.6 months; HR 0.65; p < 0.0001). Patients treated with FOLFOX 4 also had improved time to progression (TTP; 8.7 months vs. 6.9 months; HR 0.74; p = 0.0014) and overall response rate (ORR; 45.2% vs. 32.5%; p = 0.008) compared with IFL therapy. In a separate multicenter, randomized, open-label trial, previously treated patients with advanced colorectal cancer who had relapsed or progressed within 6 months of first-line therapy with IFL had improved ORR (9% vs. 0%) and median TTP (4.6 months vs. 2.7 months) after treatment with FOLFOX4 (n = 152) compared with 5FU/LV (n = 151). In another randomized, open-label, placebo-controlled, phase 3 clinical trial, previously treated patients with metastatic colorectal cancer who received FOLFOX4 plus bevacizumab (n = 286) had improved overall survival (OS) (12.9 months vs. 10.8 months; HR 0.75; p = 0.0011) and progression-free survival (PFS) (7.3 months vs. 4.7 months; HR 0.61; p < 0.0001) compared with those treated with FOLFOX4 alone (n = 291). Additionally, the overall response rate (ORR) was 56% in the FOLFOX4 plus bevacizumab arm compared with 43% in the FOLFOX4 alone arm (p < 0.0001). The significance of the effect of bevacizumab on OS is not consistent across clinical trials.

    For the treatment of metastatic colorectal cancer in combination with leucovorin, irinotecan, and bevacizumab (IFL plus bevacizumab)†.
    NOTE: Bevacizumab is FDA approved for the treatment of metastatic colorectal cancer, in combination with leucovorin, 5-FU, and irinotecan (IFL)
    Intravenous dosage
    Adults

    500 mg/m2 IV bolus, preceded first by irinotecan 125 mg/m2 IV over 90 minute, and then by leucovorin 20 mg/m2 IV bolus on days 1, 8, 15, and 22, every 6 weeks (IFL), plus bevacizumab 5 mg/kg IV over 30 to 90 minutes every 2 weeks. The sequence of administration is irinotecan, concomitantly with or without bevacizumab, followed by leucovorin, then 5-FU. In a double blind, randomized, placebo-controlled, phase 3 trial, patients who received IFL plus bevacizumab (n = 402) had improved overall survival (OS) (20.3 months vs. 15.6 months; HR 0.66; p < 0.001) and progression-free survival (PFS) (10.6 months vs. 6.2 months; HR 0.54; p < 0.001) compared with patients treated with IFL plus placebo (n = 411). Additionally, the overall response rate (ORR) 45% vs. 35% (p < 0.01) and duration of response 10.4 months vs. 7.1 months, respectively, were also improved with the addition of bevacizumab to IFL. However, IFL has been shown to have increased mortality compared with FOLFIRI in one trial, and is inferior to FOLFOX in another.

    For the adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor, in combination with leucovorin and oxaliplatin (FOLFOX4)†.
    NOTE: Oxaliplatin is FDA approved for the adjuvant treatment of colorectal cancer in combination with 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus over 2 to 4 minutes, followed by 5-FU 600 mg/m2 continuous IV infusion (CIV) over 22 hours on day 1 ; precede 5-FU bolus and CIV by oxaliplatin 85 mg/m2 IV, administered concurrently over 2 hours in separate bags via Y-site with leucovorin 200 mg/m2 IV. On day 2, again give leucovorin 200 mg/m2 IV over 2 hours prior to a 5-FU bolus (600 mg/m2 IV) and CIV (600 mg/m2 IV over 22 hours). This 2-day regimen (FOLFOX4) is repeated every 2 weeks for 12 cycles (6 months). Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for 5-FU and leucovorin need not be changed. In a multicenter trial, 2,246 patients with stage II or III completely resected colon cancer were randomized to either FOLFOX 4 or infusional 5-FU/LV (De Gramont regimen). At a median follow-up of 81.9 months in the patients with stage III disease, there was a significant improvement in 5-year disease-free survival (DFS) in patients receiving FOLFOX 4 as compared to those receiving infusional 5-FU/LV (73.3% vs. 67.4%; HR 0.80; p = 0.003). The 6-year overall survival (OS) rates were also improved with FOLFOX 4 (78.5% vs. 76%;HR 0.84; p = 0.46). In a subgroup analysis of stage III patients, the 6-year OS rates were improved with FOLFOX 4 (72.9% vs. 68.7%; HR 0.80; p = 0.023). There was no significant difference observed in DFS or OS in patients with stage II disease.

    For the treatment of metastatic colorectal cancer in combination with leucovorin and oxaliplatin, with or without bevacizumab (mFOLFOX6 with or without bevacizumab)†.
    NOTE: Bevacizumab is FDA approved for the treatment of metastatic colorectal cancer in combination with 5-FU based chemotherapy and oxaliplatin is FDA approved for advanced colorectal cancer in combination with infusional 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 to 48 hours). Prior to 5-FU bolus on day 1, administer oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV concurrently in separate bags via y-site over 2 hours. If giving mFOLFOX6 plus bevacizumab, administer bevacizumab 5 mg/kg IV over 30 to 90 minutes prior to chemotherapy on day 1; the order of administration is (bevacizumab) followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for 5-FU and leucovorin need not be changed. In 2 sequentially conducted, open-label cohorts (TREE-1 and TREE-2), patients with metastatic or recurrent colorectal cancer without prior therapy for advanced disease were randomized to receive treatment with mFOLFOX6 (n = 50), bFOL (n = 50), CapeOx (n = 50), or the same regimens with bevacizumab (n = 75; n = 74; n = 74, respectively). The primary endpoint of treatment-related grade 3 or 4 adverse events in the first 12 weeks occurred in 59% of patients treated with mFOLFOX6, compared with 36% of those receiving bFOL and 67% of patients who received CapeOx; with the addition of bevacizumab, grade 3 or 4 adverse event rates were 59%, 51%, and 56%, respectively. Overall response rate (ORR), a secondary endpoint, was 41% in patients treated with mFOLFOX6, compared with 20% in those who received bFOL and 27% in patients who received CapeOx; median time to progression (TTP) was 8.7 months vs. 6.9 months vs. 5.9 months, and median overall survival (OS) was 19.2 months vs. 17.9 months vs. 17.2 months, respectively. The addition of bevacizumab improved ORR to 52% vs. 39% vs. 46%, TTP to 9.9 months vs. 8.3 months vs. 10.3 months, and OS to 26.1 months vs. 20.4 months vs. 24.6 months, respectively.

