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    Fluorouracil, 5-FU

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    Mar.25.2024

    Fluorouracil, 5-FU

    Indications/Dosage

    Labeled

    • actinic keratosis
    • basal cell carcinoma
    • breast cancer
    • colorectal cancer
    • gastric cancer
    • pancreatic cancer

    Off-Label

    • anal cancer
    • esophageal cancer
    • head and neck cancer
    • verruca plantaris
    • verruca vulgaris
    † Off-label indication

    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 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.[26301]

    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.[47421] 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).[47418]

    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.[47421] 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).[59866]

    for the adjuvant treatment of colorectal cancer, in combination with leucovorin and oxaliplatin (FLOX)†

    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).[59877][59899]

    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)†

    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.[41958] [40864] [20587]

    for the adjuvant treatment of colorectal cancer, in combination with leucovorin and oxaliplatin (mFOLFOX6)†

    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.[40864] [20587] 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.[59867]

    for the treatment of metastatic colorectal cancer in combination with leucovorin, irinotecan, and bevacizumab (IFL plus bevacizumab)†

    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.[28177] [59718] [30469] However, IFL has been shown to have increased mortality compared with FOLFIRI in one trial, and is inferior to FOLFOX in another.[41656] [41658] [60896]

    for the treatment of metastatic colorectal cancer in combination with irinotecan and leucovorin, with or without bevacizumab (FOLFIRI with or without bevacizumab)†

    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.[41656] 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.[35395] 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.[30469]

    for the treatment of advanced colorectal cancer in combination with leucovorin (LV) and oxaliplatin with or without bevacizumab (FOLFOX4 with or without bevacizumab)†

    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).[41958] 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).[28177] [47412] The significance of the effect of bevacizumab on OS is not consistent across clinical trials.[41609]

    for the treatment of metastatic colorectal cancer in combination with leucovorin and oxaliplatin, with or without bevacizumab (mFOLFOX6 with or without bevacizumab)†

    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.[47464] [59895]

    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.[46110]

    for the first-line treatment of KRAS wild-type, EGFR-expressing metastatic colorectal cancer in combination with leucovorin, irinotecan, and cetuximab (FOLFIRI plus cetuximab)†

    Intravenous dosage

    Adults

    400 mg/m2 IV bolus followed by fluorouracil 1,200 mg/m2 per day by continuous IV infusion on days 1 and 2 (total infusional dose, 2,400 mg/m2). Prior to fluorouracil administration on day 1, administer irinotecan (180 mg/m2) concomitantly but in separate bags with leucovorin (400 mg/m2 IV) (FOLFIRI); repeat this 2-day regimen every 2 weeks until disease progression or unacceptable toxicity. Administer FOLFIRI in combination with cetuximab (400 mg/m2 IV on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks). Complete cetuximab administration 1 hour prior to chemotherapy and continue until disease progression or unacceptable toxicity.[51181] In a multicenter, randomized, phase 3 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) as first-line treatment in unselected patients with metastatic colorectal cancer. In a retrospective subgroup analysis, the addition of cetuximab to FOLFIRI was found to significantly improve the median PFS (9.9 vs 8.4 months) and overall survival (23.5 vs 20 months) in patients with KRAS wild type disease (n = 666); however, a benefit was not found in patients with KRAS-mutated disease (n = 397).[51189]

    for the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC), in combination with cetuximab, leucovorin, and oxaliplatin (mFOLFOX6 plus cetuximab)†

    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.[60036] [60037] [60038] 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.[59867]

    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)†

    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.[50100] [59908]

    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)†

    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.[59907]

    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.[27182] [35630] 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.[21310]

    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).[35720] 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.[45529]

    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.

    Intravenous dosage

    Adults

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

    for the perioperative treatment of gastric cancer in combination with epirubicin and cisplatin†

    Intravenous dosage

    Adults

    200 mg/m2 per day continuous IV infusion on days 1 through 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 3 clinical trial, surgery was performed 3 to 6 weeks after the third cycle of preoperative chemotherapy; postoperative chemotherapy was initiated 6 to 12 weeks after surgery. Overall survival and progression free survival were significantly improved in the ECF arm.[34867]

    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 per day continuous IV infusion on days 1 through 5 in combination with cisplatin (80 mg/m2 IV on day 1) and trastuzumab (8 mg/kg IV on day 1, then 6 mg/kg IV every 21 days beginning on 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 3 trial, 594 patients with inoperable, locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive cisplatin and fluorouracil or capecitabine, with or without trastuzumab. Overall survival (13.5 months vs. 11 months), the primary endpoint, and objective response rate (47% vs. 35%) 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). In addition, a subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2 months) 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% or more from baseline to an absolute value less than 50%) occurred in 5% of patients who received trastuzumab vs. 1.1% of patients who did not receive trastuzumab.[36110] [41715] [28061]

    for the first-line treatment of HER2-positive, PD-L1 positive (combined positive score [CPS] 1 or higher), locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with trastuzumab, pembrolizumab, and cisplatin†

    Intravenous dosage

    Adults

    800 mg/m2 per day by continuous IV infusion on days 1 to 5 every 3 weeks. Administer in combination with cisplatin (80 mg/m2 IV every 3 weeks for up to 6 cycles), pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), and trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles). In the clinical trial, treatment with fluorouracil could continue after completion of 6 cycles of cisplatin, per protocol. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (ORR) (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in the overall population of patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). In a prespecified subgroup analysis, the ORR in patients with PD-L1 positive disease was 76% in the pembrolizumab arm versus 51% in the control arm; in patients who were PD-L1 negative, the ORR was 63% versus 58%, respectively. In a subsequent interim analysis, the hazard ratios for progression-free survival and overall survival were nonsignificant in patients with PD-L1 negative disease.[69837] [57889] [66655]

    for the treatment of advanced or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with nivolumab, oxaliplatin, and leucovorin (mFOLFOX6)†

    Intravenous dosage

    Adults

    400 mg/m2 IV bolus on day 1 following leucovorin, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion every 2 weeks until disease progression or unacceptable toxicity. Administer following administration of oxaliplatin (85 mg/m2 IV on day 1) infused concurrently but in separate bags via Y-site with leucovorin (400 mg/m2 IV on day 1) and nivolumab (240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression).[40864] [20587] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]

    for the treatment of pancreatic cancer

    for the treatment of pancreatic cancer in combination with other chemotherapy agents

    Intravenous dosage

    Adults

    The FDA-approved dose of 5-fluorouracil for the treatment of pancreatic cancer is 400 mg/m2 IV bolus on day 1, followed by 2,400 mg/m2 continuous IV infusion over 46 hours, every 2 weeks in combination with leucovorin or as a component of a multidrug chemotherapy regimen. Refer to individual treatment protocols for specific dose recommendations.[63817]

    for the adjuvant treatment of pancreatic cancer, in combination with leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX)†

    Intravenous dosage

    Adults

    Oxaliplatin 85 mg/m2 IV over 2 hours on day 1, immediately followed by leucovorin 400 mg/m2 IV over 2 hours; begin irinotecan 150 mg/m2 IV over 90 minutes 30 minutes after the leucovorin infusion is started, followed by 5-fluorouracil 2,400 mg/m2 IV continuously over 46 hours. Repeat every 14 days for 12 cycles. In a randomized phase 3 trial, adjuvant treatment with mFOLFIRINOX significantly increased both progression-free survival (PFS) and overall survival (OS) compared with gemcitabine monotherapy in patients with pancreatic cancer. In this trial, patients were carefully selected for treatment based on age (younger than 80 years of age), R0 or R1 resection, and a CA 19-9 level of 180 units/mL or less.[64744]

    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.[51161]

    for the second-line treatment of gemcitabine-refractory advanced pancreatic cancer in combination with oxaliplatin†

    Intravenous dosage

    Adults

    2,000 mg/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 3 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). Neurologic toxicity and leukopenia occurred more frequently in the oxaliplatin arm.[35050] 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).[45671]

    For the treatment of breast cancer

    Intravenous dosage

    Adults

    According to the manufacturer, the recommended dose of 5-fluorouracil for the treatment of breast cancer is 500 mg/m2 or 600 mg/m2 IV on days 1 and 8, as a component of a cyclophosphamide-based multidrug regimen, every 28 days for 6 cycles.[29028] See individual protocols for specific dosing.

    for the neoadjuvant treatment of HER2-positive breast cancer in combination with epirubicin and cyclophosphamide (FEC-75), followed by paclitaxel and trastuzumab

    Intravenous dosage

    Adults

    500 mg/m2 IV in combination with epirubicin (75 mg/m2 IV) and cyclophosphamide (500 mg/m2 IV) on day 1, every 21 days for 4 cycles (FEC-75).[63560] [63561] Dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity.[41751] After completion of 4 cycles of FEC-75, administer paclitaxel 80 mg/m2 IV once weekly in combination with trastuzumab (4 mg/kg IV over 90 minutes on week 1, then 2 mg/kg IV over 30 minutes once weekly), every 21 days for 4 cycles (12 weeks). Surgery should be performed after completion of paclitaxel plus trastuzumab therapy, followed by trastuzumab 6 mg/kg IV every 3 weeks for a total of 52 weeks from the first preoperative dose. In a randomized, phase 3 clinical trial, neoadjuvant treatment with FEC-75 followed by paclitaxel plus trastuzumab (sequential therapy) resulted in similar rates of pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) compared with paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent therapy). Sequential therapy was better tolerated and had a lower incidence of cardiac adverse reactions.[63560] [63561]

    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.[61185] [47962] [47985] [51607]

    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.[34268]

    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 to 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.[49142]

    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

    1,000 mg/m2 per day continuous IV infusion on days 1, 2, 3, and 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.[36026]

    for the treatment of advanced nasopharyngeal head and neck cancer in combination with cisplatin and radiotherapy†

    Intravenous dosage

    Adults

    1,000 mg/m2 per day IV over 4 days on days 71 through 74, 99 through 102, and 127 through 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 to 20 minutes on days 1, 22, and 43) given concurrently with radiation therapy (RT). In a phase 3 trial of 147 patients with advanced nasopharyngeal cancer, chemoradiotherapy significantly improved 3-year progression-free (69% vs. 24%) and overall survival (76% vs. 46%) rates versus RT alone.[20929]

    for induction treatment of inoperable locally advanced squamous cell head and neck cancer in combination with docetaxel and cisplatin†

    Intravenous dosage

    Adults

    750 mg/m2 per day continuous IV infusion on days 1, 2, 3, 4, and 5 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 longer than 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/fluorouracil or cisplatin (100 mg/m2 IV day 1) and fluorouracil (1,000 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/fluorouracil arm as compared to the cisplatin/fluorouracil (11.4 months vs. 8.3 months) 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/fluorouracil as compared to those treated with cisplatin/fluorouracil (18.6 months vs. 14.2 months).[28505]

    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†

    Intravenous dosage

    Adults

    1,000 mg/m2 per day continuous IV infusion on days 1, 2, 3, and 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).[28505]

    for the treatment of advanced-stage squamous cell carcinoma of the head and neck in combination with carboplatin and radiation therapy†

