FLUOROURACIL - fluorouracil injection, solution

Alembic Pharmaceuticals Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FLUOROURACIL INJECTION
safely and effectively. See full prescribing information for FLUOROURACIL INJECTION.
FLUOROURACIL injection, for intravenous use
Pharmacy Bulk Package - Not for Direct Infusion.
Initial U.S. Approval: 1962
INDICATIONS AND USAGE
Fluorouracil is a nucleoside metabolic inhibitor indicated for the treatment of patients with (1)
Adenocarcinoma of the Colon and Rectum (1.1)
Adenocarcinoma of the Breast (1.2)
Gastric Adenocarcinoma (1.3)
Pancreatic Adenocarcinoma (1.4)

DOSAGE AND ADMINISTRATION

Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous
infusion. (2.1)
See Full Prescribing Information for dose individualization (2.1) and dose modifications due to adverse
reactions (2.6)
See Full Prescribing Information for recommended doses of fluorouracil for adenocarcinoma of the
colon and rectum (2.2) and for recommended doses of fluorouracil as a component of a chemotherapy
regimen for adenocarcinoma of the breast (2.3), gastric adenocarcinoma (2.4), pancreatic
adenocarcinoma (2.5)
Pharmacy Bulk Package: Prepare doses for more than one patient in a Pharmacy Admixture Service
under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into
patients. Use within 4 hours of puncture (2.7, 2.8)

DOSAGE FORMS AND STRENGTHS

Injection: 5 g in a 100 mL vial in a pharmacy bulk package (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency:
Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at
increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to
fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Fluorouracil is not recommended
for use in patients known to have certain homozygous or compound heterozygous DPYD variants that
result in complete absence of DPD activity. Withhold or permanently discontinue based on clinical
assessment. No fluorouracil dose has been proven safe in patients with complete absence of DPD
activity. (5.1)
Cardiotoxicity: Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia,
arrhythmia, and heart failure. Withhold fluorouracil for cardiac toxicity. (5.2)
Hyperammonemic Encephalopathy: Altered mental status, confusion, disorientation, coma, or
ataxia with elevated serum ammonia level can occur within 72 hours of initiation of fluorouracil. Withhold
fluorouracil and initiate ammonia-lowering therapy. (5.3)
Neurologic Toxicity: Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation,
ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. (5.4)
Diarrhea: Fluorouracil can cause severe diarrhea. Withhold fluorouracil for severe diarrhea until
resolved. (5.5)
Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome): Fluorouracil can cause hand-foot
syndrome. If severe, discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a
reduced dose. (5.6)
Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil
until severe myelosuppression resolves, then resume at a reduced dose. (5.7)
Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or
decreased to Grade 1, then resume at a reduced dose. (5.8)
 decreased to Grade 1, then resume at a reduced dose. (5.8)
Increased Risk of Elevated INR with Warfarin: Concurrent administration with warfarin can result
in clinically significant increases in coagulation parameters: Closely monitor INR and prothrombin time.
(5.9)
Embryofetal Toxicity: Fluorouracil can cause fetal harm. Advise females and males of reproductive
potential of the potential risk to a fetus. (5.10, 8.1, 8.6)

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-

210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
Females and Males of Reproductive Potential: Provide pregnancy planning and prevention counseling.
(5.10, 8.1, 8.6)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 2/2024

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS & USAGE
1.1. Adenocarcinoma of the Colon and Rectum
1.2. Adenocarcinoma of the Breast
1.3. Gastric Adenocarcinoma
1.4. Pancreatic Adenocarcinoma
2 DOSAGE & ADMINISTRATION
2.1. General Dosage Information
2.2. Recommended Dosage for Adenocarcinoma of the Colon and Rectum
2.3. Recommended Dosage for Adenocarcinoma of the Breast
2.4. Recommended Dosage for Gastric Adenocarcinoma
2.5. Recommended Dosage for Pancreatic Adenocarcinoma
2.6. Dose Modifications
2.7. Preparation for Administration
2.8. Administration
3 DOSAGE FORMS & STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1.Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD)
Deficiency
5.2. Cardiotoxicity
5.3. Hyperammonemic Encephalopathy
5.4. Neurologic Toxicity
5.5. Diarrhea
5.6. Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)
5.7. Myelosuppression
5.8. Mucositis
5.9. Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin
5.10. Embryofetal Toxicity
6 ADVERSE REACTIONS
 6.2. Postmarketing Experience
7 DRUG INTERACTIONS
7.1. Anticoagulants and CYP 2C9 Substrates
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6. Females and Males of Reproductive Potential
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.5 Pharmacogenomics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS & USAGE

Fluorouracil is indicated for the treatment of patients with:

1.1. Adenocarcinoma of the Colon and Rectum

.