    For the adjuvant treatment of colon cancer in combination with leucovorin (Mayo Clinic)†.
    Intravenous dosage
    Adults

    370 mg/m2 to 420 mg/m2 IV push on days 1, 2, 3, 4, and 5; precede 5-FU administration by leucovorin 20 mg/m2 to 25 mg/m2 IV push on days 1, 2, 3, 4, and 5. Repeat at week 4, week 8, and then every 5 weeks for a total of 6 courses of therapy. In a randomized clinical trial, patients with stage II or III colon cancer post-curative resection received treatment with weekly 5-FU either in combination with low dose leucovorin (Mayo Clinic regimen; n = 984), high dose leucovorin (Roswell Park regimen; n = 981), or levamisole (n = 871). There were no clinically significant differences in 10-year overall survival (OS) (52% vs. 52% vs. 50%) or 10-year disease-free survival (DFS) (49% vs. 47% vs. 45%). Grade 3 or 4 toxicities were reported in 55.6% of those who received the Mayo Clinic regimen, 40.3% of patients treated with Roswell Park, and 44.4% of patients treated with levamisole plus 5-FU. In a separate study, patients randomized to adjuvant treatment with the Mayo Clinic regimen (n = 158) had improved 5-year relapse-free survival (74% vs. 58%; p = 0.004) and 5-year OS (74% vs. 63%; p = 0.02).

    For the adjuvant treatment of colorectal cancer, in combination with leucovorin and oxaliplatin (mFOLFOX6)†.
    NOTE: Oxaliplatin is FDA approved for the adjuvant treatment of colorectal cancer in combination with 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 to 48h); on day 1, precede 5-FU bolus and infusion with leucovorin 400 mg/m2 IV administered concurrently but in separate bags via y-site over 2 hours with oxaliplatin 85 mg/m2 IV. This 2-day regimen (mFOLFOX6) is repeated every 2 weeks for 12 cycles (6 months). Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for 5-FU and leucovorin need not be changed. In a multicenter trial, 2,246 patients with stage II or III completely resected colon cancer were randomized to either FOLFOX4 or infusional 5-FU/LV (De Gramont regimen). At a median follow-up of 81.9 months in the patients with stage III disease, there was a significant improvement in 5-year disease-free survival (DFS) in patients receiving FOLFOX4 as compared to those receiving infusional 5-FU/LV (73.3% vs. 67.4%; HR 0.80; p = 0.003). The 6-year overall survival (OS) rates were also improved with FOLFOX4 (78.5% vs. 76%;HR 0.84; p = 0.46). In a subgroup analysis of stage III patients, the 6-year OS rates were improved with FOLFOX4 (72.9% vs. 68.7%; HR 0.80; p = 0.023). There was no significant difference observed in DFS or OS in patients with stage II disease. Administering 5-FU 2,400 mg/m2 over 46 to 48 hours (FOLFOX6) provides similar exposure to the daily bolus plus 22 hour 5-FU infusion in FOLFOX4, with increased patient convenience and is preferred.

    For the adjuvant treatment of colorectal cancer, in combination with leucovorin and oxaliplatin (FLOX)†.
    NOTE: Oxaliplatin is FDA approved for the adjuvant treatment of colorectal cancer in combination with 5-FU and leucovorin.
    Intravenous dosage
    Adults

    500 mg/m2 IV bolus on days 1, 8, 15, 22, 29, and 36, preceded on days 1, 15, and 29 by leucovorin 500 mg/m2 IV given concurrently via y-site over 2 hours with oxaliplatin 85 mg/m2 IV. On days 8, 22, and 36, give leucovorin 500 mg/m2 IV over 2 hours alone (without oxaliplatin) prior to 5-FU. The leucovorin infusion should be complete 1 hour prior to administration of 5-FU. Repeat every 8 weeks (56 days) for a total of 3 cycles (24 weeks). After a median 8 years of follow-up, patients with stage II or III colon cancer treated with FLOX (n = 1,247) had significantly improved disease-free survival (DFS) compared with those who received 5-FU/leucovorin alone (FULV; n = 1,245) (HR 0.82; 95% CI, 0.72 to 0.93; p = 0.002) in a randomized, phase III clinical trial. Overall survival was similar between treatment groups (HR 0.88; 95% CI, 0.75 to 1.02; p = 0.08); however, in an unplanned subgroup analysis, age < 70 years may be associated with improved survival (HR 0.8; 95% CI, 0.68 to 0.95; p = 0.013).

    For the first line treatment of metastatic colorectal cancer in combination with leucovorin, oxaliplatin, and panitumumab in patients with wild-type KRAS (exon 2 in codons 12 or 13) (FOLFOX4 plus panitumumab)†.
    NOTE: Panitumumab is FDA approved for the treatment of metastatic colorectal cancer in combination with FOLFOX chemotherapy, and oxaliplatin is FDA approved for advanced colorectal cancer in combination with infusional 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus over 2 to 4 minutes, followed by 5-FU 600 mg/m2 continuous IV infusion (CIV) over 22 hours on day 1. Prior to 5-FU bolus on day 1, administer panitumumab 6 mg/kg IV over 60 minutes (infuse doses greater than 1,000 mg over 90 minutes), followed by oxaliplatin 85 mg/m2 IV and leucovorin 200 mg/m2 IV, administered concurrently in separate bags via y-site over 2 hours. If the first panitumumab infusion is tolerated, subsequent doses of 1,000 mg or less may be infused over 30 to 60 minutes. On day 2, repeat leucovorin 200 mg/m2 IV over 2 hours followed by 5-FU 400 mg/m2 IV bolus, then 5-FU 600 mg/m2 CIV over 22 hours. The order of administration is panitumumab, followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label trial, patients with wild-type KRAS metastatic colorectal cancer who received panitumumab in combination with FOLFOX4 (n = 325) had improved progression-free survival (9.6 months vs. 8 months; p = 0.02) and overall response rate (54% vs. 47%) compared with FOLFOX4 alone (n = 331). An exploratory analysis estimated overall survival to be 23.3 months for combination therapy and 19.4 months with FOLFOX4 alone (HR 0.83; 95% CI, 0.7 to 0.98). In the same study, patients with KRAS mutation-positive tumors had decreased progression-free survival (7.3 months vs. 8.8 months; HR 1.29; 95% CI 1.04 to 1.62) and overall survival (15.5 months vs. 19.3 months; HR 1.24; 95% CI, 0.98 to 1.57) when panitumumab was combined with FOLFOX4, compared with FOLFOX4 alone.