    Intravenous dosage

    Adults

    600 mg/m2 per day continuous IV infusion on days 1, 2, 3, and 4 in combination with carboplatin (70 mg/m2 per day IV on days 1, 2, 3, and 4). Chemotherapy cycles were started on days 1, 22, and 43 and were administered concurrently with radiotherapy (RT). In a phase 3 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/fluorouracil. Overall survival at 5 years was significantly improved in the chemoradiotherapy arm (22.4% vs. 15.8%). The 5-year specific disease free survival rate (26.6% vs. 14.6%) and locoregional control rate (47.6% vs. 24.7%) 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.[43174] [43119]

    for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with carboplatin†

    Intravenous dosage

    Adults

    1,000 mg/m2 per day continuous IV infusion over 96 hours on days 1, 2, 3, and 4 in combination with carboplatin (300 mg/m2 IV day 1); repeated every 4 weeks. In a phase 3 trial, 277 patients were randomized to receive carboplatin/fluorouracil, cisplatin/fluorouracil, or methotrexate (MTX). An increase in overall response rate was achieved with carboplatin/fluorouracil versus MTX, which was of borderline statistical significance (21% vs. 10%, p = 0.05). The overall response rate was numerically lower with carboplatin/fluorouracil compared to cisplatin/fluorouracil (21% vs. 32%).[43120]

    for the first-line treatment of recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck cancer in combination with carboplatin and cetuximab†

    Intravenous dosage

    Adults

    1,000 mg/m2 IV on days 1, 2, 3, and 4 in combination with carboplatin (AUC 5 IV on day 1), repeated every 3 weeks for up to 6 cycles. Administer with cetuximab (400 mg/m2 IV as an initial loading dose on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks). Complete cetuximab administration 1 hour prior to chemotherapy and continue until disease progression or unacceptable toxicity. In a phase 3 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 to chemotherapy compared with chemotherapy alone (10.1 months vs. 7.4 months). Sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.[35055]

    for the first-line treatment of recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck cancer in combination with cisplatin and cetuximab†

    Intravenous dosage

    Adults

    1,000 mg/m2 IV on days 1, 2, 3, and 4 in combination with cisplatin (100 mg/m2 IV on day 1), repeated every 3 weeks for up to 6 cycles. Administer with cetuximab (400 mg/m2 IV as an initial loading dose on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks). Complete cetuximab administration 1 hour prior to chemotherapy and continue until disease progression or unacceptable toxicity. In a phase 3 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 to chemotherapy compared with chemotherapy alone (10.1 months vs. 7.4 months). Sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.[35055]

    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 to 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 to 2 months following completion of therapy. Close follow-up is recommended.[53825] [53831]

    Topical dosage (Carac 0.5% 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%.[48332]

    Topical dosage (Tolak 4% 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.[60171]

    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.[53825]

    For the treatment of esophageal cancer†

    for the treatment of locally advanced or metastatic esophageal cancer, including gastroesophageal junction carcinoma (GEJ), with an epicenter located 1 to 5 cm above the GEJ, not amenable to surgical resection or definitive chemoradiation, in combination with pembrolizumab and cisplatin†

    Intravenous dosage

    Adults

    800 mg/m2 IV per day continuously on days 1 to 5, every 3 weeks, for up to 24 months. Administer in combination with cisplatin (80 mg/m2 IV on day 1 every 3 weeks for up to 6 cycles) and pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression). Administer pembrolizumab prior to chemotherapy when given on the same day. In a randomized clinical trial (KEYNOTE-590), treatment with pembrolizumab plus cisplatin and fluorouracil significantly improved median overall survival (12.4 months vs. 9.8 months) and median progression-free survival (6.3 months vs. 5.8 months) compared with placebo plus cisplatin and fluorouracil in patients with locally advanced or metastatic esophageal/GEJ tumors who were not candidates for surgical resection or definitive chemoradiation. In a prespecified formal test in patients with PD-L1 CPS of 10 or higher, the median overall survival was 13.5 months in pembrolizumab-treated patients compared with 9.4 months for those who received placebo; in an exploratory analysis, the median overall survival was 10.5 months versus 10.6 months, respectively, for patients with PD-L1 CPS less than 10. The overall response rate was also significantly improved in intent-to-treat patients who received pembrolizumab (45% for a median duration of 8.3 months; complete response [CR], 6%) compared with placebo (29% for a median duration of 6 months; CR, 2.4%).[57889] [66945]

    for the treatment of advanced or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with nivolumab, oxaliplatin, and leucovorin (mFOLFOX6)†

    Intravenous dosage

    Adults

    400 mg/m2 IV bolus on day 1 following leucovorin, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion every 2 weeks until disease progression or unacceptable toxicity. Administer following administration of oxaliplatin (85 mg/m2 IV on day 1) infused concurrently but in separate bags via Y-site with leucovorin (400 mg/m2 IV on day 1) and nivolumab (240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression).[40864] [20587] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]

    For the treatment of verruca vulgaris† or verruca plantaris† (e.g., cutaneous warts)

    Topical dosage (5% cream)

    Adults

    Apply a thin layer topically to the wart(s) 1 to 2 times daily for 4 to 12 weeks.[51147] [59982] [69965] [69973]

    Children and Adolescents 5 to 17 years

    Apply a thin layer topically to the wart(s) 1 to 2 times daily for 4 to 12 weeks.[51147] [59982] [69965] [69973]

    Therapeutic Drug Monitoring

    Dosage Adjustments for Treatment-Related Toxicities:
    Hematologic toxicity:

    • 5-FU alone:

    WBC < 3500/mm3, rapidly decreasing WBC, or platelets < 100,000/mm3: Hold 5-FU. Resume therapy when WBC >= 3500/mm3 and platelets >= 100,000/mm3

    • In combination with leucovorin and irinotecan:

    ANC 1000—1499/mm3 or platelets 50,000—74,999/mm3:

    (IFL): Decrease 5-FU from 500 mg/m2 to 400 mg/m2, or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Decrease 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2; decrease the 5-FU infusion from 600 mg/m2 to 480 mg/m2, or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the original dose. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    ANC 500—999/mm3 or platelets 25,000—49,999/mm3:

    (IFL): Hold 5-FU. When ANC >= 1000/mm3 and platelets >= 50,000/mm3, decrease 5-FU from 500 mg/m2 to 400 mg/m2 or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU. When ANC >= 1000/mm3 and platelets >= 50,000/mm3, decrease 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2; decrease the 5-FU infusion from 600 mg/m2 to 480 mg/m2, or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    ANC < 500/mm3 or platelets < 25,000/mm3:

    (IFL): Hold 5-FU. When ANC >= 1000/mm3 and platelets >= 50,000/mm3, decrease 5-FU from 500 mg/m2 to 300 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU. When ANC >= 1000/mm3 and platelets >= 50,000/mm3, decrease 5-FU bolus from 400 mg/m2 to 240 mg/m2  and 5-FU infusion from 600 mg/m2 to 360 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. When ANC >= 1500/mm3 and platelets >= 100,000/mm3, begin the next cycle of therapy at the reduced dose. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Neutropenic Fever:

    • In combination with leucovorin and irinotecan: Hold 5-FU. When neutropenic fever is resolved, decrease the dose of 5-FU from 500 mg/m2 to 300 mg/m2 (IFL) or from 400 mg/m2 bolus / 600 mg/m2 infusion to 240 mg/m2 bolus / 360 mg/m2 infusion (FOLFIRI) and resume treatment; for continued toxicity, decrease treatment in decrements of approximately 20%. Do not begin subsequent cycles of therapy until ANC >= 1500/mm3; consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Diarrhea:

    • 5-FU alone: Hold 5-FU.
    • In combination with leucovorin and irinotecan:

    2—3 stools/day above baseline: Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, resume treatment at original dose. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    4—6 stools/day above baseline:

    (IFL): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease the dose of 5-FU from 500 mg/m2 to 400 mg/m2 or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary. Resume the original doses of chemotherapy at the start of the next cycle. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease the 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2 and decrease the 5-FU infusion from 600 mg/m2 to 480 mg/m2 or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary. Resume the original doses of chemotherapy at the start of the next cycle. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    7—9 stools/day above baseline:

    (IFL): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease 5-FU from 500 mg/m2 to 400 mg/m2 or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2 and the 5-FU infusion from 600 mg/m2 to 480 mg/m2 or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    >= 10 stools/day above baseline:

    (IFL): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease 5-FU from 500 mg/m2 to 300 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Consider discontinuation of therapy for treatment delays > 2 weeks.


    (FOLFIRI): Hold 5-FU and follow irinotecan instructions for management of late diarrhea. When stools are resolved to baseline without requiring antidiarrheal medication for >= 24 hours, decrease irinotecan from 180 mg/m2 to 120 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. A 5-FU dose reduction is also necessary. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Other non-hematologic toxicities: For 5-FU alone, hold treatment for intractable vomiting, GI ulceration, bleeding, at the first sign of stomatitits or esophagopharyngitis, and for hand and foot syndrome; with interruption of therapy, hand and foot syndrome may gradually resolve over 5 to 7 days.[41803] When used in combination with irinotecan, follow the recommendations below:

    Grade 2:

    (IFL): Hold 5-FU. When toxicity resolves to <= grade 1, decrease the dose of 5-FU from 500 mg/m2 to 400 mg/m2 or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle; further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Resume the original doses of chemotherapy at the start of the next cycle. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU. When toxicity resolves to <= grade 1, decrease 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2; decrease the 5-FU infusion from 600 mg/m2 to 480 mg/m2, or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Resume the original doses of chemotherapy at the start of the next cycle. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Grade 3:

    (IFL): Hold 5-FU. When toxicity resolves to <= grade 2, decrease 5-FU from 500 mg/m2 to 400 mg/m2 or from 400 mg/m2 to 300 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. Maintain the same dose of leucovorin; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU. When toxicity resolves to <= grade 2, decrease 5-FU bolus from 400 mg/m2 to 320 mg/m2 or from 320 mg/m2 to 240 mg/m2; decrease the 5-FU infusion from 600 mg/m2 to 480 mg/m2, or from 480 mg/m2 to 360 mg/m2. Further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Grade 4:

    (IFL): Hold 5-FU. When toxicity resolves to <= grade 2, decrease 5-FU from 500 mg/m2 to 300 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Consider discontinuation of therapy for treatment delays > 2 weeks.

    (FOLFIRI): Hold 5-FU. When toxicity resolves to <= grade 2, decrease 5-FU bolus from 400 mg/m2 to 240 mg/m2 and 5-FU infusion from 600 mg/m2 to 360 mg/m2 for the remainder of the current cycle as well as subsequent cycles; further dose reductions may be done in decrements of approximately 20%. Maintain the same leucovorin dose; an irinotecan dose reduction is also necessary except for cases of mucositis / stomatitis. Consider discontinuation of therapy for treatment delays > 2 weeks.[30469]

    Maximum Dosage Limits

    • 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.

    Patients with Hepatic Impairment Dosing

    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.[53549]

    Patients with Renal Impairment Dosing

    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.