1.2. Adenocarcinoma of the Breast

.

1.3. Gastric Adenocarcinoma

.

1.4. Pancreatic Adenocarcinoma

.

2 DOSAGE & ADMINISTRATION

2.1. General Dosage Information
Fluorouracil is recommended for administration either as an intravenous bolus or as an
intravenous infusion. Do not inject the entire contents of the vial directly into
patients. Individualize the dose and dosing schedule of fluorouracil based on tumor
type, the specific regimen administered, disease state, response to treatment, and
patient risk factors.

2.2. Recommended Dosage for Adenocarcinoma of the Colon and Rectum

The recommended dose of fluorouracil, administered in an infusional regimen in
combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or
irinotecan, is 400 mg/m2 by intravenous bolus on Day 1, followed by 2400 mg/m2 to
3000 mg/m2 intravenously as a continuous infusion over 46 hours every two weeks.
The recommended dose of fluorouracil, if administered in a bolus dosing regimen in
combination with leucovorin, is 500 mg/m2 by intravenous bolus on Days 1, 8, 15,
22, 29, and 36 in 8-week cycles.

2.3. Recommended Dosage for Adenocarcinoma of the Breast

The recommended dose of fluorouracil, administered as a component of a
cyclophosphamide-based multidrug regimen, is 500 mg/m2 or 600 mg/m2
intravenously on Days 1 and 8 every 28 days for 6 cycles.

2.4. Recommended Dosage for Gastric Adenocarcinoma

The recommended dose of fluorouracil, administered as a component of a platinum-
containing multidrug chemotherapy regimen, is 200 mg/m2 to 1000 mg/m2
intravenously as a continuous infusion over 24 hours. The frequency of dosing in
each cycle and the length of each cycle will depend on the dose of fluorouracil and
the specific regimen administered.

2.5. Recommended Dosage for Pancreatic Adenocarcinoma

The recommended dose of fluorouracil, administered as an infusional regimen in
combination with leucovorin or as a component of a multidrug chemotherapy
regimen that includes leucovorin, is 400 mg/m2 intravenous bolus on Day 1, followed
by 2400 mg/m2 intravenously as a continuous infusion over 46 hours every two
weeks.

2.6. Dose Modifications

Withhold fluorouracil for any of the following:

Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in

patients with no history of coronary artery disease or myocardial dysfunction [see
Warnings and Precautions (5.2)]
Hyperammonemic encephalopathy [see Warnings and Precautions (5.3)]
Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances
[see Warnings and Precautions (5.4)]
Grade 3 or 4 diarrhea [see Warnings and Precautions (5.5)]
Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings
 and Precautions (5.6)]
Grade 3 or 4 mucositis [see Warnings and Precautions (5.8)]
Grade 4 myelosuppression [see Warnings and Precautions (5.7)]

Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or

palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced
dose.

There is no recommended dose for resumption of fluorouracil administration following

development of any of the following adverse reactions:

Cardiac toxicity
Hyperammonemic encephalopathy
Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances

2.7. Preparation for Administration

Fluorouracil is supplied in a pharmacy bulk package consisting of a vial. The pharmacy
bulk package can be used to prepare doses for more than one patient. It is not supplied
with a sterile transfer device, which is required for dispensing when multiple doses will be
prepared from the single vial. The 100 mL vial is only intended for preparation in a
Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs [see
References (15)]. Store vial at room temperature.

Using aseptic conditions, penetrate the container closure once with a suitable sterile
transfer device or dispensing set that allows measured distribution of the contents.
Record the date and time the vial was opened on the vial label. Discard the pharmacy
bulk package 4 hours after penetration of the container closure.

Withdraw the calculated dose for an individual patient into a sterile syringe. Inspect the
solution in syringe for particulate matter and discoloration prior to administration or
further dilution. Discard syringe if the solution is discolored or contains
particulate matter.