    For the first line treatment of metastatic colorectal cancer in combination with leucovorin, oxaliplatin, and panitumumab in patients with wild-type KRAS (exon 2 in codons 12 or 13) (mFOLFOX6 plus panitumumab)†.
    NOTE: Panitumumab is FDA approved for the treatment of metastatic colorectal cancer in combination with FOLFOX chemotherapy, and oxaliplatin is FDA approved for advanced colorectal cancer in combination with infusional 5-FU and leucovorin.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 to 48 hours). Prior to 5-FU bolus on day 1, administer panitumumab 6 mg/kg IV over 60 minutes (infuse doses greater than 1,000 mg over 90 minutes), followed by oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV, administered concurrently in separate bags via y-site over 2 hours. If the first panitumumab infusion is tolerated, subsequent doses of 1,000 mg or less may be infused over 30 to 60 minutes. The order of administration is panitumumab, followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. In a randomized, multicenter, open-label phase II clinical trial, panitumumab plus mFOLFOX6 was compared to bevacizumab plus mFOLFOX6 in previously untreated patients with metastatic colorectal cancer (wild type KRAS exon 2). In patients with wild type KRAS (exon 2), the primary endpoint of median progression free survival (PFS) was not significantly improved with the addition of panitumumab to mFOLFOX6 compared with bevacizumab (10.9 months vs. 10.1 months; HR 0.87; p = 0.353). In combination with mFOLFOX6, treatment with panitumumab significantly improved the secondary endpoint of median overall survival (OS) compared with bevacizumab (34.2 months vs. 24.3 months; HR 0.62; p = 0.009); overall response rate (ORR) (57.8% vs. 53.5%) and resection rate (13% vs. 11%) were also improved with panitumumab. In a preplanned extended RAS analysis, panitumumab was associated with a significantly improved median PFS (13 months vs. 9.5 months; p = 0.029) and median OS (41.3 months vs. 28.9 months; p = 0.058) compared with bevacizumab in patients with wild type RAS; ORR was also improved (63.6% vs. 60.5%). Grade 3 or higher adverse events were reported in 91% of patients who received panitumumab and 83% of those treated with bevacizumab.

    For the first-line treatment of KRAS wild-type, EGFR-expressing metastatic colorectal cancer in combination with leucovorin and irinotecan, in combination with cetuximab (FOLFIRI plus cetuximab)†.
    NOTE: Cetuximab is FDA approved for the treatment of KRAS wild-type, EGRF-expressing metastatic colorectal cancer in combination with FOLFIRI.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2/day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 hours). Prior to 5-FU bolus on day 1, administer irinotecan 180 mg/m2 IV over 30 to 90 minutes, administered concomitantly but in separate bags with leucovorin 400 mg/m2 IV over 2 hours (FOLFIRI); repeat this 2-day regimen every 2 weeks until disease progression or unacceptable toxicity. Additionally, give cetuximab 400 mg/m2 IV over 2 hours on day 1 of cycle 1, followed by weekly infusions of cetuximab 250 mg/m2 IV over 1 hour until disease progression or unacceptable toxicity; the cetuximab infusion should not exceed a maximum rate of 10 mg/minute and should be completed 1 hour prior to FOLFIRI therapy. The order of infusion on day 1 of each 2 week cycle should be cetuximab, followed by leucovorin and irinotecan, followed by 5-FU. Alternatively, cetuximab 500 mg/m2 IV every 2 weeks has been administered in conjunction with irinotecan in the second-line setting for metastatic colorectal cancer; efficacy in the first-line setting compared with weekly dosing is not known. In a multicenter, randomized, phase III study (the CRYSTAL study), the primary endpoint of median progression-free survival (PFS) was significantly improved with cetuximab plus FOLFIRI (n = 599) compared with FOLFIRI alone (n = 599) (8.9 vs. 8 months; HR 0.851; p = 0.0479) as first-line treatment in unselected patients with metastatic colorectal cancer. In a retrospective subroup analysis, the addition of cetuximab to FOLFIRI was found to significantly improve the median PFS (9.9 vs 8.4 months; HR = 0.696; p = 0.0012) and overall survival (23.5 vs 20 months; HR = 0.796; p = 0.0093) in patients with KRAS wild type disease (n = 666); however, a benefit was not found in patients with KRAS-mutated disease (n = 397).

    For the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC), in combination with cetuximab, leucovorin, and oxaliplatin (mFOLFOX6 plus cetuximab)†.
    NOTE: Response rates to cetuximab do not correlate with either the percentage of EGFR-positive cells or the intensity of EGFR expression.
    Intravenous dosage
    Adults

    400 mg/m2 IV bolus on day 1, followed by 5-FU 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 to 48 hours). Prior to 5-FU bolus on day 1, administer oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV (concurrently over 120 minutes via Y-site) (mFOLFOX6). This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. Additionally, give cetuximab 400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on cycle 1, day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute); on day 1 of each 2-week cycle, begin oxaliplatin and leucovorin administration 1 hour after completion of cetuximab (order of administration on day 1 is cetuximab, followed by mFOLFOX6). First-line treatment with cetuximab plus modified FOLFOX (mFOLFOX) 4 or 6 significantly improved objective response rates (ORR) in patients with KRAS WT mCRC in two randomized clinical trials. The benefit to progression-free survival (PFS) was small to nonsignificant, and a benefit to overall survival (OS) was not demonstrated. Skin and gastrointestinal toxicities were increased in patients treated with cetuximab. Total exposure (AUC) to 5-FU was similar when administered as two 22-hour infusions of 600 mg/m2, as in FOLFOX4, or as a single 46-hour infusion of 2,400 mg/m2, as in mFOLFOX6 in a pharmacokinetic study.

    For the first line treatment of advanced colorectal cancer in combination with irinotecan and oxaliplatin-based chemotherapy (FOLFOXIRI)†.
    Intravenous dosage
    Adults

    1,600 mg/m2 per day on days 1 and 2 as a continuous IV infusion (CIV) over 48 hours (total dose 3,200 mg/m2). Prior to administration of 5-FU on day 1, give irinotecan 165 mg/m2 IV over 1 hour, followed by oxaliplatin 85 mg/m2 IV and levo-leucovorin 200 mg/m2 IV administered concurrently in separate bags via y-site over 2 hours (FOLFOXIRI). Repeat every 2 weeks for up to 12 cycles. The order of administration is irinotecan, followed by oxaliplatin plus leucovorin, followed by 5-FU. In a multicenter, randomized, phase III study of patients with unresectable metastatic colorectal cancer were treated with either FOLFOXIRI or FOLFIRI (n = 244). The primary end point of overall response rate (ORR), was significantly higher in patient who received FOLFOXIRI (60% vs. 34%; p < 0.0001). In addition, progression-free survival (PFS) (9.8 months vs. 6.9 months; p = 0.0006) and overall survival (22.6 months vs. 16.7 months; p = 0.032) were both significantly improved in patients who received FOLFOXIRI. Grade 3 and 4 neutropenia (50% vs. 28%; p < 0.001) and grade 2 and 3 peripheral neurotoxicity (19% vs. 0%; p < 0.001) were significantly worse in the FOLFOXIRI arm.