    † Off-label indication
    Revision Date: 03/25/2024, 02:12:53 PM

    References

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    Fluorouracil 1g/20ml Solution for Injection (PREMIER ProRx) (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50ml Bulk Solution for Injection (16729-0276) (Accord Healthcare, Inc.) null

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50ml Bulk Solution for Injection (68001-0266) (BluePoint Lab Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50mL Bulk Solution for Injection (62332-0751) (Alembic Pharmaceuticals, Inc.) nullFluorouracil 2.5g/50mL Bulk Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50mL Bulk Solution for Injection (68001-0525) (BluePoint Lab Injectables) nullFluorouracil 2.5g/50mL Bulk Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50mL Bulk Solution for Injection (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50mL Bulk Solution for Injection (25021-0215) (Sagent Pharmaceuticals) null

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50mL Bulk Solution for Injection (70700-0188) (Xiromed LLC a Division of the Chemo Group) null

    Fluorouracil Solution for injection

    Fluorouracil 2.5g/50ml Bulk Solution for Injection (PREMIER ProRx) (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10ml Solution for Injection (16729-0276) (Accord Healthcare, Inc.) null

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10ml Solution for Injection (68001-0266) (BluePoint Lab Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10ml Solution for Injection (63323-0117) (Fresenius Kabi AG) nullFluorouracil 500mg/10ml Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10ml Solution for Injection (70700-0186) (Xiromed LLC a Division of the Chemo Group) null

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10mL Solution for Injection (68001-0524) (BluePoint Lab Injectables) nullFluorouracil 500mg/10mL Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 500mg/10ml Solution for Injection (PREMIER ProRx) (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Bulk Solution for Injection (00069-0174) (Pfizer Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Bulk Solution for Injection (00069-0176) (Pfizer Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Solution for Injection (00069-0169) (Pfizer Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Solution for Injection (00069-0173) (Pfizer Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Solution for Injection (66758-0044) (Sandoz Inc. a Novartis Company) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/ml Solution for Injection (66758-0044) (Sandoz Inc. a Novartis Company) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 50mg/mL Solution for Injection (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Solution for injection

    Fluorouracil 5g/100ml Bulk Solution for Injection (16729-0276) (Accord Healthcare, Inc.) null

    Fluorouracil Solution for injection

    Fluorouracil 5g/100ml Bulk Solution for Injection (68001-0266) (BluePoint Lab Injectables) (off market)

    Fluorouracil Solution for injection

    Fluorouracil 5g/100mL Bulk Solution for Injection (62332-0779) (Alembic Pharmaceuticals, Inc.) nullFluorouracil 5g/100mL Bulk Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 5g/100mL Bulk Solution for Injection (68001-0525) (BluePoint Lab Injectables) nullFluorouracil 5g/100mL Bulk Solution for Injection package photo

    Fluorouracil Solution for injection

    Fluorouracil 5g/100mL Bulk Solution for Injection (63323-0117) (Fresenius Kabi USA, LLC ) null

    Fluorouracil Solution for injection

    Fluorouracil 5g/100mL Bulk Solution for Injection (25021-0215) (Sagent Pharmaceuticals) null

    Fluorouracil Solution for injection

    Fluorouracil 5g/100mL Bulk Solution for Injection (70700-0189) (Xiromed LLC a Division of the Chemo Group) null

    Fluorouracil Solution for injection

    Fluorouracil 5g/100ml Bulk Solution for Injection (PREMIER ProRx) (63323-0117) (Fresenius Kabi AG) null

    Fluorouracil Topical cream

    Carac 0.5% Topical Cream (00066-7150) (Bausch Health US, LLC) (off market)Carac 0.5% Topical Cream package photo

    Fluorouracil Topical cream

    Carac 0.5% Topical Cream (00066-7150) (Bausch Health US, LLC) (off market)

    Fluorouracil Topical cream

    Carac 0.5% Topical Cream (00187-5200) (Bausch Health US, LLC) nullCarac 0.5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 0.5% Topical Cream (00378-8078) (Mylan Pharmaceuticals Inc.) null

    Fluorouracil Topical cream

    Fluorouracil 0.5% Topical Cream (66530-0258) (Spear Pharmaceuticals) nullFluorouracil 0.5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluoroplex 1% Topical Cream (00023-0812) (Allergan USA, Inc.) (off market)Fluoroplex 1% Topical Cream package photo

    Fluorouracil Topical cream

    Fluoroplex 1% Topical Cream (00023-0812) (Almirall, LLC formerly Aqua Pharmaceuticals) (off market)

    Fluorouracil Topical cream

    Fluoroplex 1% Topical Cream (16110-0812) (Almirall, LLC formerly Aqua Pharmaceuticals) nullFluoroplex 1% Topical Cream package photo

    Fluorouracil Topical cream

    Tolak 4% Topical Cream (28105-0421) (Hill Dermaceuticals, Inc) (off market)Tolak 4% Topical Cream package photo

    Fluorouracil Topical cream

    Tolak 4% Topical Cream (28105-0421) (Hill Dermaceuticals, Inc) null

    Fluorouracil Topical cream

    Tolak 4% Topical Cream (28105-0421) (Pierre Fabre Pharmaceuticals, Inc) (off market)

    Fluorouracil Topical cream

    Tolak 4% Topical Cream (64370-0421) (Pierre Fabre Pharmaceuticals, Inc) (off market)Tolak 4% Topical Cream package photo

    Fluorouracil Topical cream

    Efudex 5% Topical Cream (00187-3204) (Bausch Health US, LLC) nullEfudex 5% Topical Cream package photo

    Fluorouracil Topical cream

    Efudex 5% Topical Cream Occlusion Pack Kit (00187-3600) (Bausch Health US, LLC) (off market)

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (16729-0542) (Accord Healthcare, Inc.) null

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (68682-0004) (Bausch Health US, LLC) (off market)Fluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (75907-0095) (Dr. Reddy's Laboratories, Inc.) null

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (66530-0249) (Mayne Pharma) (off market)Fluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (51862-0362) (Mayne Pharma) (off market)Fluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (68682-0004) (Mylan Pharmaceuticals Inc.) (off market)

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (00378-4791) (Mylan Pharmaceuticals Inc.) nullFluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (16714-0178) (NorthStar Rx LLC) nullFluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (66530-0249) (Spear Pharmaceuticals) (off market)Fluorouracil 5% Topical Cream package photo

    Fluorouracil Topical cream

    Fluorouracil 5% Topical Cream (51672-4118) (Taro Pharmaceuticals USA Inc) nullFluorouracil 5% Topical Cream package photo

    Fluorouracil Topical solution

    Fluoroplex 1% Topical Solution (00023-0810) (Allergan USA, Inc.) (off market)Fluoroplex 1% Topical Solution package photo

    Fluorouracil Topical solution

    Efudex 2% Topical Solution (00187-3202) (Bausch Health US, LLC) (off market)Efudex 2% Topical Solution package photo

    Fluorouracil Topical solution

    Fluorouracil 2% Topical Solution (43547-0259) (Solco Healthcare US LLC) (off market)

    Fluorouracil Topical solution

    Fluorouracil 2% Topical Solution (51672-4062) (Taro Pharmaceuticals USA Inc) nullFluorouracil 2% Topical Solution package photo

    Fluorouracil Topical solution

    Efudex 5% Topical Solution (00187-3203) (Bausch Health US, LLC) (off market)Efudex 5% Topical Solution package photo

    Fluorouracil Topical solution

    Fluorouracil 5% Topical Solution (68682-0085) (Bausch Health US, LLC) null

    Fluorouracil Topical solution

    Fluorouracil 5% Topical Solution (21922-0041) (Encube Ethicals Private Limited) nullFluorouracil 5% Topical Solution package photo

    Fluorouracil Topical solution

    Fluorouracil 5% Topical Solution (43547-0258) (Solco Healthcare US LLC) (off market)

    Fluorouracil Topical solution

    Fluorouracil 5% Topical Solution (51672-4063) (Taro Pharmaceuticals USA Inc) nullFluorouracil 5% Topical Solution package photo

    Description/Classification

    Description

    NOTE: The FDA has issued a warning regarding the occurrence of adverse events resulting from name confusion between fluorouracil cream (Carac™) and ketoconazole cream (Kuric™). Use caution when using either one of these products.

     

    Fluorouracil (5-FU) is a fluorinated pyrimidine and acts as an antimetabolite antineoplastic agent. It differs from the naturally occurring product, uracil, by the addition of a fluoride at position 5. Fluorouracil is a component of chemotherapy regimens for many solid tumors, including breast, colorectal, gastrointestinal, and head and neck cancers. The clinical pharmacology of 5-FU is complex and the pharmacokinetics are complicated by intra- and inter-patient variability, nonlinear elimination, and erratic bioavailability. The toxicities and efficacy of 5-FU differ depending upon the route of administration of the drug. A meta-analysis of 5-FU studies in the treatment of colorectal cancer found that continuous infusion led to a superior response and overall survival rate with a decreased incidence of severe hematologic toxicity as compared to bolus injection. However, there was an increased incidence of hand-foot syndrome with the continuous infusion as compared to the bolus injection.[26296] Fluorouracil commonly is given intravenously but is also used topically for malignant keratoses of the skin. Fluorouracil was approved by the FDA in 1962. In October 2000, a new formulation of fluorouracil cream using a microsponge delivery system (Carac™) was FDA-approved. The new delivery system allows for once daily dosing and a sustained release of fluorouracil.

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Antimetabolite Antineoplastic Agents
          • Pyrimidine Analogs
    • Dermatologicals
      • Topical Antineoplastics
        • Topical Antimetabolites
    Revision Date: 03/25/2024, 02:12:53 PM

    References

    26296 - No authors listed. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol 1998;16:301-308.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Hazardous Drugs Classification

    • NIOSH 2016 List: Group 1 [63664]
    • NIOSH (Draft) 2020 List: Table 1
    • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    • Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.[63664]

    Emetic Risk

    • Low
    • Administer routine antiemetic prophylaxis prior to treatment.[67389]

    Extravasation Risk

    • Irritant [67387]

    Route-Specific Administration

    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.

     

    Precipitation:

    • Fluorouracil for IV administration is a supersaturated solution; potential precipitation at low temperatures is a known phenomenon. Precipitate is typically white and flaky, versus particulate matter that will not dissolve.
    • Resolubilization has no negative effect on the product characteristics and formulation. If precipitation occurs, redissolve by placing vials into a water bath at 60 degrees C (140 degrees F), shake, and then allow to cool to body temperature before preparing a dose. Ensure that each vial is only heated once.[69496]

     

    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

    Ensure the correct topical product is used based on indication. ONLY THE 5% strength is approved for treatment of basal cell carcinoma.[53825]