2.8. Administration
Do not administer in the same intravenous line concomitantly with other medicinal
products.

For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at
room temperature (25°C). Administer fluorouracil as an intravenous bolus through an
established intravenous line.

Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C)

prior to administration to the patient. For intravenous infusion regimens, administer
through a central venous line using an infusion pump.
3 DOSAGE FORMS & STRENGTHS
Fluorouracil injection, USP is supplied as a pharmacy bulk package as a vial containing 5
g/100 mL
(50 mg/mL) fluorouracil.

4 CONTRAINDICATIONS
None.

5 WARNINGS AND PRECAUTIONS

5.1.Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD)

Deficiency
Patients with certain homozygous or compound heterozygous variants in the DPYD
gene known to result in complete or near complete absence of DPD activity (complete
DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including
fatal, adverse reactions due to fluorouracil (e.g., mucositis, diarrhea, neutropenia, and
neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have
increased risk of serious, including fatal, adverse reactions.

Fluorouracil is not recommended for use in patients known to have certain homozygous
or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue fluorouracil based on clinical assessment of the

onset, duration, and severity of the observed adverse events in patients with evidence
of acute early-onset or unusually severe reactions, which may indicate complete DPD
deficiency. No fluorouracil dose has been proven safe for patients with complete DPD
deficiency. There are insufficient data to recommend a specific dose in patients with
partial DPD deficiency.

Consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the
risk of serious adverse reactions if the patient’s clinical status permits and based on
clinical judgement [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still
occur even if no DPYD variants are identified.

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients
at risk of serious adverse reactions due to increased systemic exposure to fluorouracil
is not currently available. Currently available tests used to identify DPYD variants may
vary in accuracy and design (e.g., which DPYD variant(s) they identify).

5.2. Cardiotoxicity
Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia,
arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for
cardiotoxicity are administration by continuous infusion rather than intravenous bolus
and presence of coronary artery disease. Withhold fluorouracil for cardiotoxicity. The
risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have
not been established.

5.3. Hyperammonemic Encephalopathy

Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease
or other identifiable cause, based on postmarketing reports. Signs or symptoms of
hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil
infusion; these included altered mental status, confusion, disorientation, coma, or ataxia,
in the presence of concomitant elevated serum ammonia level. Withhold fluorouracil for
hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of
resumption of fluorouracil in patients with hyperammonemic encephalopathy that has
resolved have not been established.

5.4. Neurologic Toxicity

Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and
other neurologic events, based on postmarketing reports. Neurologic symptoms
included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil
for neurologic toxicity. There are insufficient data on the risks of resumption of
fluorouracil in patients with neurologic toxicity that has resolved.

5.5. Diarrhea
Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea
until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced
dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as
necessary.

5.6. Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)

Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot
syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and
erythema with tenderness, and desquamation. HFS occurs more commonly when
fluorouracil is administered as a continuous infusion than when fluorouracil is
administered as a bolus injection, and has been reported to occur more frequently in
patients with previous exposure to chemotherapy. HFS is generally observed after 8-9
weeks of fluorouracil administration but may occur earlier. Institute supportive
measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2
or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or
decreased in severity to Grade 1.

5.7. Myelosuppression
Fluorouracil can cause severe and fatal myelosuppression which may include
neutropenia, thrombocytopenia, and anemia. The nadir in neutrophil counts commonly
occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood
counts prior to each treatment cycle, weekly if administered on a weekly or similar
schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves;
resume fluorouracil at a reduced dose when myelosuppression has resolved or
improved to Grade 1 in severity.
5.8. Mucositis
Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or
ulceration, can occur with fluorouracil. The incidence is reported to be higher with
administration of fluorouracil by intravenous bolus compared with administration by
continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis;
resume fluorouracil at a reduced dose once mucositis has resolved or decreased in
severity to Grade 1.

5.9. Increased Risk of Elevated International Normalized Ratio (INR) with

Warfarin
Clinically significant elevations in coagulation parameters have been reported during
concomitant use of warfarin and fluorouracil. Closely monitor patients receiving
concomitant coumarin-derivative anticoagulants such as warfarin for INR or
prothrombin time in order to adjust the anticoagulant dose accordingly [see Drug
Interactions (7)].