    For the treatment of gastric cancer.
    NOTE: Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    For the treatment of previously untreated patients with metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and trastuzumab†.
    Intravenous dosage
    Adults

    800 mg/m2/day continuous IV infusion on days 1—5 in combination with cisplatin (80 mg/m2 IV on day 1) and trastuzumab (8 mg/kg IV over 90 minutes on day 1, then 6 mg/kg IV over 30—90 minutes every 21 days from day 22); repeat cycles every 3 weeks. Chemotherapy should be continued up to a maximum of 6 cycles; trastuzumab should be continued until disease progression or unacceptable toxicity. In a phase III trial, 594 patients with inoperable, locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive cisplatin and 5-FU or capecitabine, with or without trastuzumab. Overall survival (13.5 months vs. 11 months, p = 0.0038), the primary endpoint, and objective response rate (47% vs. 35%, p = 0.0017) were significantly increased with the addition of trastuzumab. An updated survival analysis conducted 1-year after the final analysis showed a continued overall survival benefit in the trastuzumab arm (13.1 months vs. 11.7 months, HR 0.8, 95% CI 0.67, 0.97). In addition, a subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2 months, HR 0.66, 95% CI 0.5, 0.87) for the trastuzumab arm in patients with high expression of the HER2 protein (FISH-negative and IHC3 +; or, FISH-positive). Cardiac dysfunction (LVEF decrease >= 10% from baseline to an absolute value < 50%) occurred in 5% of patients who received trastuzumab vs. 1.1% of patients who did not receive trastuzumab.

    For the perioperative treatment of gastric cancer in combination with epirubicin and cisplatin†.
    Intravenous dosage
    Adults

    200 mg/m2/day CIVI on days 1—21 in combination with cisplatin 60 mg/m2 IV on day 1 and epirubicin 50 mg/m2 IV on day 1, repeated every 3 weeks (ECF regimen). Treatment should be given for 3 cycles before and 3 cycles after surgical resection. In a phase III clinical trial, surgery was performed 3—6 weeks after the third cycle of preoperative chemotherapy; postoperative chemotherapy was initiated 6—12 weeks after surgery. Overall survival and progression free survival were significantly improved in the ECF arm.

    Intravenous dosage
    Adults

    As a single agent, 5-FU 500 mg/m2 IV bolus days 1—5 every 28 days has shown response rates of 15—35%; however, it is most commonly used in combination with other chemotherapy agents. Common combination regimens include 5-FU 600 mg/m2 IV bolus on days 1, 8, 29, and 36 with doxorubicin and mitomycin every 8 weeks (FAM); 5-FU 1500 mg/m2 IV bolus (1 hour after methotrexate) on day 1 with doxorubicin, methotrexate, and leucovorin every 28 days (FAMTX); 5-FU 300 mg/m2 IV bolus on days 1—5 in combination with doxorubicin and cisplatin every 5 weeks (FAP); or 5-FU 500 mg/m2 IV bolus days 1—3 with etoposide and leucovorin every 21 days (ELF).

    For the treatment of breast cancer.
    NOTE: Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    For the treatment of breast cancer in patients with evidence of axillary node involvement following resection of the primary tumor in combination with cyclophosphamide and epirubicin.
    Intravenous dosage
    Adults

    500 mg/m2 IV on day 1 in combination with epirubicin (100 mg/m2 IV) and cyclophosphamide (500 mg/m2 IV) (FEC regimen) every 21 days for 6 cycles. Alternatively, FEC may be administered for 3 cycles, then followed by docetaxel (100 mg/m2 IV) given every 21 days for 3 cycles (FEC-D regimen). A phase III trial of 1944 patients with node-positive breast cancer compared the FEC-D regimen for 3 cycles to FEC for 6 cycles. The primary endpoint, 5-year disease-free survival, was significantly longer in the FEC-D arm (78.4% vs. 73.2%, p = 0.012). Overall survival at 5 years was also increased by FEC-D (90.7% vs. 86.7%, p = 0.017). Grade 3/4 neutropenia and the incidence of nausea/vomiting were higher with FEC, while stomatitis, edema, and nail changes were more common with FEC-D.

    For the neoadjuvant treatment of HER2-positive breast cancer with fluorouracil and cyclophosphamide (FEC regimen) in sequence, and in combination, with paclitaxel and trastuzumab†.
    Intravenous dosage
    Adults

    Fluorouracil 500 mg/m2 IV given in combination with epirubicin and cyclophosphamide (FEC regimen), plus trastuzumab, sequentially with paclitaxel and trastuzumab. Give trastuzumab 4 mg/kg IV on week 1 just prior to paclitaxel, then, starting on week 2, trastuzumab 2 mg/kg IV once weekly for 23 weeks. Trastuzumab is given concomitantly with paclitaxel (225 mg/m2 IV continuous infusion over 24 hours on day 1) every 3 weeks for 4 cycles, followed by fluorouracil (500 mg/m2 IV on day 1), epirubicin (75 mg/m2 IV on day 1), and cyclophosphamide (500 mg/m2 IV on day 1) every 3 weeks for 4 cycles. Alternately, in a retrospective trial, paclitaxel 80 mg/m2 IV weekly for 12 weeks was substituted for every 3 week dosing in the above regimen.

    For the treatment of metastatic breast cancer in combination with epirubicin and cyclophosphamide.
    Intravenous dosage
    Adults

    400 mg/m2 IV on days 1 and 8 in combination with epirubicin 50 mg/m2 IV on days 1 and 8, plus cyclophosphamide 500 mg/m2 IV on days 1 and 8, every 3—4 weeks depending on patient recovery. In a phase III clinical trial, treatment was planned for 6 cycles, but was given up to 9 cycles in patients with a partial or complete response.

    For the adjuvant treatment of early breast cancer, in combination with methotrexate and cyclophosphamide (CMF)†.
    Intravenous dosage
    Adults

    600 mg/m2 IV plus methotrexate 40 mg/m2 IV on days 1 and 8, in combination with cyclophosphamide 100 mg/m2 by mouth on days 1 through 14, repeated every 28 days for 6 cycles.

    Intravenous dosage
    Adults

    A variety of different dosing schemes have been used, including 5-FU 300 mg/m2/day IV bolus for 5 days in combination with cyclophosphamide and prednisone (CFP). In combination with cyclophosphamide and doxorubicin, 5-FU 500 mg/m2 IV bolus on days 1 and 8 is given every 21 to 28 days (CAF). Less commonly, 5-FU as a single agent is given for 5 consecutive days at a dose of 300 to 400 mg/m2/day IV bolus every 3 to 6 weeks.

