Adrucil

Name: Adrucil

Uses of Adrucil

Injectable:

Fluorouracil is a prescription medication used in combination with other medications to treat colon cancer or rectal cancer (cancer that begins in the large intestine) that has gotten worse or spread to other parts of the body. Fluorouracil is used in combination with other medications to treat certain types of breast cancer after surgery to remove the tumor or radiation therapy. Fluorouracil is also used to treat cancer of the pancreas and stomach cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Topical:

Fluorouracil cream and topical solution are prescription medications used to treat a skin condition on the face and front part of the scalp known as actinic keratosis (also called solar keratosis). Actinic keratosis is a precancerous condition marked by scaly, crusty patches of skin.  It is caused by long term exposure to the sun.

The 5% strength topical formulations are also useful in the treatment of superficial basal cell carcinomas. This is a slow-growing form of skin cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Adrucil Precautions

Injectable:

Serious side effects of fluorouracil injection include

  • hand-foot syndrome. Symptoms include a tingling sensation of hands and feet which may progress over the next few days to pain when holding objects or walking. The palms and soles become swollen, red and tender. Desquamation, or skin peeling, may also occur.
  • stomatitis (mouth inflammation and ulceration)
  • esophagopharyngitis (throat and feeding tube inflammation and ulceration)
  • a rapidly falling white blood count, which increases your chance of infection
  • stomach and intestinal ulceration and bleeding
  • low platelet counts, which increases your chance of bleeding

Plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Fluorouracil may make your skin sensitive to sunlight.

Do not use fluorouracil injectable if you:

  • are in poor nutritional state
  • have depressed bone marrow function
  • have a serious infections
  • have a known hypersensitivity to fluorouracil

Topical:

Do not use fluorouracil cream or topical solution if you:

  • have dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. Fluorouracil, can cause serious side effects in patients who are DPD enzyme deficient. If you have DPD enzyme deficiency and use medications containing fluorouracil, you may develop serious side effects such as stomach pain, bloody diarrhea, vomiting, fever, or chills.
  • are allergic to the ingredients in fluorouracil
  • are under 18 years of age. Fluorouracil should not be used in children.
  • are pregnant or breastfeeding

Uses for Adrucil

Cancers

Principally for GI, breast, and head and neck cancers.a b

Palliative treatment of carcinoma of the colon, rectum, anus, stomach, biliary tract, esophagus, and pancreas that is not amenable to surgery or irradiation.a b 205

Adjunct to surgery for the treatment of various solid tumors (e.g., adenocarcinoma of the colon,226 227 228 229 230 231 232 233 252 253 256 261 280 rectal carcinoma).230 234 235 236 237 238 239 240 242 243 280

Colorectal Cancer

Drug of choice (combined with leucovorin) as an adjunct to surgery for colorectal cancer.b

Drug of choice (combined with leucovorin and other drugs [e.g., irinotecan, oxaliplatin]) for metastatic colorectal cancer.b

Combination fluorouracil/leucovorin regimens have replaced fluorouracil monotherapy regimens218 266 286 292 294 295 296 300 304 305 as adjuvant therapy for stage III disease.388

Weekly schedule of fluorouracil/leucovorin (high-dose leucovorin or Roswell Park regimen) has equal efficacy as monthly schedule (low-dose or Mayo Clinic schedule), but the weekly schedule is a preferred regimen for adjuvant therapy because of ease of use and less toxicity.386 388 (See Colorectal Cancer under Dosage and Administration.)

Bimonthly, continuous IV infusion schedule of fluorouracil/leucovorin (LV5FU2 or deGramont regimen)† also evaluated as adjuvant therapy390 and shown to be safer than direct IV injection regimen of these drugs.388 390 Simplified version of this regimen also evaluated.391 (See Colorectal Cancer under Dosage and Administration.)

Role of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion†) for liver metastases requires further elucidation.230 253 256 257 258 259 260 264 275 280

Leucovorin and levoleucovorin enhance cytotoxicity,221 286 291 303 305 306 307 308 309 310 395 397 potentiate fluorouracil antineoplastic activity, and improve response for palliative advanced colorectal carcinoma treatment;200 201 211 215 216 218 219 220 266 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 311 313 314 315 317 395 designated an orphan drug by FDA for use with leucovorin for metastatic colorectal adenocarcinoma.335

Leucovorin and levoleucovorin may potentiate risk of fluorouracil GI toxicity (e.g., diarrhea, nausea, stomatitis, vomiting) and myelosuppression.214 215 217 218 266 286 289 292 293 294 295 296 311 395

Esophageal Cancer

Drug of choice for treatment of esophageal cancer†.b

Has been used alone330 334 336 and in combination therapy (e.g., with cisplatin)b 249 329 330 331 334 336 for the treatment of localized or advanced esophageal cancer†.

