DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Utoral is indicated for the treatment of patients with:
Utoral® (fluorouracil injection) is a nucleoside metabolic inhibitor 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 AND ADMINISTRATION
2.1 General Dosage Information
Utoral 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 Utoral 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
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
Withhold Utoral for any of the following:
Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume Utoral administration at a reduced dose.
There is no recommended dose for resumption of Utoral administration following development of any of the following adverse reactions:
2.7 Preparation for Administration
Utoral 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 50 mL vial is only intended for preparation in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs . 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.
Do not administer in the same intravenous line concomitantly with other medicinal products.
For bolus administration, store undiluted Utoral in the syringe for up to 4 hours at room temperature (25°C). Administer Utoral as an intravenous bolus through an established intravenous line.
Store diluted solutions of Utoral 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 AND STRENGTHS
Utoral (fluorouracil injection USP) is supplied as:
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity
Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Utoral (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by Utoral.
Withhold or permanently discontinue Utoral based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Utoral dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.
Utoral 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 Utoral for cardiotoxicity. The risks of resumption of Utoral in patients with cardiotoxicity that has resolved have not been established.
5.3 Hyperammonemic Encephalopathy
Utoral 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 Utoral infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level. Withhold Utoral for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of Utoral in patients with hyperammonemic encephalopathy that has resolved have not been established.
5.4 Neurologic Toxicity
Utoral 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 Utoral for neurologic toxicity. There are insufficient data on the risks of resumption of Utoral in patients with neurologic toxicity that has resolved.
Utoral can cause severe diarrhea. Withhold Utoral for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume Utoral at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary.
5.6 Palmar-Plantar Erythrodysesthesia
Utoral 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 Utoral is administered as a continuous infusion than when Utoral 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 to 9 weeks of Utoral administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold Utoral administration for Grade 2 or 3 HFS; resume Utoral at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1.
Utoral 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 Utoral administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold Utoral until Grade 4 myelosuppression resolves; resume Utoral at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity.
Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with Utoral. The incidence is reported to be higher with administration of Utoral by intravenous bolus compared with administration by continuous infusion. Withhold Utoral administration for Grade 3 or 4 mucositis; resume Utoral at a reduced dose once mucositis has resolved or decreased in severity to Grade 1.
5.9 Increased Risk of Elevated International Normalized Ratio with Warfarin
Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and Utoral. Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly .
5.10 Embryofetal Toxicity
Based on its mechanism of action, Utoral can cause fetal harm when administered to a pregnant woman. In animal studies, administration of Utoral 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 Utoral .
6 ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Utoral. 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.
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
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 Utoral concomitantly with warfarin. While pharmacokinetic data are not available to assess the effect of Utoral administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with the Utoral prodrug capecitabine is accompanied by an increase in warfarin concentrations. Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by Utoral or its metabolites.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category D
There are no adequate and well-controlled studies with Utoral in pregnant women. Based on its mechanism of action, Utoral can cause fetal harm when administered to a pregnant woman. Administration of Utoral 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 Utoral 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 .
Malformations including cleft palate, skeletal defects and deformed appendages (paws and tails) were observed when Utoral 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 Utoral intramuscularly at doses lower than those administered in commonly used clinical treatment regimens. In rats, administration of Utoral 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 Utoral 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 Utoral 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 Utoral, 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
Based on its mechanism of action, Utoral can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Utoral and for up to 3 months following cessation of therapy .
Utoral 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 Utoral .
Advise females of reproductive potential that, based on animal data, fertility may be impaired while receiving Utoral .
Advise males of reproductive potential that, based on animal data, fertility may be impaired while receiving Utoral .
Administer uridine triacetate within 96 hours following the end of Utoral infusion for management of Utoral overdose.
Utoral® (fluorouracil injection USP), a nucleoside metabolic inhibitor, is a colorless to faint yellow aqueous, sterile, nonpyrogenic injectable solution available in a 50 mL and 100 mL Pharmacy Bulk Package for intravenous administration. Each mL contains 50 mg Utoral, USP in water for injection, USP, pH is adjusted to 8.6 to 9.4 with sodium hydroxide.
Chemically, Utoral, USP, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. It is a white to practically white crystalline powder which is sparingly soluble in water. The structural formula is:
C4H3FN2O2 M.W. 130.08
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Utoral is a nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid and to a lesser extent inhibits the formation of ribonucleic acid (RNA); these affect rapidly growing cells and may lead to cell death. Utoral 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.
Following bolus intravenous injection, Utoral distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue.
Following bolus intravenous injection, 5 to 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 Utoral (e.g., urea and α-fluoro-ß-alanine) are excreted in the urine over 3 to 4 hours.
Following bolus intravenous injection of Utoral, as a single agent, the elimination half-life increased with dose from 8 to 20 minutes.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with Utoral. Utoral 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 Utoral 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 Utoral 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.
"OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Utoral® is available in two pharmacy bulk vials as follows:
PHARMACY BULK PACKAGES
The 50 mL and 100 mL pharmacy bulk packages are packaged 5 vials per shelf pack.
16.2 Storage and Handling
Store at 20° to 25°C (68° to 77°F). Do not freeze. Protect from light. Retain in carton until time of use.
Utoral is a cytotoxic drug. Follow applicable special handling and disposable procedures .
17 PATIENT COUNSELING INFORMATION
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Rev. D 1/2017
(fluorouracil injection USP)
2.5 grams/50 mL
For Intravenous Use Only
PHARMACY BULK PACKAGE
NOT FOR DIRECT INFUSION
CAUTION: Cytotoxic Agent
5 x 50 mL Vials
(fluorouracil injection USP)
5 grams/100 mL
For Intravenous Use Only
PHARMACY BULK PACKAGE
NOT FOR DIRECT INFUSION
CAUTION: Cytotoxic Agent
5 x 100 mL Vials
Utoral pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Utoral available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Utoral destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Utoral Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Utoral pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Utoral?
Depending on the reaction of the Utoral after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Utoral not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Utoral addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Utoral, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Utoral consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
One visitor reported time for resultsWhat is the time duration Utoral drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sDrugs.com website users needed 1 week to notice the result from using Utoral drug. The time needed to show improvement in health condition after using the medicine Utoral need not be same for all the users. It varies based on other factors.
The information was verified by Dr. Arunabha Ray, MD Pharmacology