    For the treatment of actinic keratosis (solar keratosis).
    Topical dosage (Efudex or Fluoroplex cream or topical solution)
    Adults

    Apply sufficient topical solution or cream to cover affected area; apply twice daily. The 1% preparations are usually used on the head, neck, and chest; the 2% and 5% preparations are used on the hands. A treatment period of at least 2—6 weeks is usually required. Increasing the frequency of application and longer period of administration may be required on areas other than the head and neck. Complete healing of the lesions may not be evident for 1—2 months following completion of therapy. Close follow-up is recommended.

    Topical dosage (Carac cream)
    Adults

    Apply enough cream to cover lesions on face or anterior scalp once daily. Apply at least 10 minutes after thoroughly washing, rinsing, and drying the entire area. May be applied with fingertips, but immediately wash hands after applying. Therapy should continue up to 4 weeks, as tolerated. Continued treatment up to 4 weeks results in greater lesion reduction. In patients treated for 1 week, 74% of the lesions disappeared, with 2 weeks of treatment, the clearance rate is 85%, and following 4 weeks of treatment the clearance rate increased to 90%.

    Topical dosage (Tolak cream)
    Adults

    Apply enough cream to cover lesions on face, ears, and/or scalp once daily with a thin film. Apply after thoroughly washing, rinsing, and drying the entire area. May be applied with fingertips to gently massage the medication uniformly into the skin, but immediately wash hands after applying. Therapy should continue up to 4 weeks, as tolerated.

    For the treatment of superficial basal cell carcinoma.
    Topical dosage (5% cream or topical solution only)
    Adults

    Apply fluorouracil 5% cream or solution twice daily; use a sufficient amount to cover the lesions. Continue treatment for at least 3 to 6 weeks; complete resolution of lesions may take up to 10 to 12 weeks. In an analysis of 54 patients with a total of 113 superficial basal cell carcinoma lesions, approximately 93% of lesions resolved following treatment with fluorouracil 5% cream or solution. There was 1 failure in 25 lesions treated with fluorouracil 5% solution and 7 failures in 88 lesions treated with fluorouracil 5% cream.

    For the treatment of anal cancer†.
    For the treatment of anal cancer in combination with mitomycin and radiation therapy.
    Intravenous dosage
    Adults

    1000 mg/m2/day continuous IV for 4 days on days 1—4 and 29—32 in combination with mitomycin (10 mg/m2 IV bolus on days 1 and 29) and radiation therapy has been studied. A smaller phase III study has also considered 5-FU 750 mg/m2 IV continuous infusion over 4 days on days 1—4 and 29—32 in combination with mitomycin (15 mg/m2 IV on day 1) and radiotherapy in patients with locally advanced anal cancer.

    For the treatment of anal cancer in combination with cisplatin and radiation therapy.
    Intravenous dosage
    Adults

    Multiple dosage regimens have been studied. 5-fluorouracil (5-FU) 750 mg/m2/day continuous IV infusion (CIVI) on days 1—4 in combination with cisplatin (100 mg/m2 IV on day 1), repeated every 21 days for 2—3 cycles has been given with concomitant radiation (XRT). Alternately, 5-FU 1000 mg/m2/day has been given as a CIVI on days 1—4 in combination with cisplatin 75 mg/m2 IV over 60 minutes on day 1, repeated every 28 days for 4 cycles.

    For the treatment of pancreatic cancer†.
    NOTE: Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    For the treatment of pancreatic cancer in combination with other chemotherapy agents.
    Intravenous dosage
    Adults

    Common regimens include 5-FU 600 mg/m2 IV bolus on days 1, 8, 29, and 36 with doxorubicin and mitomycin every 8 weeks (FAM) or 5-FU 600 mg/m2 IV bolus on days 1, 8, 29, and 36 with streptozocin and mitomycin.

    For the second-line treatment of gemcitabine-refractory advanced pancreatic cancer in combination with oxaliplatin†.
    Intravenous dosage
    Adults

    5-fluorouracil 2 g/m2 IV over 24 hours on days 1, 8, 15, and 22 and leucovorin (200 mg/m2 IV over 30 minutes on days 1, 8, 15, and 22) in combination with oxaliplatin (85 mg/m2 IV on days 8 and 22), every 42 days until disease progression or unacceptable toxicity. In a phase III trial, 160 patients with pancreatic cancer that progressed while receiving gemcitabine, were randomized to receive 5-fluorouracil and leucovorin with or without oxaliplatin (OFF vs. FF). Overall survival, the primary endpoint, was significantly longer in patients receiving oxaliplatin (26 weeks vs. 13 weeks, p = 0.014). Neurologic toxicity and leukopenia occurred more frequently in the oxaliplatin arm. Initially, this clinical trial randomized patients to receive OFF plus best supportive care (BSC) or BSC alone. Due to the rejection of BSC as an acceptable second-line treatment modality and subsequent poor accrual, the study was amended after the recruitment of 46 patients to OFF vs. FF. Final analysis of OFF vs. BSC revealed a significant improvement in OS (4.83 months vs. 2.3 months, p = 0.008).

    For the first-line treatment of metastatic pancreatic cancer† in combination with oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX).
    Intravenous dosage
    Adults

    Oxaliplatin 85 mg/m2 IV over 2 hours, immediately followed by leucovorin 400 mg/m2 IV over 2 hours, and 30 minutes after the start of the leucovorin infusion, add irinotecan 180 mg/m2 IV over 90 minutes through a Y-connector, which was immediately followed by fluorouracil 400 mg/m2 IV bolus and a continuous infusion of fluorouracil 2,400 mg/m2 over 46 hours (FOLFIRINOX). The regimen was repeated every 2 weeks for a period of 6 months in patients who exhibited a response.

    For the treatment of head and neck cancer†.
    NOTE: Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    For the treatment of advanced or recurrent head and neck cancer in combination with cisplatin†.
    Intravenous dosage
    Adults

    1000 mg/m2/day continuous IV infusion on days 1—4 in combination with cisplatin (100 mg/m2 IV on day 1), repeated every 3 weeks has been studied. No difference in overall survival was seen when compared to cisplatin and paclitaxel.

    For the treatment of advanced nasopharyngeal head and neck cancer in combination with cisplatin and radiotherapy†.
    Intravenous dosage
    Adults

    1000 mg/m2/day IV over 4 days on days 71—74, 99—102, and 127—130 in combination with cisplatin (80 mg/m2 IV on days 71, 99, and 127); this regimen is preceded by cisplatin (100 mg/m2 IV over 15—20 minutes on days 1, 22, and 43) given concurrently with radiation therapy (RT). In a phase III trial of 147 patients with advanced nasopharyngeal cancer, chemoradiotherapy significantly improved 3-year progression-free (69% vs. 24%, p < 0.001) and overall survival (76% vs. 46%, p < 0.001) rates versus RT alone.