Gastric Cancer

Drug of choice (with or without leucovorin and/or other drugs [e.g., cisplatin, epirubicin]) for treatment of gastric cancer.b

Anal Cancer

Drug of choice (e.g., combined with mitomycin or cisplatin) for treatment of anal cancer.b

Pancreatic Cancer

Drug of choice as adjunct to surgery and for localized unresectable pancreatic cancer.b

Biliary Tract Cancer

Drug of choice (with or without leucovorin) for treatment of biliary tract cancer.b

Breast Cancer

Drug of choice combined with other drugs (e.g., cyclophosphamide and doxorubicin or methotrexate) as an adjunct to surgery and for metastatic breast cancer.b 244 249 251 279 319 320 322 323 324 325 326 328

Palliative treatment of carcinoma of the breast not amenable to surgery or irradiation.a

Adjunct to surgery, may improve outcome.244 245 246 247 248 249 250 251 254 270 271 272

Has been used most extensively with cyclophosphamide and methotrexate, and is considered a regimen of choice.244 249 251 279 319 320 321 322 323 324 325 326 328

Head and Neck Cancer

Drug of choice combined with cisplatin for head and neck cancer†.b

In combination chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck†.349

Has been used in combination chemotherapy with radiation therapy for palliative treatment of unresectable locally advanced head and neck cancer,337 and for larynx preservation in locally advanced laryngeal or hypopharyngeal cancer.354 355 356 357

Used in combination with docetaxel and cisplatin as induction therapy prior to radiotherapy or chemoradiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.393 394

Cervical Cancer

Drug of choice combined with other drugs (e.g., cisplatin) for treatment of locally advanced cervical cancer†.b

In combination with cisplatin concurrently with radiation therapy for invasive cervical cancer†.249 359 360 361 362 364

Metastatic or recurrent cervical cancer†.249 365 366 367 369 370 371

Renal Cell Carcinoma

Has been used alone374 or in combination regimens375 376 377 378 379 380 381 382 383 384 for the treatment of metastatic renal cell carcinoma†.

Carcinoid Tumors

Drug of choice for treatment of carcinoid tumors†.b

Other Uses

Second-line therapy in the treatment of ovarian epithelial cancer†, including platinum-refractory disease.b 241 Also, cancers of the liver† (e.g., hepatoblastoma†).b 249

Stability

Storage

Parenteral

Injection

Discard unused portion of 2.5 or 5 g pharmacy bulk package 1 hour after the vial has been entered.a

15–30°C;205 do not freeze, protect from light.a

Slight discoloration during storage does not adversely affect potency or safety.205 a

Fluorouracil precipitation occurs commonly, particularly following exposure to low temperatures.274 Dissolve precipitate by heating to 60°C and shaking vigorously; cool to body temperature before using.205 a

Ease of dissolution may depend on the crystal size and location (e.g., those lodged between the stopper and glass container).274 Attempts to dissolve precipitate with heat and agitation may be unsuccessful.274

Store in adequately heated areas during cold weather to minimize frequency of precipitation.274

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility Admixture CompatibilityHID