    • 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, mouth, or other mucous membranes because irritation, local inflammation, and ulceration 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.
    • For actinic or solar keratosis and superficial basal cell carcinomas, a porous gauze dressing may be applied; do NOT use an occlusive dressing.[53825][60171]
    • For verruca vulgaris or verruca plantaris, cover cream with an occlusive dressing.[51147][59982][69965][69973]
    • Advise patients with pets to take care to prevent exposure of the pet to topical fluorouracil; accidental ingestion (from licking medicine on skin or from chewing the container/tube) may be fatal.[60171][66136]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Fluorouracil

    pH Range
    pH 8.6 to 9.2
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    Osmolality/Osmolarity
    Fluorouracil injection 50 mg/mL is hypertonic having an osmolality of 650 mOsm/kg.
    ReferencesTrissel LA. Drug information- osmolalities. Data on file.
    Stability
    Martel et al. (1997) reported that the stability of fluorouracil in intact containers stored at an elevated temperature of 33 degrees C protected from exposure to light for 12 months exhibited about 4% loss of drug when tested by stability-indicating HPLC analysis. In addition, a yellow discoloration appeared. The authors stated such temperatures might be reached during transportation of the vials during summer months. The color of fluorouracil injection results from the presence of free fluorine. A slight yellow color is normal, but a dark yellow solution indicates greater decomposition and more free fluorine. Storage of fluorouracil at elevated temperatures may result in increased decomposition. Solutions that are more than slightly yellow should be discarded. Exposure of fluorouracil injection to low temperatures may result in precipitation. Packaging in Syringes: Fluorouracil undiluted or diluted in common infusion solutions has been reported to be stable for periods ranging up to 28 days at room and refrigerator temperatures. Adams et al. reported that fluorouracil 25 mg/mL packaged in Braun Omnifix polypropylene syringes was stable for 28 days at both 4 and 20 degrees C. Stiles et al. reported that undiluted fluorouracil 50 mg/mL packaged in Pharmacia Deltec polypropylene infusion pump syringes was stable. HPLC analysis found little or no fluorouracil loss in 21 days at 30 degrees C. Baud-Camus et al. reported that fluorouracil at concentrations of 12 and 40 mg/mL in 5% Dextrose Injection and in 0.9% Sodium Chloride Injection and packaged in 60-mL polypropylene syringes was physically and chemically stable room temperature protected from exposure to light. No precipitation appeared, and HPLC analysis found fluorouracil loss of 5% or less in 72 hours. Barberi-Heyob et al. reported the stability of undiluted fluorouracil 50 mg/mL packaged in plastic syringes (manufacturer not cited) stored at room temperature of 21 degrees C and refrigerated at 4 degrees C both exposed to and protected from exposure to artificial light. HPLC analysis found about 10% loss in 15 days at room temperature. Unfortunately, crystalline precipitation appeared within 24 hours in the refrigerated samples. Implanted Pumps: Sadjik and Wintersteiger evaluated fluorouracil 50 mg/mL for 8 weeks at 37 degrees C with no loss and no leached materials from the Fresenius VIP 30 pump. Ambulatory Pumps: Fluorouracil stability in ambulatory pump reservoirs was reported in several research studies. The studies found the fluorouracil to be stable for the respective durations of the studies as long as precipitation did not occur. In fact, increased drug concentrations may occur at room and elevated temperatures due to moisture loss upon storage. Quebbeman et al. reported that fluorouracil 10 mg/mL in 5% Dextrose Injection in polyvinyl chloride (PVC) reservoirs for the Travenol PL146 MVP ambulatory pump was stable with no loss of fluorouracil over 16 weeks under refrigeration. An increase in fluorouracil concentration occurred over 16 weeks at room temperature due to moisture loss. Stiles et al. reported that fluorouracil 50 mg/mL in 4 ambulatory pump reservoirs (CADD-1 Model 5100, Cormed II Model 10500, Infumed 200, and Provider IV Model 2000) was stable for 7 days at room temperature and 37 degrees C with no drug loss and minimal leached plasticizer. However, fine white precipitation developed in the tubing and migrated to the reservoirs of all the pumps. Rochard et al., Baud-Camus et al, and Martel et al. all reported that fluorouracil was stable in ethylene vinyl acetate (EVA) plastic infusion pump reservoirs for periods up to 28 days under refrigeration, at room temperature, and at elevated temperature of 35 degrees C. Fluorouracil 50 mg/mL was reported to be stable for 8 weeks under refrigeration in elastomeric reservoirs for Homepump ambulatory infusion devices. Fluorouracil diluted to 5 to 42 mg/mL in 0.9% Sodium Chloride Injection was reported to be stable in Infusor and Intermate elastomeric reservoirs for up to 14 days refrigerated, 10 days at room temperature, and 7 days at 37 degrees C. Roberts and Sewell reported that ICN fluorouracil 50 mg/mL in Braun Easypump elastomeric infusion pumps (also available as the Fresenius Homepump) was physically and chemically stable for 21 days at 25 degrees C and an "in use" temperature of 31 degrees C. No visual changes or increase in microparticulates and little loss of water was found and HPLC analysis found no loss of fluorouracil. Although Corbrion et al. reported that large crystals precipitated from fluorouracil solution in contact with the elastomeric reservoirs of Baxter Infusers, this result was not confirmed in subsequent testing by Trissel. In Trissel's study, the fluorouracil in contact with the elastomeric reservoirs of Baxter Multi-Day Infusers remained in solution with no untoward crystal formation for 5 days at 25 and 32 degrees C. Trissel and also Allwood suggested the crystals were unfortunate artifacts of the collection and testing procedure permitting evaporation of water rather than a result of contacting the elastomeric reservoir. Perez and Salvatierra evaluated the physical and chemical stability of fluorouracil undiluted at 50 mg/mL and diluted in 0.9% Sodium Chloride Injection to drug concentrations of 30, 15, and 5 mg/mL and packaged in both glass containers and Dosi-Fuser (Leventon) portable elastomeric pumps. No precipitation, turbidity, or color change appeared over 30 days stored at room temperature of 20 to 25 degrees C. HPLC analysis found that at least 90% of the drug was retained in the solution over 30 days at room temperature as well. Barberi-Heyob et al. reported the stability of undiluted fluorouracil 50 mg/mL packaged in plastic cassettes for the Deltec pump stored at body temperature of 37 degrees C, room temperature of 21 degrees C, and refrigerated at 4 degrees C both exposed to and protected from exposure to artificial light. HPLC analysis found about 10 to 12% loss at both body temperature and room temperature in 7 days. Unfortunately, crystalline precipitation appeared within 24 hours in the refrigerated samples. However, Fournet et al. found increasing levels of highly toxic decomposition products formed when fluorouracil was administered using an ambulatory pump over long periods of time. The authors noted it would be preferable not to exceed three days for patients receiving the drug by ambulatory pump. Hyperthermic Isolated Hepatic Perfusion: Colville et al. evaluated the stability of fluorouracil and oxaliplatin during simulated hyperthermic hepatic isolated perfusion. Fluorouracil 100 mcg/mL and oxaliplatin 20 mcg/mL prepared in whole blood and in Lactated Ringer's injection were circulated through the perfusion system at 37 degrees C over 60 minutes. The perfusion system consisted of Terumo X coated 1/4 inch i.d. tubing with a standard Terumo hard shell venous reservoir and Terumo blood sampling manifold on the venous side and a Terumo SXR-1.0 oxygenator, Terumo blood sampling manifold, and a Pall 5-micron pediatric arterial blood filter on the arterial side. LC/MS analysis found no loss of fluorouracil during the test period. Atomic absorption spectrophotometry found no decrease in total platinum, but ultra filterable platinum concentrations decreased slowly with a half-life of 85 minutes. The authors stated that the stability of the two drugs was sufficient in the hyperthermic hepatic isolated perfusion system for the one-hour period.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesAdams PS, Haines-Nutt RF, Bradford E, et al. Pharmaceutical aspects of home infusion therapy for cancer patients. Pharm J. 1987; 238
    ReferencesAllwood MC. Fluorouracil precipitate. Am J Health-Syst Pharm. 1997; 55
    ReferencesAnon. Drug stability data for Intermate and Infusor portable elastomeric infusion devices. Round Lake, IL: Baxter Healthcare Corporation.. 2008;
    ReferencesAnon. Guidelines for the administration of drugs using the Homepump Eclipse and C-Series disposable elastomeric infusion systems. Lake Forest, CA: I-Flow Corporation. 2004;
    ReferencesBarberi-Heyob M, Watelet M, Merlin JL, et al. Stabilite des preparations de 5-fluorouracile en fonction de differents parametres [Stability of 5-fluorouracil solutions according to different parameters]. Bull Cancer. 1995; 82
    ReferencesBaud-Camus F, Crauste-Manciet S, Klein E, et al. Stability of fluorouracil in polypropylene syringes and ethylene vinyl actate infusion-pump reservoirs. Am J Health-Syst Pharm. 1996; 53
    ReferencesBiondi L, Nairn JG. Stability of 5-fluorouracil and flucytosine in parenteral solutions. Can J Hosp Pharm. 1986; 39
    ReferencesColville H, Dzadony R, Kemp R, et al. In vitro circuit stability of 5-fluorouracil and oxaliplatin in support of hyperthermic isolated hepatic perfusion. J Extracorp Tech. 2010; 42
    ReferencesCorbrion V, Crauste-Manciet S, Allain P, et al. Precipitation of fluorouracil in elastomeric infusers with a polyisoprene reservoir and in polypropylene syringes with an elastomeric joint. Am J Health-Syst Pharm. 1997; 54
    ReferencesFarhang-Asnafi S, Callaert S, Barre J, et al. Influence du solvant de dilution sur la stabilite de la nouvelle forme de 5-fluorouracile en perfusion. [Influence of intravenous admixtures on the stability of the new solution of 5-fluorouracil.]. J Pharm Clin. 1997; 16
    ReferencesFournet A, Gilard V, Malet-Martino M, et al. Stability of commercial solutions of 5-fluorouracil for continuous infusion in an ambulatory pump. Cancer Chemother Pharmacol. 2000; 46
    ReferencesFuhrman LC, Godwin DA, Davis RA. Stability of 5-fluorouracil in an extemporaneously compounded ophthalmic solution. Int J Pharmaceut Compound. 2000; 4
    ReferencesKim JT, Chung SH. Infusion rate and stability of 5-fluorouracil in disposable infusion device, Anapa. ASHP Midyear Clinical Meeting. 2009; 44
    ReferencesKleinberg ML, Stauffer GL, Latiolais CJ. Effect of microwave radiation on redissolving precipitated matter in fluorouracil injection. Am J Hosp Pharm. 1980; 37
    ReferencesMartel P, Petit I, Pinguet F, et al. Long-term stability of 5-fluorouracil stored in PVC bags and in ambulatory pump reservoirs. J Pharm Biomed Anal. 1996; 14
    ReferencesMartel P, Pinguet F, Petit I, et al. Stability of the principal cytostatic agents during storage at unusual temperatures. Int J Pharm. 1997; 149
    ReferencesNavarro JN, Aznar MT, Ruiz MD, et al. Estabilidad de 5-fluorouracilo en soluciones intravenosas de gran volumen. [Stability of 5-fluorouracil in large volume intravenous solutions.]. Rev Asoc Esp Farm Hosp. 1985; 9
    ReferencesNorthcott M, Allsopp MA, Powell H, et al. The stability of carboplatin, diamorphine, 5-fluorouracil and mitozantrone infusions in an ambulatory pump under storage and prolonged "in-use" conditions. J Clin Pharm Ther. 1991; 16
    ReferencesPerez S, Salvatierra D (Quality Assurance, Leventon). Personal communication: Stability of 5-fluorouracil in Dosi-Fuser elastomeric infusion pump storage for 30 days. Data on file. 2005;
    ReferencesPinguet F, Favre G, Canal P, et al. Stability of 5-fluorouracil solutions to heat and light. J Pharm Clin. 1990; 9
    ReferencesRoberts S, Sewell GJ. Stability and compatibility of 5-fluorouracil infusions in the Braun Easypump. J Oncol Pharm Pract. 2003; 9
    ReferencesRoche Laboratories. Personal communication. Data on file.
    ReferencesRochard EB, Barthes DMC, Courtouis PY. Stability of fluorouracil, cytarabine, or doxorubicin hydrochloride in ethylene vinylacetate portable infusion-pump reservoirs. Am J Hosp Pharm. 1992; 49
    ReferencesSadjak A, Wintersteiger R. Compatibility of morphine, baclofen, floxuridine and fluorouracil in an implantable medication pump. Arzneim Forsch. 1995; 45
    ReferencesStiles ML, Allen LV Jr, Prince SJ. Stability of deferoxamine mesylate, floxuridine, fluorouracil, hydromorphone hydrochloride, lorazepam, and midazolam hydrochloride in polypropylene infusion-pump syringes. Am J Health-Syst Pharm. 1996; 53
    ReferencesTrissel LA. Fluorouracil precipitate. Am J Health-Syst Pharm. 1998; 55
    ReferencesVincke BJ, Verstraeten AE, El Eini DID, et al. Extended stability of 5-fluorouracil and methotrexate solution in PVC containers. Int J Pharm. 1989; 54
    pH Effects
    The solubility of fluorouracil is pH-sensitive. At a pH less than 8, solubility is reduced, and precipitation becomes a possibility depending on the fluorouracil concentration. Stiles et al. reported precipitation appearing at even higher pH values. For a fluorouracil 50-mg/mL solution, a pH around 8.6 resulted in precipitation in 2 to 4 hours while at pH 8.5 precipitation appeared immediately. The precipitation consisted of needle-shaped crystals that became clustered as the pH continued to be decreased to about 8.2 and lower. Fluorouracil is alkaline and should not be mixed with acidic drugs or drugs that degrade in alkaline environments.
    ReferencesAllwood M, Stanley A, Wright P. The cytotoxics handbook, 3rd ed., Oxford, England: Radcliffe Medical Press, 1997.
    ReferencesDorr RT. Incompatibilities with parenteral anticancer drugs. Am J IV Ther. 1979; 6
    ReferencesStiles ML, Allen LV Jr, Tu YH. Stability of fluorouracil administered through four portable infusion pumps. Am J Hosp Pharm. 1989; 46
    ReferencesWilliams DA. Stability and compatibility of admixtures of antineoplastic drugs, in Lokich JJ (ed), Cancer chemotherapy by infusion, 2nd ed. Chicago: Precept Press. 1990.
    Light Exposure
    Sesin et al. reported that exposure of fluorouracil to direct sunlight or even to intense incandescent light may cause degradation resulting in amber to brown discoloration of the injection. However, Lorillon et al. reported that fluorouracil 1 mg/mL in 5% Dextrose Injection in five types of translucent containers exposed to sunlight for 28 days did not result in photodegradation of the fluorouracil. Blondi and Nairn reported no unacceptable adverse effect on drug concentration due to normal fluorescent light exposure in a stability study of fluorouracil in infusion solutions. Fuhrman et al. reported no adverse effect on fluorouracil stability of exposure to normal fluorescent light on a 10-mg/mL dilution in 0.9% Sodium Chloride Injection over 7 days at room temperature. Yadav et al. reported that fluorouracil remained stable when exposed to sunlight for 7 days or exposed to ultraviolet radiation for 45 days. Pinguet F, et al. reported fluorouracil 1 and 10 mg/mL in 5% Dextrose Injection packaged in polyvinyl chloride plastic bags was stable for 72 hours when stored at 4 and 25 degrees C exposed to light and protected from exposure to light. The authors concluded no photoprotection was required for fluorouracil admixtures during preparation and administration.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesBiondi L, Nairn JG. Stability of 5-fluorouracil and flucytosine in parenteral solutions. Can J Hosp Pharm. 1986; 39