    For induction treatment of inoperable locally advanced squamous cell head and neck cancer in combination with docetaxel and cisplatin†.
    NOTE: Docetaxel is FDA-approved for this indication.
    Intravenous dosage
    Adults

    750 mg/m2/day continuous IV infusion for 1—5 days in combination with cisplatin (75 mg/m2 IV over 1 hour) on day 1 immediately before docetaxel (75 mg/m2 IV over 1 hour) on day 1; this regimen is given every 3 weeks for 4 cycles. After completion of chemotherapy, patients should receive radiation therapy. All patients must receive prophylaxis for neutropenic infections, premedication with antiemetics, and appropriate hydration (before and after cisplatin administration). During clinical trials, colony-stimulating factors were recommended during the second and/or subsequent cycles for prophylaxis of febrile neutropenia, documented infections with neutropenia, or neutropenia lasting > 7 days. In a randomized trial of 358 patients with inoperable, locally advanced squamous head and neck cancer, patients were treated with the FDA-approved regimen of docetaxel/cisplatin/5-FU or cisplatin (100 mg/m2 IV day 1) and 5-FU (1000 mg/m2/day continuous IV infusion for 5 days) every 3 weeks for 4 cycles. Progression-free survival (PFS), the primary end-point of the study, was significantly longer in the docetaxel/cisplatin/5-FU arm as compared to the cisplatin/5-FU (median PFS, 11.4 months vs. 8.3 months, respectively) with a median follow-up of 33.7 months. With a follow-up of 51.2 months, the median overall survival also favored patients treated with docetaxel/cisplatin/5-FU as compared to those treated with cisplatin/5-FU (18.6 months vs. 14.2 months, respectively).

    For induction treatment of locally advanced squamous cell head and neck cancer in combination with docetaxel and cisplatin for unresectable disease, low surgical cure, or organ preservation†.
    NOTE: Docetaxel is FDA-approved for this indication.
    NOTE: Survival was significantly improved among patients who got the 3 drugs (see Dosage below) as compared with receipt of only cisplatin 100 mg/m2 IV on day 1 and 5- fluorouracil 1000 mg/m2/day by continuous IV infusion for 5 days. Specifically, the relative risk of death was 30% lower. Also, the median overall survival was 70.6 months as compared with 30.1 months for patients receiving only cisplatin and 5-fluorouracil. Three to 8 weeks after the start of the last cycle, all patients in both treatment arms who did not have progressive disease got carboplatin (AUC 1.5 weekly for 7 doses) and radiation therapy (2 Gy per day, 5 days per week for 7 weeks) followed by surgery, if appropriate.
    Intravenous dosage
    Adults

    1000 mg/m2/day continuous IV infusion on days 1—4 in combination with cisplatin (100 mg/m2 IV over 1 hour) on day 1 immediately before docetaxel (75 mg/m2 IV over 30 minutes to 3 hours) on day 1; this regimen is given every 3 weeks for 3 cycles. After completion of chemotherapy, patients should receive chemoradiotherapy. All patients must receive prophylaxis for neutropenic infections, premedication with antiemetics, and appropriate hydration (before and after cisplatin administration).

    For the treatment of advanced-stage squamous cell carcinoma of the head and neck in combination with carboplatin and radiation therapy†.
    Intravenous dosage
    Adults

    5-fluorouracil (5-FU) 600 mg/m2/day continuous IV infusion on days 1—4 in combination with carboplatin (70 mg/m2/day IV on days 1—4). Chemotherapy cycles were started on days 1, 22, and 43 and were administered concurrently with radiotherapy (RT). In a phase III trial, 226 patients with stage III or IV squamous cell carcinoma of the oropharynx (no evidence of distant metastasis) were randomized to receive radiotherapy alone or concomitantly with carboplatin/5-FU. Overall survival at 5 years was significantly improved in the chemoradiotherapy arm (22.4% vs. 15.8%, p = 0.05). The 5-year specific disease free survival rate (26.6% vs. 14.6%, p = 0.01) and locoregional control rate (47.6% vs. 24.7%, p = 0.002) were also significantly improved with chemoradiotherapy. Hematologic and skin toxicities were more common in chemoradiotherapy arm. In addition, grades 3 and 4 mucositis and poor nutritional status occurred more frequently with concomitant therapy. There were no significant differences in late toxic effects between the arms when assessed at 5 years.

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with carboplatin†.
    Intravenous dosage
    Adults

    5-fluorouracil (5-FU) 1000 mg/m2/day continuous IV infusion over 96 hours on days 1—4 in combination with carboplatin (300 mg/m2 IV day 1); repeated every 4 weeks. In a phase III trial, 277 patients were randomized to receive carboplatin/5-FU, cisplatin/5-FU, or methotrexate (MTX). An increase in overall response rate was achieved with carboplatin/5-FU versus MTX, which was of borderline statistical significance (21% vs. 10%, p = 0.05). The overall response rate was numerically lower with carboplatin/5-FU compared to cisplatin/5-FU (21% vs. 32%).

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck cancer in combination with carboplatin and cetuximab†.
    Intravenous dosage
    Adults

    1000 mg/m2/day IV infusion over days 1—4 in combination with carboplatin (AUC 5 IV on day 1) and cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8); regimen was repeated every 3 weeks for 6 cycles. In a phase III trial, 442 patients were randomized to receive platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab. Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab (10.1 months vs. 7.4 months, p = 0.04). Sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck cancer in combination with cisplatin and cetuximab†.
    Intravenous dosage
    Adults

    1000 mg/m2/day IV infusion over days 1—4 in combination with cisplatin (100 mg/m2 on day 1) and cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8); regimen was repeated every 3 weeks for 6 cycles. In a phase III trial, 442 patients were randomized to receive platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab. Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab (10.1 months vs. 7.4 months, p = 0.04). Sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: The suggested maximum tolerated dose (MTD) for systemic fluorouracil is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. The optimal dose or infusion duration of fluorouracil alone or in combination has not been determined. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    Adults

    The manufacturer recommends a maximum 5-FU dose of 800 mg/day IV; however, higher doses as are routinely given. Intravenous bolus doses of 20—25 mg/kg generally result in severe toxicity or fatalities due to hemorrhagic colitis or bone marrow suppression. By continuous infusion, higher daily doses (i.e., 1—2 g/day) have been given successfully with less hematologic toxicity. Maximum doses are not available for topical products.