5.10. Embryofetal Toxicity

Based on its mechanism of action, fluorouracil can cause fetal harm when administered
to a pregnant woman. In animal studies, administration of fluorouracil at doses lower
than a human dose of 12 mg/kg caused teratogenicity. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to a fetus. Advise females of reproductive potential
and males with female partners of reproductive potential to use effective contraception
during and for 3 months following cessation of therapy with fluorouracil [see Use in
Specific Populations (8.1, 8.6), Clinical Pharmacology (12.1), and Nonclinical Toxicology
(13.1)].

6 ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the
labeling:

Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency

[see Warnings and Precautions (5.1)]
Cardiotoxicity [see Warnings and Precautions (5.2)]
Hyperammonemic encephalopathy [see Warnings and Precautions (5.3)]
Neurologic toxicity [see Warnings and Precautions (5.4)]
Diarrhea [see Warnings and Precautions (5.5)]
Palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and
Precautions (5.6)]
Myelosuppression [see Warnings and Precautions (5.7)]
Mucositis [see Warnings and Precautions (5.8)]
Increased risk of elevated INR when administrated with warfarin [see Warnings and
Precautions (5.9)]

6.2. Postmarketing Experience

The following adverse reactions have been identified during postapproval use of
fluorouracil. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.

Hematologic: pancytopenia [see Warnings and Precautions (5.7)]

Gastrointestinal: gastrointestinal ulceration, nausea, vomiting
Allergic Reactions: anaphylaxis and generalized allergic reactions
Neurologic: nystagmus, headache
Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or
increased pigmentation of the skin; vein pigmentation
Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia
Psychiatric: euphoria
Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails)

7 DRUG INTERACTIONS

7.1. Anticoagulants and CYP 2C9 Substrates

Elevated coagulation times have been reported in patients taking fluorouracil
concomitantly with warfarin. While pharmacokinetic data are not available to assess the
effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of
coagulation times that occurs with the fluorouracil prodrug capecitabine is accompanied
by an increase in warfarin concentrations. Thus, the interaction may be due to inhibition
of cytochrome P450 2C9 by fluorouracil or its metabolites.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Pregnancy Category D

Risk Summary

There are no adequate and well-controlled studies with fluorouracil in pregnant women.
Based on its mechanism of action, fluorouracil can cause fetal harm when administered
to a pregnant woman. Administration of fluorouracil to rats and mice during selected
periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused
embryolethality and teratogenicity. Malformations included cleft palate and skeletal
defects. In monkeys, maternal doses of fluorouracil higher than an approximate human
dose of 12 mg/kg resulted in abortion. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, apprise the patient of the potential
hazard to a fetus [see Clinical Pharmacology (12.1)].
Animal Data

Malformations including cleft palate, skeletal defects and deformed appendages (paws
and tails) were observed when fluorouracil was administered by intraperitoneal injection
to mice at doses at or above 10 mg/kg (approximately 0.06 times a human dose of 12
mg/kg on a mg/m2 basis) for 4 days during the period of organogenesis. Similar results
were observed in hamsters administered fluorouracil intramuscularly at doses lower
than those administered in commonly used clinical treatment regimens. In rats,
administration of fluorouracil by intraperitoneal injection at doses greater than 15 mg/kg
(approximately 0.2 times a human dose of 12 mg/kg on a mg/m2 basis) for a single day
during organogenesis resulted in delays in growth and malformations including micro-
anophthalmos. In monkeys, administration of fluorouracil during organogenesis at
doses approximately equal to a human dose of 12 mg/kg on a mg/m2 basis resulted in
abortion; at a 50% lower dose, resorptions and decreased fetal body weights were
reported.

8.3 Nursing Mothers

It is not known whether fluorouracil or its metabolites are present in human milk.
Because many drugs are present in human milk and because of the potential for serious
adverse reactions in nursing infants from fluorouracil, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Reported clinical experience has not identified differences in safety or effectiveness
between the elderly and younger patients.

8.6. Females and Males of Reproductive Potential

Contraception

Females

Based on its mechanism of action, fluorouracil can cause fetal harm when administered
to a pregnant woman. Advise females of reproductive potential to use effective
contraception during treatment with fluorouracil and for up to 3 months following
cessation of therapy [see Use in Specific Populations (8.1)].

Males

Fluorouracil may damage spermatozoa. Advise males with female partners of

reproductive potential to use effective contraception during and for 3 months following
cessation of therapy with fluorouracil [see Nonclinical Toxicology (13.1)].