    ReferencesFuhrman LC, Godwin DA, Davis RA. Stability of 5-fluorouracil in an extemporaneously compounded ophthalmic solution. Int J Pharmaceut Compound. 2000; 4
    ReferencesLorillon P, Corbel JC, Mordelet MF, et al. Photosensibilities du 5-fluoro-uracile et du methotrexate dans des perfuseurs transludides ou opaques. [Photosensibility of 5-fluorouracil and methotrexate in transluscent or opaque infusors.]. J Pharm Clin. 1992; 11
    ReferencesPinguet F, Favre G, Canal P, et al. Stability of 5-fluorouracil solutions to heat and light. J Pharm Clin. 1990; 9
    ReferencesSesin GP, Millette LA, Weiner B. Stability study of 5-fluorouracil following repackaging in plastic disposable syringes and multidose vials. Am J IV Ther Clin Nutr. 1982; 9
    ReferencesYadav N, Singh P, Mehrota R. Evaluation of stability of 5-fluorouracil under different stress conditions: high performance liquid chromatography and infrared spectroscopic approach. Curr Pharm Anal. 2012; 8
    Freezing
    Low temperature storage of fluorouracil 50 mg/mL injection may result in precipitation. Stolk and Chandi reported that fluorouracil 10 mg/mL in 0.9% Sodium Chloride Injection packaged in polypropylene syringes and stored frozen at -20 degrees C for 8 weeks did not result in fluorouracil loss. Thawing and refreezing for an additional 2 weeks did not result in loss of fluorouracil. Galanti et al. evaluated the stability of fluorouracil at an approximate concentration of 6.8 mg/mL in 0.9% Sodium Chloride Injection in polyvinyl chloride (PVC) bags frozen at -20 degrees C for 79 days. After frozen storage, the bags were thawed by exposure to microwave radiation in a carousel-equipped microwave oven for 13 minutes, mixing the solution, and exposure to microwave radiation for an additional 7 minutes. The thawed bags were then stored for an additional 28 days refrigerated. No physical instability was found. Stability-indicating HPLC analysis found little or no loss of fluorouracil after frozen storage and microwave thawing. About 6% loss occurred after 28 days of refrigerated storage.
    ReferencesGalanti L, Lebitasy MP, Hecq JD, et al. Long-term stability of 5-fluorouracil in 0.9% sodium chloride after freezing, microwave thawing, and refrigeration. Can J Hosp Pharm. 2009; 62
    ReferencesStolk LML, Chandi LS. Stabiliteit van fluorouracil (0,5 mL= 5 mg) in polypropyleen spuiten bij -20 degree C. [Stability of fluorouracil 5 mg/0.5 mL) in polypropylene syringes at -20 degree C.]. Ziekenhuisfarmacie. 1991; 7
    Filtration
    Fluorouracil at a concentration in the range of 10 to 75 mcg/mL delivered through Millex OR cellulose nitrate/cellulose acetate or Millex FG Teflon membrane filters exhibited little or no loss due to binding to the filters. Pall reports that fluorouracil 1 mg/mL underwent no loss due to filtration through a Supor membrane filter.
    ReferencesAnon. Pall Medical Supor-membrane IV filter device drug-adsorption data. Data on file. 2004; 8
    ReferencesPavlik EJ, van Nagell JR, Hanson MB, et al. Sensitivity to anticancer agents in vitro: standardizing the cytotoxic response and characterizing the sensitivities of a reference cell line. Gynecol Oncol. 1982; 14
    ReferencesPavlik EJ, Kenady DE, van Nagell JR, et al. Properties of anticancer agents relevant to in vitro determination of human tumor cell sensitivity. Cancer Chemother Pharmacol. 1983; 11
    Sorption Leaching
    Sorption: Fluorouracil has been shown not to undergo sorption to polyvinyl chloride (PVC) plastic bags and PVC administration tubing, ethylene vinyl acetate (EVA) bags, polyethylene tubing, Silastic tubing, cellulose propionate burettes, polypropylene/polyethylene plastic syringes, polypropylene syringes, or to elastomeric pump reservoirs. In addition, Xu et al. reported no sorption occurred to a polyurethane central catheter from Arrow International as well as no leaching of the chlorhexidine antimicrobial in it. . Driessen et al. reported greater loss of fluorouracil to glass surfaces than to polyethylene or polypropylene plastic surfaces. The loss was believed to be surface adsorption. Benvenuto et al. also noted an increased loss of fluorouracil to glass surfaces compared to PVC. However, Benaji et al. reported no loss of fluorouracil from either glass or PVC containers within 7 days. Also, Perez and Salvatierra found no substantive difference in fluorouracil loss when comparing glass containers to elastomeric pump reservoirs. Leaching: Stiles et al. reported the fluorouracil 50 mg/mL leached minimal amounts of diethylhexyl phthalate (DEHP) plasticizer from ambulatory infusion pump reservoirs.
    ReferencesBaud-Camus F, Crauste-Manciet S, Klein E, et al. Stability of fluorouracil in polypropylene syringes and ethylene vinyl actate infusion-pump reservoirs. Am J Health-Syst Pharm. 1996; 53
    ReferencesBeitz C, Einberger C, Wehling M. Stabilitat und kompatibilitat von zytostatika-zubereitungen mit infusionslosungensbehaltern aus polyethylen. [Stability and compatibility of cytotoxic drug solutions with polyethylene infusion containers.]. Krankenhauspharmazie. 1999; 20
    ReferencesBeitz C, Bertsch T, Hannak D, et al. Compatibility of plastics with cytotoxic drug solutions - comparison of polyethylene with other container materials. Int J Pharm. 1999; 185
    ReferencesBenaji B, Faouzi MA, Dine T, et al. Compatibility study of 5-fluorouracil with PVC bags after repackaging into two types of infusion admixtures. Therapie. 1999; 54
    ReferencesBenvenuto JA, Anderson RW, Kerkof K, et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm. 1981; 38
    ReferencesDine T, Lebegue S, Benaji B, et al. Stability and compatibility studies of four cytostatic agents (fluorouracil, dacarbazine, cyclophosphamide and ifosfamide) with PVC infusion bags. Pharm Sci Commun. 1994; 4
    ReferencesFuhrman LC, Godwin DA, Davis RA. Stability of 5-fluorouracil in an extemporaneously compounded ophthalmic solution. Int J Pharmaceut Compound. 2000; 4
    ReferencesHecq JD, Cadrobbi J, Gillet P, et al. Stability of 5-fluorouracil and sodium folinate solutions in ambulatory infusion systems. Pharm World Sci. 2009; 31
    ReferencesKim JT, Chung SH. Infusion rate and stability of 5-fluorouracil in disposable infusion device, Anapa. ASHP Midyear Clinical Meeting. 2009; 44
    ReferencesKowaluk EA, Roberts MA, Blackburn HD, et al. Interactions between drugs and polyvinyl chloride infusion bags. Am J Hosp Pharm. 1981; 38
    ReferencesKowaluk EA, Roberts MS, Polack AE. Interactions between drugs and intravenous delivery systems. Am J Hosp Pharm. 1982; 39
    ReferencesMariani EP, Southard BJ, Woolever JT, et al. Physical compatibility and chemical stability of cisplatin in various diluents and in large-volume parenteral solutions, in Presatyko AW, Crooke ST, Carter SK (eds) Cisplatin current status and new developments. New York: Academic Press, 1980.
    ReferencesMartel P, Petit I, Pinguet F, et al. Long-term stability of 5-fluorouracil stored in PVC bags and in ambulatory pump reservoirs. J Pharm Biomed Anal. 1996; 14
    ReferencesNorthcott M, Allsopp MA, Powell H, et al. The stability of carboplatin, diamorphine, 5-fluorouracil and mitozantrone infusions in an ambulatory pump under storage and prolonged "in-use" conditions. J Clin Pharm Ther. 1991; 16
    ReferencesPerez S, Salvatierra D (Quality Assurance, Leventon). Personal communication: Stability of 5-fluorouracil in Dosi-Fuser elastomeric infusion pump storage for 30 days. Data on file. 2005;
    ReferencesPinguet F, Favre G, Canal P, et al. Stability of 5-fluorouracil solutions to heat and light. J Pharm Clin. 1990; 9
    ReferencesRochard EB, Barthes DMC, Courtouis PY. Stability of fluorouracil, cytarabine, or doxorubicin hydrochloride in ethylene vinylacetate portable infusion-pump reservoirs. Am J Hosp Pharm. 1992; 49
    ReferencesRochard E, Chapelle G, Bouquet S, et al. Stabilite du 5-fluoro-uracile et de la cytarabine dans des reservpoirs en EVA [Stability of fluorouracil and cytarabine in ethylvinylacetate containers]. J Pharm Clin. 1989; 9
    ReferencesSesin GP, Millette LA, Weiner B. Stability study of 5-fluorouracil following repackaging in plastic disposable syringes and multidose vials. Am J IV Ther Clin Nutr. 1982; 9
    ReferencesStiles ML, Allen LV Jr, Tu YH. Stability of fluorouracil administered through four portable infusion pumps. Am J Hosp Pharm. 1989; 46
    ReferencesXu QA, Zhang Y, Trissel LA, et al. Adequacy of a new chlorhexidine-bearing polyurethane central catheter for administration of 82 selected parenteral drugs. Ann Pharmacother. 2000; 34
    Other Information
    Aluminum: Ogawa et al. reported that an aluminum needle immersed in Adria fluorouracil 50 mg/mL resulted in no visually observable effect in 7 days at room temperature protected from light. Dacarbazine: Horton et al. reported that fluorouracil and dacarbazine mixed in solution did not display altered ultraviolet and visible light spectral changes. This is suggestive of but not definitive evidence of stability of the combination. Doxorubicin: Fluorouracil mixed with doxorubicin results in a dark purple color change that indicates doxorubicin decomposition. Leucovorin: Leucovorin calcium and levoleucovorin calcium are incompatible with fluorouracil for periods longer than 24 hours. Trissel et al. identified a microprecipitation developing in admixtures after 24 hours that had gone unrecognized in previous studies. The microparticulates developed at refrigeration, room and elevated temperatures and were in sufficient amounts to clog filters and disrupt drug delivery. Bruch and Esser reported that the combination of fluorouracil and leucovorin calcium mixed together for repeated administration via a Fresenius implanted port resulted in blockage of the port catheter at the distal end that required surgical removal of the port. X-ray spectroscopic analysis of the material creating the blockage in the catheter showed it to be mainly calcium carbonate. Lokiec et al. also reported that leucovorin calcium or levoleucovorin calcium and fluorouracil mixed together at high concentrations resulted in precipitation in as little as eight hours. Although Lokiec et al. did not report visible precipitation from leucovorin calcium or levoleucovorin calcium with fluorouracil in low concentrations, they did not evaluate microprecipitation, which is known to occur. Microbial Growth Potential: Gaj et al., Holmes et al., and Briceland et al. all reported that fluorouracil 50 mg/mL resulted in the loss of viability of multiple microbial species; fluorouracil may have an antimicrobial effect at this concentration. Paris et al. also reported that B. subtilis and C. albicans exhibited a loss of viability in undiluted fluorouracil and a dilution of unreported concentration. Hamilton-Miller reported that fluorouracil exhibited little or no antimicrobial activity against Gram-negative aerobic bacteria, anaerobic bacteria, and yeasts, but did have some antimicrobial activity against Gram-positive aerobic bacteria. Favier et al. evaluated the antimicrobial effects of fluorouracil 5 mg/mL in 5% Dextrose Injection against five microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. Test samples were packaged in plastic bags and were stored at room temperature for up to 98 hours. The authors indicated a decrease in the growth rate for Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa but did not demonstrate increased antimicrobial activity for the other microorganisms tested compared to the negative controls. Tromethamine in Fluorouracil Formulation: Fournier et al. reported that a fluorouracil formulation containing tromethamine as a buffer of solution pH caused the loss of cisplatin and carboplatin due to the tromethamine content. HPLC analysis of both cisplatin and carboplatin combined with this tromethamine-containing fluorouracil formulation demonstrated that the tromethamine caused 75% cisplatin loss in 3.5 hours and 55% carboplatin loss in 24 hours. Quality Control: Lelievre et al. described an approach to quality control and accuracy assessment for 22 cancer chemotherapy drugs, including fluorouracil, which is designed to reduce the risk of erroneously prepared doses reaching patients. The technique utilized an ultraviolet (UV)-visible and infrared (IR) scanning analysis (Multispec, Microdom) of the finished dosage forms to verify the right molecule, concentration, and solution. Of 3149 doses of the 22 drugs tested, 7.82% varied by more than 10% from the intended concentration.
    ReferencesAnon. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH Publication No. 2004-165. 2004; 165
    ReferencesBriceland LL, Fudin J, Johnson KR. Evaluation of microbial growth in select inoculated antineoplastic solutions. Hosp Pharm. 1990; 25
    ReferencesBruch HR, Esser M. Catheter occlusion by calcium carbonate during simultaneous infusion of 5-FU and calcium folinate. Onkologie. 2003; 26
    ReferencesFavier B, Latour JF, Fuhrmann C. Viability of microorganisms in bags of cytotoxic drugs. J Oncol Pharm Pract. 2001; 6
    ReferencesFournier C, Hecquet B, Bastian G, et al. Modification of the physicochemical and pharmacological prperties of anticancer platinum compounds by commercial 5-fluorouracil formulations: a comparative study using cisplatin and carboplatin. Cancer Chemother Pharmacol. 1992; 29
    ReferencesGaj E, Griffin RE. Evaluation of growth of six microorganisms in fluorouracil, bacteriostatic sodium chloride 0.9% and sodium chloride 0.9% media. Hosp Pharm. 1983; 18
    ReferencesHamilton-Miller JMY. Antimicrobial activity of 21 anti-neoplastic agents. Br J Cancer. 1984; 49
    ReferencesHolmes CJ, Kubey WY, Love DI. Viability of microorganisms in fluorouracil and cisplatin small-volume injections. Am J Hosp Pharm. 1988; 45
    ReferencesHorton JK, Stevens MFG. Search for drug interactions between the anti-tumor agent DTIC and other cytotoxic agents. J Pharm Pharmacol (Supplement). 1979; 31
    ReferencesLelievre B, Devys C, Daouphars M, et al. Qualitative and quantitative analysis of chemotherapy preparations. Eur J Hosp Pharm Pract. 2010; 16
    ReferencesLokiec F, Amirault P, Bonnans H, et al. Stability of 5-fluorouracil-folinic acid mixture: influence of concentrations, container and form of folinic acid. Bull Cancer. 1999; 86
    ReferencesOgawa GS, Young R, Munar M. Dispensing-pin problems. Am J Hosp Pharm. 1985; 42
    ReferencesParis I, Paci A, Rey JB, et al. Microbial growth tests in anti-neoplastic injectable solutions. J Oncol Pharm Pract. 2005; 11
    ReferencesTrissel LA, Kleinman LM, Davignon JP, et al. Investigational drug information - daunorubicin hydrochloride and streptozotocin. Drug Intell Clin Pharm. 1978; 12
    ReferencesTrissel LA, Martinez JF, Xu QA. Incompatibility of fluorouracil with leucovorin calcium and levoleucovorin calcium. Am J Health-Syst Pharm. 1995; 52
    Revision Date: 03/25/2024, 02:12:53 PMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