Compatible

Bleomycin sulfate

Cyclophosphamide

Cyclophosphamide with methotrexate sodium

Etoposide

Floxuridine

Hydromorphone HCl

Ifosfamide

Methotrexate sodium

Mitoxantrone HCl

Vincristine sulfate

Incompatible

Carboplatin

Ciprofloxacin

Cisplatin

Cytarabine

Diazepam

Doxorubicin HCl

Epirubicin HCl

Fentanyl citrate

Leucovorin calcium

Metoclopramide HCl

Morphine sulfate

Y-site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Anidulafungin

Aztreonam

Bleomycin sulfate

Cisplatin

Cyclophosphamide

Doripenem

Doxorubicin HCl

Doxorubicin HCl liposome injection

Etoposide phosphate

Fludarabine phosphate

Furosemide

Gemcitabine HCl

Granisetron HCl

Heparin sodium

Hydrocortisone sodium succinate

Leucovorin calcium

Linezolid

Mannitol

Melphalan HCl

Methotrexate sodium

Metoclopramide HCl

Mitomycin

Paclitaxel

Palonosetron HCl

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Potassium chloride

Propofol

Sargramostim

Teniposide

Thiotepa

Vinblastine sulfate

Vincristine sulfate

Incompatible

Aldesleukin

Amphotericin B cholesteryl sulfate complex

Droperidol

Filgrastim

Gallium nitrate

Topotecan HCl

Vinorelbine tartrate

Variable

Ondansetron HCl

Proper Use of Adrucil

This medicine is sometimes given together with certain other medicines. If you are using a combination of medicines, it is important that you receive each one at the proper time. If you are taking some of these medicines by mouth, ask your health care professional to help you plan a way to remember to take them at the right times.

Fluorouracil often causes nausea and vomiting. However, it is very important that you continue to receive the medicine, even if your stomach is upset. Ask your health care professional for ways to lessen these effects.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

What are some things I need to know or do while I take Adrucil?

  • Tell all of your health care providers that you take Adrucil. This includes your doctors, nurses, pharmacists, and dentists.
  • You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
  • If loose stools (diarrhea) or throwing up happens, you will need to make sure to avoid dehydration and electrolyte problems. Talk with the doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • The chance of very bad and sometimes deadly side effects is raised in patients who do not have the enzyme dihydropyrimidine dehydrogenase (DPD) in the body. These include mouth irritation or sores, loose stools (diarrhea), low white blood cell counts, or nerve problems. Talk with the doctor.
  • This medicine may cause heart problems like heart attack, heart failure, and an abnormal heartbeat. These effects may be more common in people who have had heart disease before. Talk with the doctor.
  • If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
  • Talk with your doctor before getting any vaccines. Use with Adrucil may either raise the chance of an infection or make the vaccine not work as well.
  • You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
  • This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 3 months after care ends. Use birth control that you can trust.
  • If you are a man and your sex partner gets pregnant while you take this medicine or within 3 months after your last dose, call your doctor right away.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • Use birth control that you can trust to prevent pregnancy while taking Adrucil and for 3 months after care ends.
  • If you get pregnant while taking this medicine or within 3 months after your last dose, call your doctor right away.

What are some other side effects of Adrucil?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Upset stomach or throwing up.
  • Not hungry.
  • Loose stools (diarrhea).
  • Mouth irritation or mouth sores.
  • Hair loss.
  • Dry skin.
  • Change in nails.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Indications and Usage for Adrucil

Adrucil (fluorouracil injection) is indicated for the treatment of patients with:

Adenocarcinoma of the Colon and Rectum

Adenocarcinoma of the Breast

Gastric Adenocarcinoma

Pancreatic Adenocarcinoma

Adverse Reactions

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

• Increased risk of serious or fatal adverse reactions in patients with low or absent dipyrimidine dehydrogenase activity [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)]

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)

Use in specific populations

Pregnancy

Teratogenic Effects
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.

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.

Pediatric Use

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

Geriatric Use

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

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)].

Patient Counseling Information

Advise:

• Patients to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity [see Warnings and Precautions (5.1)]. • 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 [seeWarnings 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 andPrecautions (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)].

Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Rev. C 10/2016

Pharmacology

Half-Life: 16 min

Onset: 2-7 d, but may take up to 12 wk

Duration: 24 hr

Metabolism: liver

Metabolites: urea, fluorouracil, dihydrofluorouracil, expired CO2 metabolite

Excretion: urine

Pharmacogenomics

Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates >80% of 5FU standard doses and the 5FU prodrug capecitabine

Contraindicated in patients with DPD deficiency; causes severe toxicity with conventional doses (ie, grade III/IV toxicity and potentially fatal neutropenia, mucositis, and diarrhea)

Because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted

Genetic testing laboratories

  • The following companies currently offer testing for DPYD*2A mutations
  • EntroGen (http://www.entrogen.com)
  • Myriad (http://www.myriadtests.com)
  • LabCorp (http://www.labcorp.com)
  • Molecular Diagnostics Laboratories (http://www.mdl-labs.com)

Mechanism of Action

Inhibits DNA synthesis during S phase by inhibition of thymidylate synthetase

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