Adrucil

Name: Adrucil

Drug interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: certain antibiotics (metronidazole, tinidazole), warfarin.

Overdose

If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Notes

Laboratory and/or medical tests (e.g., complete blood counts) should be performed to monitor your progress or check for side effects. Consult your doctor for more details.

Other Requirements

Injectable:

  • Store at room temperature 15° to 30°C (59° to 86°F).
  • Protect from light.
  • Retain in carton until time of use.

Topical:

  • Keep this medicine at room temperature (68–77° F/ 20–25° C). Throw away unused medicine.
  • Keep this medicine out of the reach of children.
  • Medicines are sometimes prescribed for conditions that are not described in patient information leaflets. Do not use it for a condition for which it was not prescribed. This medicine is for your use only. Never give it to other people. It may harm them even if their skin problem appears to be the same as yours. Do not use Carac after the expiration date on the tube.

Adrucil Dosage and Administration

Administration

Administer IV.205 a

Has been administered by regional infusion into the venous or arterial blood supply of a tumor† (e.g., portal vein or hepatic artery infusions for liver metastases).230 253 256 258 259 264 275 280 a

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

2.5- or 5-g pharmacy bulk package is intended for individual dose preparation, not for direct IV infusion.a

Avoid extravasation.205 a

Dilution

No dilution necessary for usual injection formulation.205 a

Rate of Administration

Administer through a 25-gauge needle at any convenient rate.a

Dosage

Base dosage on actual weight.205 a

Base dosage on estimated lean body mass if patient is obese or has fluid retention.205 a

May calculate dosage based on body surface area.215 218 220 266 275 286 289 292 293 294 295 296 298 300 304 305 317 320 321 322 323 328

Base dosage on clinical and hematologic response and patient tolerance to obtain optimum results with minimum adverse effects.a

Consult published protocols for the dosage and method and sequence of administration of fluorouracil with other chemotherapeutic agents.a

Adults

Usual Dosage IV

Initially, manufacturers recommend a course of 12 mg/kg once daily for 4 consecutive days, up to 800 mg daily; then (if toxicity does not preclude) administer 6 mg/kg on the 6th, 8th, 10th and 12th days (unless toxicity occurs before then).205 a

Poor risk and inadequate nutrition: initially, manufacturers suggest a course of 6 mg/kg daily for 3 days, up to 400 mg daily; then (if toxicity does not preclude) may administer 3 mg/kg on the 5th, 7th, and 9th days (unless toxicity occurs before then).205 a

Repeat courses: adjust schedule according to reaction to the previous course.205 a

Repeat course at 30-day intervals if toxicity has not been a problem.205 a

Alternatively, when toxicity of initial course has subsided, may administer 10–15 mg/kg (up to 1 g) once weekly for maintenance.205 a

Colorectal Cancer

Various fluorouracil/leucovorin combination dosage regimens have been used.215 220 266 289 296 298 304 305 317

Monthly Schedule (Mayo Clinic Regimen) Direct IV Injection

Leucovorin 20 mg/m2 IV or levoleucovorin 10 mg/m2 IV followed by fluorouracil 425 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 289 386 388 395 Frequently administered for a total of 6 cycles in the adjuvant setting.386 388

Alternatively, leucovorin 200 mg/m2 IV or levoleucovorin 100 mg/m2 IV over ≥3 minutes followed by fluorouracil 370 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 395 397

Adjust fluorouracil dosage in subsequent courses according to tolerance;286 395 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 395 (leucovorin or levoleucovorin dosage is not adjusted286 395 ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286 395

Weekly Schedule (Roswell Park Regimen) IV Infusion

Leucovorin 500 mg/m2 as a 2-hour IV infusion followed by fluorouracil 500 mg/m2 as a slow IV injection administered 1 hour after the start of the leucovorin infusion†.386 388 Administer both drugs weekly for 6 consecutive weeks followed by a 2-week rest; repeat cycles every 8 weeks for a total of 4 courses in the adjuvant setting.386 388

Adjust fluorouracil dosage in subsequent courses according to tolerance;286 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 (leucovorin dosage is not adjusted286 ).