    References

    51147 - Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2006:CD00178153825 - Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Bausch Health US, LLC, 2021 May.59982 - Sterling JC, Gibbs S, Hussain SS. British Association of Dermatologists' guidelines for the management of cutaneous warts 2014. Br J Dermatol 2014;171:696-712.60171 - Tolak (fluorouracil) 4% topical cream package insert. Sanford, FL: Hill Dermaceuticals, Inc.; 2022 Aug.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616166136 - FDA Advice on Pet Exposure to Prescription Topical (Human) Cancer Treatment: Fluorouracil. Food and Drug Administration (US FDA) Alert. Retrieved November 24, 2020. Available on the World Wide Web at https://www.fda.gov/animal-veterinary/animal-health-literacy/fda-advice-pet-exposure-prescription-topical-human-cancer-treatment-fluorouracil.67387 - Perez Fidalgo, JA, Garcia Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012 Oct;23 Suppl; vii167-73.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.69496 - Institute for Safe Medication Practices (ISMP). Fluorouracil injection may precipitate. Acute Care ISMP Medication Safety Alert. Fluorouracil injection may precipitate. 2023 July; 28(14):2-3.69965 - Hursthouse MW. A controlled trial on the use of topical 5-fluorouracil on viral warts. Br J Dermatol 1975;92:93-6.69973 - Salk RS, Grogan KA, Chang TJ. Topical 5% 5-fluorouracil cream in the treatment of plantar warts: a prospective, randomized, and controlled clinical study. J Drugs Dermatol 2006;5:418-24.

    Adverse Reactions

    Mild

    • alopecia
    • anorexia
    • diarrhea
    • dysgeusia
    • epistaxis
    • headache
    • ichthyosis
    • infection
    • injection site reaction
    • insomnia
    • irritability
    • lacrimation
    • leukocytosis
    • maculopapular rash
    • nail discoloration
    • nasal irritation
    • nausea
    • ocular irritation
    • ocular pain
    • ocular pruritus
    • pharyngitis
    • photosensitivity
    • pruritus
    • rash
    • sinusitis
    • skin hyperpigmentation
    • skin irritation
    • telangiectasia
    • urticaria
    • vomiting
    • xerosis

    Moderate

    • anemia
    • angina
    • bleeding
    • chest pain (unspecified)
    • confusion
    • conjunctivitis
    • contact dermatitis
    • edema
    • eosinophilia
    • erythema
    • esophagitis
    • euphoria
    • leukopenia
    • nystagmus
    • oral ulceration
    • palmar-plantar erythrodysesthesia (hand and foot syndrome)
    • palpitations
    • phlebitis
    • photophobia
    • skin erosion
    • skin ulcer
    • ST-T wave changes
    • stomatitis
    • thrombocytopenia

    Severe

    • acute cerebellar syndrome
    • agranulocytosis
    • anaphylactoid reactions
    • bowel ischemia
    • coronary vasospasm
    • GI bleeding
    • myocardial infarction
    • pancytopenia
    • peptic ulcer
    • pulmonary embolism
    • spontaneous fetal abortion
    • teratogenesis
    • thromboembolism
    • ventricular tachycardia

    Bleeding and epistaxis have been reported with IV fluorouracil use. Discontinue IV fluorouracil in patients who develop bleeding from any site.[53824]

    Medicinal taste (dysgeusia) and stomatitis have been reported infrequently in patients treated with fluorouracil solution or cream.[53825] [60171] Stomatitis and esophagitis/pharyngitis (including oral ulceration and sloughing), diarrhea, anorexia, nausea, and vomiting occurred commonly with IV fluorouracil therapy; gastrointestinal (GI) ulceration (peptic ulcer) and GI bleeding were also reported. Discontinue IV fluorouracil in patients who develop stomatitis, esophagopharyngitis, intractable vomiting, diarrhea, GI ulceration, or GI bleeding.[53824] Antiemetics, such as metoclopramide or phenothiazines, are often effective in alleviating GI symptoms. Diarrhea and stomatitis are more common with constant infusions than with bolus therapy; however both may be dose limiting regardless of administration. Concurrent leucovorin therapy can increase severity of fluorouracil-induced diarrhea and stomatitis. Life-threatening and sometimes fatal enterocolitis, dehydration, and diarrhea have occurred when high-dose fluorouracil is given in combination with leucovorin, especially in elderly patients. Octreotide has been reported to be useful in the treatment of severe fluorouracil-induced diarrhea.