    Geriatric

    The manufacturer recommends a maximum 5-FU dose of 800 mg/day IV; however, higher doses as are routinely given. Intravenous bolus doses of 20—25 mg/kg generally result in severe toxicity or fatalities due to hemorrhagic colitis or bone marrow suppression. By continuous infusion, higher daily doses (i.e., 1—2 g/day) have been given successfully with less hematologic toxicity. Maximum doses are not available for topical products.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    5-FU has been administered to patients with hepatic insufficiency without dose reduction; however, it has been recommended to avoid the use of fluorouracil in patients with elevated serum bilirubin > 5 mg/dL.

    Renal Impairment

    It does not appear that the dosage of fluorouracil, 5-FU, needs to be adjusted in normal patients with renal impairment. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency and renal impairment may require a dosage reduction of 5-FU.

    ADMINISTRATION

    Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter prior to administration whenever solution and container permit.

    Intravenous Administration

    Dosage should be based upon body surface area using actual body weight unless patient is obese or has significant fluid retention. In these cases the dose should be based upon the ideal weight or dry weight.
    No dilution necessary. Pharmacy bulk packages are for preparation of individual doses and should not be used for direct IV infusion; after vial has been entered, any unused portion should be discarded after 1 hour.
    The solution may discolor during storage but this does not affect potency.
     
    Intravenous injection:
    Administer by direct IV push through a 25-gauge needle at any convenient rate.
    Dilution is not required. Protect from light.
    Care should be taken to avoid extravasation.
     
    Intravenous infusion:
    May be diluted in 0.9% Sodium Chloride injection or 5% Dextrose injection. Protect from light.
    When diluted in 0.9% Sodium Chloride injection or 5% Dextrose injection to a concentration of 1.5 mg/mL in either glass or polyvinyl chloride containers fluorouracil is stable for 8 weeks at room temperature. In ethylene vinyl chloride pumps, fluorouracil 10 mg/mL in 0.9% Sodium Chloride injection or 5% Dextrose injection is stable for 28 days at 4 to 35 degrees C.

    Topical Administration

    Fluorouracil cream or solution is for topical use only; it is NOT for ophthalmic, oral, or intravaginal use.
    Do NOT apply to the eyelids, nose, or mouth because irritation may occur.
    Apply cream or solution with a nonmetallic applicator or using gloves.
    If unprotected fingers are used to apply fluorouracil, the hands should be washed immediately afterward.
    A porous gauze dressing may be applied; do NOT use an occlusive dressing.

    STORAGE

    Adrucil:
    - Discard unused portion 4 hours after initial entry of container
    - Do not freeze
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Carac:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Efudex:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Fluoroplex:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    Tolak:
    - Do not freeze
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Requires a specialized care setting, requires an experienced clinician

    Systemic therapy with fluorouracil, 5-FU therapy requires an experienced clinician. Fluorouracil, 5-FU injection should be given only by or under the supervision of a qualified clinician who is experienced in cancer chemotherapy and intra-arterial therapy and is well versed in the use of potent antimetabolites and the potential for adverse reactions due to these effects. Systemic administration of fluorouracil, 5-FU requires a specialized care setting and patients should be hospitalized at least during the initial course of therapy because of the possibility of severe toxic reactions.

    Bleeding, bone marrow suppression, infection, leukopenia, radiation therapy, thrombocytopenia

    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.

    Diarrhea, GI bleeding, malnutrition, stomatitis, vomiting

    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. 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.

    Dihydropyrimidine dehydrogenase (DPD) deficiency, renal impairment

    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. 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.

    Biliary tract disease, hepatic disease, jaundice

    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. 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.

    Accidental exposure, ocular exposure

    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. 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.

    Occlusive dressing, skin abrasion

    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.

    Sunlight (UV) exposure

    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.

    Pregnancy

    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). 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. 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.

    Breast-feeding

    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.

    Intrathecal administration

    Intrathecal administration of fluorouracil, 5-FU, is not recommended because of severe neurotoxicity associated with intrathecal exposure to 5-FU.

    Vaccination

    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.

    Dental disease, dental work

    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.

    Children

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

    ADVERSE REACTIONS

    Severe

    peptic ulcer / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    acute cerebellar syndrome / Early / Incidence not known
    thromboembolism / Delayed / Incidence not known
    coronary vasospasm / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    erythema / Early / 89.4-99.0
    edema / Delayed / 14.1-69.0
    skin erosion / Delayed / 24.7-68.0
    esophagitis / Delayed / 10.0
    oral ulceration / Delayed / 10.0
    stomatitis / Delayed / 10.0
    leukopenia / Delayed / 10.0
    bleeding / Early / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    palpitations / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    angina / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    confusion / Early / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    xerosis / Delayed / 69.0-95.0
    pruritus / Rapid / 85.0-85.0
    lacrimation / Early / 3.4-5.9
    ocular pain / Early / 3.4-5.9
    ocular irritation / Rapid / 3.4-5.9
    ocular pruritus / Rapid / 0-5.4
    infection / Delayed / 0-4.7
    sinusitis / Delayed / 0-4.7
    headache / Early / 0-3.1
    skin irritation / Early / 0-2.4
    nausea / Early / 10.0
    vomiting / Early / 10.0
    anorexia / Delayed / 10.0
    pharyngitis / Delayed / 10.0
    diarrhea / Early / 10.0
    epistaxis / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    nail discoloration / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    telangiectasia / Delayed / Incidence not known
    ichthyosis / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    insomnia / Early / Incidence not known
    irritability / Delayed / Incidence not known
    nasal irritation / Early / Incidence not known