May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286

Bimonthly Schedule (Modified deGramont Regimen) IV Infusion

Leucovorin 400 mg/m2 as a 2-hour IV infusion on day 1 followed by fluorouracil 400 mg/m2 as an IV injection on day 1; then fluorouracil 1500 mg/m2 as a continuous IV infusion over 23 hours on days 1 and 2 (i.e., total 3000 mg/m2 by continuous IV infusion over 46 hours);391 repeat cycles every 2 weeks.

Breast Cancer

Various combination regimens have been used; consult published protocols for dosages and method and sequence of administration.246 269 271 272 320 321 322 323 324 325 326 328

Avoid arbitrary dose reductions of adjuvant combination chemotherapy; dose intensity appears to be an important factor influencing clinical outcome in early node-positive breast cancer (increasing response with increasing intensity).244 322

Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil IV

Regimen containing IV fluorouracil in combination with oral cyclophosphamide and IV methotrexate is described in the table.320 321

Drug

Dose

Administration Days per Cycle

Fluorouracil

600 mg/m2 IV (≤60 yrs of age)320 321

Days 1 and 8320 321

Cyclophosphamide

100 mg/m2 orally320 321

Days 1 through 14 320 321

Methotrexate

40 mg/m2 IV (≤60 yrs of age)320 321

Days 1 and 8 320 321

Repeat monthly (i.e., allow a 2-week rest period between cycles).320 321

Total of 6–12 cycles (i.e., 6–12 months of therapy); clinical superiority between 6- versus 12-month regimens not demonstrated.244 319 320 321

Initial fluorouracil and methotrexate dosages have been reduced in patients >60 years of age.321 (See Geriatric Patients under Special Populations.)

Also, dosage was reduced if myelosuppression developed.320 321

Sequential Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil Plus Doxorubicin

In early breast cancer and >3 positive axillary lymph nodes, doxorubicin addition may improve outcome, and sequential regimens (i.e., several courses of doxorubicin first) may be more effective than alternating regimens; no additional benefit when fewer positive nodes are present.323 326

IV

Initially, doxorubicin hydrochloride 75 mg/m2 IV at 3-week intervals for 4 doses.323 328

Subsequently, fluorouracil 600 mg/m2 IV, methotrexate 40 mg/m2 IV, and cyclophosphamide 600 mg/m2 IV at 3-week intervals for 8 cycles.323 328

Total of about 9 months of therapy.323 328

Generally, myelosuppression has delayed cycle rather than reducing dosage.323 328

Prescribing Limits

Adults

General Dosage IV

Initially (first 4 days), manufacturers recommend maximum of 800 mg daily.205 a

Poor risk and inadequate nutrition: manufacturers recommend initially (first 3 days) maximum of 400 mg daily.205 a

Alternative dosage for maintenance once toxicity of initial course has subsided: manufacturers recommend maximum of 1 g once weekly.205 a

Special Populations

Geriatric Patients

Breast Cancer

In patients >60 years of age receiving oral cyclophosphamide, IV methotrexate, and IV fluorouracil combination therapy, reduce initial methotrexate dosage to 30 mg/m2 and fluorouracil dosage to 400 mg/m2.321

Interactions for Adrucil

Specific Drugs

Drug

Interaction

Comments

Leucovorin

Leucovorin potentiates cytotoxicity of fluorouracil in certain GI cancers215 216 218 219 220 221 222 223 224 225 230 253 262 263 265 266 267

Leucovorin enhances fluorouracil toxicity214 286

Used to therapeutic advantage in GI cancers200 201 202 203 204 212 215 216 218 219 220 230 253

Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286

Levoleucovorin

Levoleucovorin enhances therapeutic effects of fluorouracil in colorectal cancer395

Levoleucovorin enhances fluorouracil toxicity395

Used to therapeutic advantage in colorectal cancer395 397

Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286 315 395

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluorouracil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

50 mg/mL*

Adrucil

Teva

Fluorouracil Injection

50 mg/mL (2.5 or 5 g) pharmacy bulk package*

Adrucil

Teva

Fluorouracil Injection

How is this medicine (Adrucil) best taken?