    Leukocytosis has been reported in patients treated with fluorouracil solution or cream; pancytopenia, eosinophilia, thrombocytopenia, and toxic granulation have also occurred infrequently.[53825] [60171] Leukopenia occurred commonly with IV fluorouracil therapy; pancytopenia, thrombocytopenia, agranulocytosis, and anemia were also reported. White blood cell (WBC) count nadirs typically occur between day 9 and 20 following treatment, with recovery by day 30. WBC counts with differential are recommended prior to each IV dose. Discontinue IV fluorouracil in patients who develop leukopenia (WBC less than 3,500/mm3), a rapidly falling WBC count, thrombocytopenia (platelets less than 100,000/mm3) or bleeding from any site.[53824]

    Palmar-plantar erythrodysesthesia (hand and foot syndrome) has been reported with IV fluorouracil therapy. Symptoms gradually resolve over 5 to 7 days after fluorouracil is discontinued; use of pyridoxine may ameliorate this adverse event.[53824] Prolonged fluorouracil infusions are more commonly associated with this syndrome than bolus injections. With high-dose continuous infusions, this toxicity can be dose-limiting.

    Headache was reported in 3.1% of patients treated with fluorouracil 0.5% cream (n = 257) compared with 2.4% of patients who received vehicle alone (n = 127) in a pooled analysis from 2 phase III studies.[48332] Acute cerebellar syndrome, nystagmus, and headache have been reported with IV fluorouracil therapy. Acute cerebellar syndrome may persist after discontinuing therapy.[53824]

    Ocular irritation was reported in 3.4% to 5.9% of patients treated with fluorouracil cream. Symptoms of ocular irritation were burning, watering (lacrimation), sensitivity, stinging (ocular pain) and ocular pruritus. Conjunctival reaction (conjunctivitis), corneal reaction, and lacrimation have been reported infrequently in patients treated with fluorouracil solution or cream.[48332] [53825] [60171] Lacrimal duct stenosis, visual changes, lacrimation, and photophobia have been reported with IV fluorouracil therapy.[53824]

    Myocardial ischemia and angina have been reported with IV fluorouracil therapy.[53824] Cardiotoxicity due to systemic fluorouracil, 5-FU, therapy has been reported. Reported toxicities include angina, arrhythmias including ventricular tachycardia, cardiogenic shock, chest pain (unspecified), coronary vasospasm, electrocardiographic changes, myocardial infarction, palpitations, and sudden death. In general patients who have developed chest pain following 5-FU did so within several hours of receiving the third or fourth dose of drug. Rechallenge with 5-FU is usually associated with recurrence of the chest pain, which usually resolves, but has been associated with more serious sequelae. Cardiac catheterization reveals normal coronary arteries in these patients. It is believed that fluorouracil causes vasospastic angina. Asymptomatic ST-T wave changes have been seen in up to 65% of monitored patients, which suggests cardiac ischemia. Continuous infusions of 5-FU, especially high doses, have been associated with an increased incidence of cardiac effects; although, cardiotoxicity may occur after bolus injections as well. The chest pain responds to nitrates, calcium-channel blockers, or beta-blockers similar to other forms of angina. Thromboembolism, including pulmonary embolism, has also been reported with 5-FU therapy.

    In two trials sponsored by the National Cancer Institute for initial treatment of metastatic colorectal cancer, an imbalance in the number of deaths occurring within 60 days of the initiation of treatment was associated with irinotecan, leucovorin, and 5-fluorouracil (5-FU) treatment as compared to 5-FU and leucovorin (Trial C89803) or oxaliplatin, 5-FU, and leucovorin therapy (Study N9741). In study N9741 of patients with advanced disease, 12/14 deaths associated with irinotecan, 5-FU, and leucovorin had several characteristics in common: dehydration (resulting from diarrhea, nausea, and vomiting), neutropenia, and sepsis (alone or in combination with shock), leading to death. Thirteen deaths occurred during the first 6-week cycle or immediately afterward. In the surgical adjuvant study (Trial C89803), 14 deaths in the group assigned to receive irinotecan, 5-FU, and leucovorin included pulmonary embolism (3 patients), sepsis (3), aspiration (3), myocardial infarction (1), dehydration and neutropenia (1), stroke (1), bowel ischemia or infarct or both (1), and one unknown. Dose modifications to these trials have been made in an attempt to decrease toxicity. Close monitoring of patients receiving the combination of irinotecan, 5-FU, and leucovorin is warranted.[26489]

    Injection site reaction has been associated with IV fluorouracil administration. An erythematous eruption overlying the veins on both arms has been reported in several patients after IV fluorouracil. No superficial phlebitis or extravasation were observed.[25526] Vein discoloration following fluorouracil administration has been reported. The veins remain patent but show darkening of the skin immediately over the vein.[53824]

    Dermatologic reaction to the topical products were the most commonly reported. These included erythema (89.4% to 99%), scaling or xerosis (69% to 95%), crusting (87%), pruritus (85%), stinging or burning (60% to 87%), edema (14.1% to 69%), skin erosion (24.7% to 68%), pain (30.6% to 62.2%), application site reaction (91.8% to 96.5%), skin irritation (up to 2.4%), allergic contact dermatitis, scarring, rash, skin ulcer, inflammation, telangiectasia, alopecia, blistering, skin hyperpigmentation, bullous pemphigoid, ichthyosis, suppuration, swelling, soreness, tenderness, urticaria, and photosensitivity. These adverse events generally increased over the treatment period and diminished to baseline levels weeks after treatment cessation.[48332][53825] [53831] [60171] Alopecia and dermatitis has occurred with IV fluorouracil therapy; the dermatitis typically is a reversible pruritic maculopapular rash on the extremities or the trunk. Other dermatologic adverse events reported with IV fluorouracil include xerosis, fissuring, photosensitivity (observed as erythema or skin hyperpigmentation), and nail discoloration.[53824] Patients should wear a sunscreen with SPF 15 or greater and should cover exposed skin when outside after fluorouracil treatment. Sunlight may worsen other dermatologic reactions (i.e., rash) to fluorouracil.

    Cleft lip/palate was reported in a newborn whose mother used topical fluorouracil as recommended. Additionally, cases of spontaneous fetal abortion (miscarriage) and teratogenesis (specifically, ventricular septal defect) have been reported when fluorouracil was applied to mucous membranes during pregnancy. Multiple birth defects were reported in a fetus of a patient who received IV fluorouracil.[53825]

    Emotional upset, insomnia, and irritability occurred infrequently in patients treated with fluorouracil solution or cream.[53825] [60171] Disorientation, confusion, and euphoria have been reported with IV fluorouracil therapy.[53824]

    Nasal irritation has been reported infrequently in patients treated with fluorouracil 2% or 5% solution or 5% cream.[53825]

    Infection [e.g., common cold virus (up to 4.7%), sinusitis (up to 4.7%)] was reported in patients treated with fluorouracil 0.5% cream; however, the incidence of infection was not greater in the fluorouracil arm compared with the vehicle alone arm.[48332] Herpes simplex viral infection occurred infrequently in patients treated with fluorouracil solution or cream.[53825] [60171]

    Generalized allergic reactions including anaphylactoid reactions have been reported with IV fluorouracil therapy.[53824]

    Thrombo-phlebitis has been reported with IV fluorouracil use.[53824]

    Revision Date: 03/25/2024, 02:12:53 PM

    References

    25526 - Pujol RM, Rocamora V, Lopez-Poussa A, et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol 1998;39:839-42.26489 - Sargent DJ, Niedzwiecki D, O'Connell MJ, et al. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001;345:144-145.48332 - Carac (fluorouracil) cream package insert. Bridgewater, NJ: Bausch Health US, LLC; 2022 May53824 - Fluorouracil injection package insert. New York, NY: Pfizer Labs; 2012 Aug.53825 - Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Bausch Health US, LLC, 2021 May.53831 - Fluoroplex (fluorouracil) cream package insert. Exton, PA: Almirall, LLC; 2022 Feb.60171 - Tolak (fluorouracil) 4% topical cream package insert. Sanford, FL: Hill Dermaceuticals, Inc.; 2022 Aug.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • bone marrow suppression
    • dihydropyrimidine dehydrogenase (DPD) deficiency
    • infection
    • malnutrition
    • pregnancy
    • accidental exposure
    • biliary tract disease
    • bleeding
    • breast-feeding
    • children
    • dental disease
    • dental work
    • diarrhea
    • ensure correct formulation selection
    • GI bleeding
    • hepatic disease
    • intrathecal administration
    • jaundice
    • leukopenia
    • occlusive dressing
    • ocular exposure
    • radiation therapy
    • skin abrasion
    • stomatitis
    • sunlight (UV) exposure
    • thrombocytopenia
    • vaccination
    • vomiting

    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.[53824]

    Prescribers and health care professionals administering fluorouracil should ensure correct formulation selection during prescribing and before administration. Basal cell carcinoma is treated with the 5% formulation.[48332] [53825] [53831] [60171] [70287]

    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.[53824] 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.

    Some formulations of topical fluorouracil are contraindicated in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Only 1 case of serious systemic toxicity associated with DPD deficiency during the topical administration of fluorouracil 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 fluorouracil.[48332] [60498] [60499] [53825] [60171] Systemic fluorouracil is not recommended for patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency due to an increased risk of acute early-onset toxicities and serious adverse reactions that can result in death (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity); patients with partial DPD deficiency may also have an increased risk of serious adverse reactions. DPD is responsible for the metabolism of fluorouracil; deficiency of this enzyme leads to elevated concentrations of fluorouracil due to decreased clearance. Fluorouracil has not been proven safe for patients with complete DPD deficiency at any dose, and there is insufficient data regarding fluorouracil dosing in patients with partial DPD activity. Consider testing for DPD deficiency prior to starting therapy if clinically appropriate. There is not an FDA-approved test to detect DPYD mutations; currently available tests may vary in accuracy and design. Hold or permanently discontinue fluorouracil in patients with acute early-onset or unusually severe toxicities, which may indicate near complete or total absence of DPD activity.[70470]

    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.[53824] 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.[53549]

    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.[29028] [53824] 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. 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, local inflammation, and ulceration may occur. Avoid allowing pets to contact the fluorouracil, 5-FU container or the skin where topical 5-FU has been applied, as the product may be fatal if ingested by pets. Safely discard or clean any cloth or applicator that may retain fluorouracil, 5-FU and avoid leaving any residue on your hands, clothing, carpeting, or furniture.[48332] [53825] [60171] [60498] [60499]

    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.[48332] [53825] [60171] [60498] [60499]

    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.[48332] [53825] [60171] [60498] [60499]

    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.[48332] [53825] [60498] [60499] Systemic 5-FU should only be used during pregnancy if the benefit justifies the potential risks.[29028] 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.[29028] [48332]

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

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy with systemic fluorouracil, 5-FU is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.[43236]

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

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

    Revision Date: 03/25/2024, 02:12:53 PM

    References

    29028 - Adrucil (fluorouracil injection) package insert. Irvine, CA: Teva Parenteral Medicines, Inc.; 2007 July.43236 - National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60(2):1-64.48332 - Carac (fluorouracil) cream package insert. Bridgewater, NJ: Bausch Health US, LLC; 2022 May53549 - Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33(1):50-67.53824 - Fluorouracil injection package insert. New York, NY: Pfizer Labs; 2012 Aug.53825 - Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Bausch Health US, LLC, 2021 May.53831 - Fluoroplex (fluorouracil) cream package insert. Exton, PA: Almirall, LLC; 2022 Feb.60171 - Tolak (fluorouracil) 4% topical cream package insert. Sanford, FL: Hill Dermaceuticals, Inc.; 2022 Aug.60498 - Topical fluorouracil 5% cream package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.60499 - Topical fluorouracil 2% or 5% solution package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.70287 - Institute for Safe Medication Practices (ISMP). Community/Ambulatory Care ISMP Medication Safety Alert. Fluorouracil cream ensure formulation corresponds to indication 2023 Dec; 22(12):3.70470 - Fluorouracil injection. India: Gland Pharma Limited; 2024 Feb.