Infertility

Females

Advise females of reproductive potential that, based on animal data, fertility may be
impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].

Males

Advise males of reproductive potential that, based on animal data, fertility may be
impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE
Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for
management of fluorouracil overdose.

11 DESCRIPTION
Fluorouracil injection USP, a nucleoside metabolic inhibitor, is a colorless to faint yellow,
aqueous, sterile, nonpyrogenic injectable solution available in 100 mL pharmacy bulk
package, a sterile preparation that contains doses for multiple patients for intravenous
administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The pH
is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a
fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. Its structural formula is:
12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fluorouracil is a nucleoside metabolic inhibitor that interferes with the synthesis of
deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic
acid (RNA); these affect rapidly growing cells and may lead to cell death. Fluorouracil is
converted to three main active metabolites: 5-fluoro-2′- deoxyuridine-5′-monophosphate
(FdUMP), 5-fluorouridine-5′-triphosphate (FUTP) and 5-fluoro-2′-deoxyuridine-5′-
triphosphate (FdUTP). These metabolites have several effects including the inhibition of
thymidylate synthase by FdUMP, incorporation of FUTP into RNA and incorporation of
FdUTP into DNA.

12.3 Pharmacokinetics
Distribution

Following bolus intravenous injection, fluorouracil distributes throughout the body

including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue.

Elimination

Following bolus intravenous injection, 5 – 20 % of the parent drug is excreted

unchanged in the urine in six hours. The remaining percentage of the administered dose
is metabolized, primarily in the liver. The metabolites of fluorouracil (e.g., urea and α-
fluoro-ß-alanine) are excreted in the urine over 3 to 4 hours.

Following bolus intravenous injection of fluorouracil, as a single agent, the elimination

half-life increased with dose from 8 to 20 minutes.
12.5 Pharmacogenomics
The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of
>80% of fluorouracil. Approximately 3-5% of White populations have partial DPD
deficiency and 0.2% of White populations have complete DPD deficiency, which may be
due to certain genetic no function or decreased function variants in DPYD resulting in
partial to complete or near complete absence of enzyme activity. DPD deficiency is
estimated to be more prevalent in Black or African American populations compared to
White populations. Insufficient information is available to estimate the prevalence of DPD
deficiency in other populations.

Patients who are homozygous or compound heterozygous for no function DPYD

variants (i.e., carry two no function DPYD variants) or are compound heterozygous for
a no function DPYD variant plus a decreased function DPYD variant have complete DPD
deficiency and are at increased risk for acute early-onset of toxicity and serious life-
threatening, or fatal adverse reactions due to increased systemic exposure to
fluorouracil. Partial DPD deficiency can result from the presence of either two decreased
function DPYD variants or one normal function plus either a decreased function or a no
function DPYD variant. Patients with partial DPD deficiency may also be at an increased
risk for toxicity from fluorouracil.

Four DPYD variants have been associated with impaired DPD activity in White
populations, especially when present as homozygous or compound heterozygous
variants: c.1905+1G>A (DPYD *2A), c.1679T>G (DPYD *13), c.2846A>T, and c.1129-
5923C>G (Haplotype B3). DPYD*2A and DPYD*13 are no function variants, and
c.2846A>T and c.1129-5923C>G are decreased function variants. The decreased
function DPYD variant c.557A>G is observed in individuals of African ancestry. This is
not a complete listing of all DPYD variants that may result in DPD deficiency [see
Warnings and Precautions (5.1)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenicity studies have not been performed with fluorouracil. Fluorouracil was
mutagenic
in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal
aberrations in hamster fibroblasts in vitro and in mouse bone marrow in the in vivo
mouse micronucleus assay.

Administration of fluorouracil intraperitoneally to male rats at dose levels equal to or

greater than 1.7-fold the human dose of 12 mg/kg induced chromosomal aberrations in
spermatogonia and inhibition of spermatogonia differentiation resulting in transient
infertility. In female rats, intraperitoneal administration of fluorouracil during the pre-
ovulatory phases of oogenesis at dose levels equal to or greater than 0.33 times a
human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased
pre-implantation loss, and fetotoxicity.
15 REFERENCES
"OSHA Hazardous Drugs." OSHA.
http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Fluorouracil injection, USP is supplied in a pharmacy bulk package available in a box
containing one vial, as follows:

NDC 62332-779-31: one box with one vial, containing 5 g/100 mL (50 mg/mL)
fluorouracil

Note: Although Fluorouracil solution may discolor slightly during storage, the potency
and safety are not adversely affected.