Use Adrucil as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as an infusion into a vein over a period of time.
  • It may be given as a shot into a vein.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Chest pain or pressure.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • A heartbeat that does not feel normal.
  • Dizziness or passing out.
  • Black, tarry, or bloody stools.
  • Throwing up blood or throw up that looks like coffee grounds.
  • Very bad belly pain.
  • Very upset stomach or throwing up.
  • Very loose stools (diarrhea).
  • Very bad mouth irritation.
  • Change in eyesight.
  • If bright lights bother your eyes.
  • Redness or irritation of the palms of hands or soles of feet.
  • Swelling in the feet or hands.
  • Feeling confused.
  • Change in balance.
  • Feeling very sleepy.
  • A burning, numbness, or tingling feeling that is not normal.
  • Not able to control eye movements.
  • Headache.
  • This medicine may irritate the vein. It may burn the skin if the drug leaks from the vein when it is given. Tell your nurse if you have any redness, burning, pain, swelling, or leaking of fluid where the drug is going into your body.
  • This medicine may lower the ability of your bone marrow to make blood cells that your body needs. This can lead to very bad and sometimes deadly bleeding problems or infections. Tell your doctor right away if you have signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, a wound that will not heal; any bruising or bleeding; or if you feel very tired or weak.

Adrucil Dosage and Administration

General Dosage Information

Adrucil is recommended for administration either as an intravenous bolus or as an intravenous infusion. 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.

Recommended Dosage for Adenocarcinoma of the Colon and Rectum

• The recommended dose of Adrucil, 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 Adrucil, 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.

Recommended Dosage for Adenocarcinoma of the Breast

• The recommended dose of Adrucil, 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.

Recommended Dosage for Gastric Adenocarcinoma

• The recommended dose of Adrucil, 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 Adrucil and the specific regimen administered.

Recommended Dosage for Pancreatic Adenocarcinoma

• The recommended dose of Adrucil, 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.

Dose Modifications

Withhold Adrucil 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 Adrucil administration at a reduced dose.

There is no recommended dose for resumption of Adrucil administration following development of any of the following adverse reactions:

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

Preparation for Administration

The 10 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.

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.

Administration

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

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

Store diluted solutions of Adrucil 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.

Contraindications

None.

Warnings and Precautions

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 fluorouracil (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 fluorouracil.

Withhold or permanently discontinue fluorouracil 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 fluorouracil 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.

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.

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.

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.

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.

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 to 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.

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.

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.

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)].

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)].

Administration

IV Incompatibilities

Additive: carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, fentanyl, leucovorin, metoclopramide, morphine sulfate

Syringe: doxorubicin (at high conc of doxo & 5FU, compatible at lower conc), droperidol, epirubicin

Y-site: aldesleukin, amphotericin B cholesteryl SO4, droperidol, filgrastim, ondansetron(?), topotecan, vinorelbine

IV Compatibilities

Solution: compatible w/ most common solvents

Additive: bleomycin, cyclophosphamide, cyclophosphamide/methotrexate, etoposide, floxuridine, hydromorphone, ifosfamide, methotrexate, mitoxantrone, vincristine

Syringe: bleomycin, cisplatin, cyclophosphamide, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

Y-site: (partial list) allopurinol, furosemide, granisetron, heparin, hydrocortisone-Na-succinate, leucovorin, linezolid, metoclopramide, piperacillin/tazobactam, KCl, propofol, vit B/C

IV Preparation

IV Push: dose/syringe (concentration: 50 mg/mL); max syringe size for IVP is 30 mL syringe and syringe should be <75% full

Continuous IV Infusion/IVPB: dose/50-1000 mL D5W or NS; syringe and solution are stable for 72 hr at 4 to 25°C

IV Administration

Direct IV push injection (50 mg/mL solution needs no further dilution) or by IV infusion

Toxicity may be reduced by giving the drug as a constant infusion

Bolus doses may be administered by slow IVP or IVPB

Warm to body temperature before using

Continuous IV infusion may be administered in D5W or NS

Solution should be protected from direct sunlight

5-FU may also be administered intra-arterially or intra-hepatically

Use plastic IV containers for continuous infusions (stable in plastic IV bags than in glass bottles)

Storage

Store intact vials at room temp & protect from light

Slight discoloration does not usually denote decomposition

Don't use cloudy solutions

  • If crystals form, redissolve by warming

Don't refrigerate

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