    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.

    Revision Date: 03/25/2024, 02:12:53 PM

    References

    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.[26297] 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.[29028]

    Route-Specific Pharmacokinetics

    Topical Route

    After a 12 hour application of 1 g of topical fluorouracil, 5-FU to the head and neck, approximately 6% of the dose was absorbed systemically.[53825] 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.[48332] 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.[60171]

    Other Route(s)

    Regional Administration

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

    Special Populations

    Hepatic Impairment

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

    Renal Impairment

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

    Revision Date: 03/25/2024, 02:12:53 PM

    References

    26297 - Diasio RB. Oral administration of fluorouracil: A new approach utilizing modulators of dihydropyrimidine dehydrogenase activity. Cancer Therapeutics 1999;2:97-106.29028 - Adrucil (fluorouracil injection) package insert. Irvine, CA: Teva Parenteral Medicines, Inc.; 2007 July.48332 - Carac (fluorouracil) cream package insert. Bridgewater, NJ: Bausch Health US, LLC; 2022 May53825 - Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Bausch Health US, LLC, 2021 May.60171 - Tolak (fluorouracil) 4% topical cream package insert. Sanford, FL: Hill Dermaceuticals, Inc.; 2022 Aug.

    Pregnancy/Breast-feeding

    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.[48332] [53825] [60498] [60499] Systemic 5-FU should only be used during pregnancy if the benefit justifies the potential risks.[29028] 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.[29028] [48332]

    Revision Date: 03/25/2024, 02:12:53 PM

    References

    29028 - Adrucil (fluorouracil injection) package insert. Irvine, CA: Teva Parenteral Medicines, Inc.; 2007 July.48332 - Carac (fluorouracil) cream package insert. Bridgewater, NJ: Bausch Health US, LLC; 2022 May53825 - Efudex (fluorouracil) solution and cream package insert. Bridgewater, NJ: Bausch Health US, LLC, 2021 May.60498 - Topical fluorouracil 5% cream package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.60499 - Topical fluorouracil 2% or 5% solution package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A. Inc.; 2010 Feb.

    Interactions

    Level 1 (Severe)

    • Bacillus Calmette-Guerin Vaccine, BCG
    • Chikungunya Vaccine, Live
    • Intranasal Influenza Vaccine
    • Live Vaccines
    • Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live
    • Measles/Mumps/Rubella Vaccines, MMR
    • Rotavirus Vaccine
    • Smallpox and Monkeypox Vaccine, Live, Nonreplicating
    • Smallpox Vaccine, Vaccinia Vaccine
    • Typhoid Vaccine
    • Varicella-Zoster Virus Vaccine, Live
    • Yellow Fever Vaccine, Live

    Level 2 (Major)

    • Acetaminophen; Ibuprofen
    • Amlodipine; Celecoxib
    • Bupivacaine; Meloxicam
    • Celecoxib
    • Celecoxib; Tramadol
    • Chlorpheniramine; Ibuprofen; Pseudoephedrine
    • Dapsone
    • Diclofenac
    • Diclofenac; Misoprostol
    • Diflunisal
    • Diphenhydramine; Ibuprofen
    • Diphenhydramine; Naproxen
    • Dronabinol
    • Erdafitinib
    • Ethotoin
    • Etodolac
    • Fenoprofen
    • Flurbiprofen
    • food
    • Fosphenytoin
    • Hydantoins
    • Hydrocodone; Ibuprofen
    • Ibuprofen
    • Ibuprofen; Famotidine
    • Ibuprofen; Oxycodone
    • Ibuprofen; Pseudoephedrine
    • Indomethacin
    • Ketoprofen
    • Ketorolac
    • Leucovorin
    • Levoleucovorin
    • Lonafarnib
    • Meclofenamate Sodium
    • Mefenamic Acid
    • Meloxicam
    • Nabumetone
    • Naproxen
    • Naproxen; Esomeprazole
    • Naproxen; Pseudoephedrine
    • Nonsteroidal antiinflammatory drugs
    • Oxaprozin
    • Phenytoin
    • Piroxicam
    • Porfimer
    • Pyrimethamine
    • Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole
    • Sulindac
    • Sumatriptan; Naproxen
    • Tolmetin
    • Trimethoprim

    Level 3 (Moderate)

    • Bosentan
    • Cholera Vaccine
    • Dengue Tetravalent Vaccine, Live
    • Drospirenone; Ethinyl Estradiol; Levomefolate
    • Glimepiride
    • Lamotrigine
    • Levomefolate
    • Losartan
    • Losartan; Hydrochlorothiazide, HCTZ
    • Nateglinide
    • Neomycin
    • Pioglitazone; Glimepiride
    • Ramelteon
    • SARS-CoV-2 (COVID-19) vaccines
    • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
    • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
    • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
    • Siponimod
    • Terbinafine
    • Tinidazole
    • Tuberculin Purified Protein Derivative, PPD
    • Warfarin

    Level 4 (Minor)

    • Allopurinol
    • Bismuth Subcitrate Potassium; Metronidazole; Tetracycline
    • Bismuth Subsalicylate; Metronidazole; Tetracycline
    • Cimetidine
    • Hydroxyurea
    • Interferon Alfa-2b
    • Methotrexate
    • Metronidazole
    Acetaminophen; 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. [5170] [5763] Allopurinol: (Minor) Allopurinol may interfere with the activation of fluorouracil, 5-FU, and decrease the effectiveness of 5-FU. [6461] [6462] [6463] Amlodipine; 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. [5170] [5763] Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Caution is warranted with the coadministration of systemic metronidazole and systemic fluorouracil, 5-FU. Concomitant use with metronidazole may increase the serum concentrations of fluorouracil; thereby, increasing the risk of side effects. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. [28384] [36894] Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Caution is warranted with the coadministration of systemic metronidazole and systemic fluorouracil, 5-FU. Concomitant use with metronidazole may increase the serum concentrations of fluorouracil; thereby, increasing the risk of side effects. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. [28384] [36894] 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. [4718] [8845] Bupivacaine; 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. [5170] [5763] 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. [5170] [5763] Celecoxib; Tramadol: (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. [5170] [5763] Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Chlorpheniramine; 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. [5170] [5763] Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] 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. [5261] 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. [29028] Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine. [60092] [64100] [65107] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] Dronabinol: (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. [30431] [32034] [60951] 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. [26073] [28942] [29720] Erdafitinib: (Major) Avoid coadministration of erdafitinib and fluorouracil due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP2C9 substrate and fluorouracil is a moderate CYP2C9 inhibitor. [32034] [64064] 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. [4741] [5265] [6471] [6472] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] Food: (Major) Advise patients to avoid cannabis use during fluorouracil treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP2C9 substrates and fluorouracil is a moderate CYP2C9 inhibitor. [32034] [67470] [67471] [67473] [67474] 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. [4741] [5265] [6471] [6472] 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. [7566] [8583] 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. [4741] [5265] [6471] [6472] 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. [5170] [5763] 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. [5126] 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. [5170] [5763] Ibuprofen; Famotidine: (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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] 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. [6468] [6469] Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] 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. [5170] [5763] 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. [5170] [5763] Lamotrigine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering fluorouracil, 5-FU, which may inhibit this enzyme. [5181] Leucovorin: (Major) Administration of leucovorin concurrently with fluorouracil, 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy (e.g., gastrointestinal toxicities, myelosuppression). The dosage of 5-FU must be decreased when given in combination with leucovorin. Closely monitor for gastrointestinal toxicities (e.g., stomatitis, diarrhea) and myelosuppression including leukopenia and thrombocytopenia. Stop use of these medications in patients who develop gastrointestinal toxicities, and do not reinitiate treatment until symptoms have resolved. A similar interaction is anticipated with levoleucovorin. [26073] [28942] [29720] [63785] Levoleucovorin: (Major) Administration of leucovorin concurrently with fluorouracil, 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy (e.g., gastrointestinal toxicities, myelosuppression). The dosage of 5-FU must be decreased when given in combination with leucovorin. Closely monitor for gastrointestinal toxicities (e.g., stomatitis, diarrhea) and myelosuppression including leukopenia and thrombocytopenia. Stop use of these medications in patients who develop gastrointestinal toxicities, and do not reinitiate treatment until symptoms have resolved. A similar interaction is anticipated with levoleucovorin. [26073] [28942] [29720] [63785] 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. [26073] [28942] [29720] Live Vaccines: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Lonafarnib: (Major) Avoid coadministration of lonafarnib and fluorouracil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and fluorouracil is a CYP2C9 inhibitor. [32034] [66129] Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluorouracil; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluorouracil is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%. [28608] [32034] [67924] [67925] Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluorouracil; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluorouracil is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%. [28608] [32034] [67924] [67925] Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] 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. [5170] [5763] 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. [5170] [5763] 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. [5170] [5763] 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. [29468] [29469] [29470] Metronidazole: (Minor) Caution is warranted with the coadministration of systemic metronidazole and systemic fluorouracil, 5-FU. Concomitant use with metronidazole may increase the serum concentrations of fluorouracil; thereby, increasing the risk of side effects. Toxicity may manifest as granulocytopenia, oral ulceration, anemia, and nausea and vomiting. [28384] [36894] 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. [5170] [5763] 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. [5170] [5763] Naproxen; Esomeprazole: (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. [5170] [5763] 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. [5170] [5763] Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with fluorouracil is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and fluorouracil is a moderate CYP2C9 inhibitor. Concomitant use with another moderate CYP2C9 inhibitor increased nateglinide overall exposure by 48%. [27603] [32034] [45644] Neomycin: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of fluorouracil, 5-FU. Caution is warranted with concomitant use. [40041] 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. [5170] [5763] 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. [5170] [5763] 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. [4741] [5265] [6471] [6472] Pioglitazone; 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. [7566] [8583] 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. [5170] [5763] Porfimer: (Major) Avoid coadministration of porfimer with topical fluorouracil preparations due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like topical fluorouracil may increase the risk of a photosensitivity reaction. [42968] [60171] 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. [4610] Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as fluorouracil, may lead to increases in the serum concentrations of ramelteon. [4718] Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Siponimod: (Moderate) Concomitant use of siponimod and fluorouracil may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate or strong CYP3A4 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fluorouracil is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. [32034] [64031] Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] 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. [43888] [43890] [5763] (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. [5073] 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. [5170] [5763] Sumatriptan; 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. [5170] [5763] 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. [37590] [43880] [43881] [56538] [8845] Tinidazole: (Moderate) Monitor for fluorouracil-related toxicities if concomitant use of tinidazole and fluorouracil cannot be avoided. Another nitroimidazole was shown to decrease fluorouracil clearance resulting in an increase in side effects without an increase in therapeutic benefits. [29931] 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. [5170] [5763] 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. [5073] 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. [43298] [43299] Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824] Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluorouracil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluorouracil is a CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. [28549] [53824] Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to fluorouracil recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving fluorouracil. At least 2 weeks before initiation of fluorouracil therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Fluorouracil recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased. [43236] [53824]
    Revision Date: 03/25/2024, 02:12:53 PM

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    Monitoring Parameters

    • CBC with differential
    • LFTs
    • neurologic function

    US Drug Names

    • Adrucil
    • Carac
    • Efudex
    • Fluoroplex
    • Tolak
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