    DRUG INTERACTIONS

    Allopurinol: (Minor) Allopurinol may interfere with the activation of fluorouracil, 5-FU, and decrease the effectiveness of 5-FU.
    Anticoagulants: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Antithrombin III: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apixaban: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Argatroban: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Azathioprine: (Minor) Additive immunosuppressant affects may be seen when azathioprine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Basiliximab: (Minor) Additive immunosuppressant affects may be seen when basiliximab is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Betrixaban: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Fluorouracil, 5-FU is an inhibitor of CYP2C9 isoenzymes. The inhibition of CYP2C9 appears to be greater after higher total doses of fluorouracil are administered. Fluorouracil, 5-FU may significantly inhibit CYP2C9-mediated metabolism of bosentan. Monitor for potential adverse effects of bosentan during coadministration; excessive dosage may result in hypotension or elevated hepatic enzymes.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Celecoxib: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cimetidine: (Minor) Chronic administration of cimetidine with fluorouracil, 5-FU, can increase 5-FU serum concentrations, but it is not clear if this interaction results in increased 5-FU efficacy or toxicity. Patients receiving either 5-FU should be monitored for a possible increased response to 5-FU if cimetidine is used concurrently.
    Cisplatin: (Minor) A synergistic reaction between cisplatin and fluorouracil, 5-FU, etoposide, and radiation therapy may occur. Enhanced formation of the FdUMP-thymidylate complex resulting in increased cytotoxicity has been reported when cisplatin and fluorouracil are given together.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cyclosporine: (Minor) Additive immunosuppressant affects may be seen when cyclosporine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Dabigatran: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Dalteparin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Danaparoid: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Dapsone: (Major) Agranulocytosis has been reported in the second to third month of weekly concomitant treatment with dapsone and other hemolytic agents such as fluorouracil. These combinations increase the likelihood of adverse hematologic events.
    Desirudin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Diclofenac: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with fluorouracil, 5-FU is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; 5-FU is a moderate inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Efalizumab: (Minor) Concurrent use of efalizumab with other agents which cause bone marrow or immune suppression such as antineoplastic agents may result in additive effects. Dosage reductions may be required.
    Enoxaparin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Ethotoin: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
    Etodolac: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Folic Acid, Vitamin B9: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Fondaparinux: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with fluorouracil, 5-FU. Fluorouracil is an inhibitor of CYP2C9, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluorouracil, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosphenytoin: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluorouracil, 5-FU. Monitor serum glucose concentrations if glimepiride is coadministered with fluorouracil, 5-FU. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluorouracil, 5-FU. Monitor serum glucose concentrations if glimepiride is coadministered with fluorouracil, 5-FU. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluorouracil, 5-FU. Monitor serum glucose concentrations if glimepiride is coadministered with fluorouracil, 5-FU. Dosage adjustments may be necessary.
    Heparin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hydantoins: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydroxyurea: (Minor) High levels of deoxyuridine monophosphate have been associated with resistance to fluorouracil, 5-FU. Hydroxyurea may inhibit the formation of dUMP and lead to increased efficacy of 5-FU when administered after 5-FU.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Interferon Alfa-2a: (Minor) Interferon alfa-2a has been studied extensively in clinical trials with systemic fluorouracil, 5-FU. It has been shown in vitro that the addition of alfa interferon to 5-FU increases single-strand and double-strand DNA breaks and increases natural killer cell-mediated cytotoxicity. However, in clinical trials the addition of alfa interferons to 5-FU therapy resulted in an increased incidence of adverse effects with no increase in response rate versus 5-FU alone.
    Interferon Alfa-2b: (Minor) Interferon alfa-2b has been studied extensively in clinical trials with systemic fluorouracil, 5-FU. It has been shown in vitro that the addition of alfa interferon to 5-FU increases single-strand and double-strand DNA breaks and increases natural killer cell-mediated cytotoxicity. However, in clinical trials the addition of alfa interferons to 5-FU therapy resulted in an increased incidence of adverse effects with no increase in response rate versus 5-FU alone.
    Interferon Alfa-2b; Ribavirin: (Minor) Interferon alfa-2b has been studied extensively in clinical trials with systemic fluorouracil, 5-FU. It has been shown in vitro that the addition of alfa interferon to 5-FU increases single-strand and double-strand DNA breaks and increases natural killer cell-mediated cytotoxicity. However, in clinical trials the addition of alfa interferons to 5-FU therapy resulted in an increased incidence of adverse effects with no increase in response rate versus 5-FU alone.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lamotrigine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering fluorouracil, 5-FU, which may inhibit this enzyme.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Lesinurad: (Moderate) Use lesinurad and fluorouracil, 5-FU together with caution; fluorouracil may increase the systemic exposure of lesinurad. Fluorouracil is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and fluorouracil, 5-FU together with caution; fluorouracil may increase the systemic exposure of lesinurad. Fluorouracil is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. (Minor) Allopurinol may interfere with the activation of fluorouracil, 5-FU, and decrease the effectiveness of 5-FU.
    Leucovorin: (Major) Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. The dosage of 5-FU must be decreased when given in combination with leucovorin. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. A similar interaction is anticipated with levoleucovorin.
    Levoleucovorin: (Major) Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. The dosage of 5-FU must be decreased when given in combination with leucovorin. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. A similar interaction is anticipated with levoleucovorin.
    Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methotrexate: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Thus, the scheduling of these agents in combination is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
    Metronidazole: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, has been reported in a limited number of patients during concurrent treatment with metronidazole. This toxicity occurred without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil.
    Nabumetone: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Neomycin: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of fluorouracil, 5-FU. Caution is warranted with concomitant use.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Phenytoin: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
    Piroxicam: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Pyrimethamine: (Major) Pyrimethamine should be used cautiously with other folate antagonists, such as fluorouracil, 5-FU, or agents that cause bone marrow suppression because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. CBCs should be monitored routinely in patients receiving both drugs simultaneously.
    Pyrimethamine; Sulfadoxine: (Major) Pyrimethamine should be used cautiously with other folate antagonists, such as fluorouracil, 5-FU, or agents that cause bone marrow suppression because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. CBCs should be monitored routinely in patients receiving both drugs simultaneously.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as fluorouracil, may lead to increases in the serum concentrations of ramelteon.
    Rivaroxaban: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sorafenib: (Minor) Both increases (21%-47%) and decreases (10%) in the AUC of fluorouracil, 5-FU were observed with concomitant treatment with sorafenib. The clinical relevance of this interactions is not known.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Use of other folate antagonists should be avoided during therapy with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Hematologic toxicity, such as leukopenia and/or thrombocytopenia, can be increased by concurrent use of fluorouracil, 5-FU or other bone marrow depressants. (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of fluorouracil, 5-FU.
    Sulindac: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tamoxifen: (Moderate) Fluorouracil, 5-FU is a CYP2C9 inhibitor. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a lesser extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). By inhibiting CYP2C9, fluorouracil may decrease the concentrations of the active metabolites of tamoxifen. Theoretically, concomitant use of fluorouracil and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Additionally, there is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering fluorouracil, 5-FU. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; fluorouracil is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tinidazole: (Minor) Enhancement of toxicity of fluorouracil, 5-FU, may occur during concurrent treatment with tinidazole. This toxicity may occur without an increase in efficacy of fluorouracil. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. This interaction is believed to occur through reduced clearance of fluorouracil. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities.
    Tinzaparin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Tolmetin: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Trimethoprim: (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of fluorouracil, 5-FU.
    Trimetrexate: (Major) Additive antifolate effects may be seen with concomitant treatment with trimetrexate and fluorouracil, 5-FU.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Warfarin: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.

    PREGNANCY AND LACTATION

    Pregnancy

    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). 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. 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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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. 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.

    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. 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. 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.

    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.