16.2 Storage
Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature]. DO NOT
FREEZE. Protect from light. Retain in carton until time of use.

Fluorouracil is a cytotoxic drug. Follow applicable special handling and disposable

procedures [see References (15)].

17 PATIENT COUNSELING INFORMATION

Advise:

Inform patients of the potential for serious and life-threatening adverse reactions due
to DPD deficiency and discuss with your patient whether they should be tested for
genetic variants of DPYD that are associated with an increased risk of serious
adverse reactions from the use of fluorouracil. Advise patients to immediately contact
their healthcare provider if symptoms of severe mucositis, diarrhea, neutropenia, and
neurotoxicity occur [see Warnings and Precautions (5.1) and Clinical Pharmacology
(12.5)].
Patients of the risk of cardiotoxicity. Advise patients to immediately contact their
healthcare provider or to go to an emergency room for new onset of chest pain,
shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions
(5.2)].
Patients to immediately contact their healthcare provider or go to an emergency
room for new onset of confusion, disorientation, or otherwise altered mental status;
difficulty with balance or coordination; or visual disturbances [see Warnings and
Precautions (5.3, 5.4)].
Patients to contact their healthcare provider for severe diarrhea or for painful mouth
sores with decreased oral intake of food or fluids [see Warnings and Precautions
(5.5, 5.8)].
 Patients to contact their healthcare provider for tingling or burning, redness, flaking,
swelling, blisters, or sores on the palms of their hands or soles of their feet [see
Warnings and Precautions (5.6)].
Patients of the importance of keeping appointments for blood tests. Instruct patients
to monitor their temperature on a daily basis and to immediately contact their
healthcare provider for fever or other signs of infection [see Warnings and
Precautions (5.7)].
Patients to notify their healthcare provider of all drugs they are taking, including
warfarin or other coumarin-derivative anticoagulants. Advise patients of the
importance of keeping appointments for blood tests [see Warnings and Precautions
(5.9)].
Females of reproductive potential and males with female partners of reproductive
potential to use effective contraception during treatment with fluorouracil and for up
to 3 months after the last dose of fluorouracil. Instruct female patients to contact
their healthcare provider if they become pregnant, if pregnancy occurs during
fluorouracil treatment or during the 3 months following the last dose [see Warnings
and Precautions (5.10), Use in Specific Populations (8.1 and 8.6), and Nonclinical
Toxicology (13.1)].
Females and males of reproductive potential may have impaired fertility while
receiving fluorouracil, based on animal data [see Use in Specific Populations (8.6) and
Nonclinical Toxicology (13.1)].
Nursing mothers to discontinue nursing [see Use in Specific Populations (8.3)].

Manufactured for:
Alembic Pharmaceuticals, Inc.

Bedminster, NJ 07921, USA

Made in India.

Manufactured by:
Alembic Pharmaceuticals Limited

Panelav - 389 350,

Gujarat, India.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Fluorouracil Injection, USP 5 g/100 mL (50 mg/mL) Vial-Label

Fluorouracil Injection, USP 5 g/100 mL (50 mg/mL) Carton-Label
FLUOROURACIL
fluorouracil injection, solution

Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62332-779

Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
FLUOROURACIL (UNII: U3P01618RT) (FLUOROURACIL - UNII:U3P01618RT) FLUOROURACIL 50 mg in 1 mL

Inactive Ingredients
Ingredient Name Strength
WATER (UNII: 059QF0KO0R)
SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging
Marketing Marketing End
# Item Code Package Description
Start Date Date
NDC:62332-
1 1 in 1 CARTON 10/18/2023
779-31
100 mL in 1 VIAL, PHARMACY BULK PACKAGE; Type 0: Not a
1
Combination Product

Marketing Information
Marketing Application Number or Monograph Marketing Start Marketing End
Category Citation Date Date
ANDA ANDA217676 10/18/2023

Labeler - Alembic Pharmaceuticals Inc. (079288842)

Establishment
Name Address ID/FEI Business Operations
Alembic Pharmaceuticals Limited 675480402 MANUFACTURE(62332-779)

Revised: 2/2024 Alembic Pharmaceuticals Inc.