Usual Adult Dose for Breast Cancer - Adjuvant

Initial dose: 100 to 120 mg/m2 IV in repeated 3- to 4-week cycles; either total dose on Day 1 of each cycle, or divided equally and given on Days 1 and 8 of each cycle

CEF-120 regimen (repeat every 28 days for 6 cycles):

• Cyclophosphamide: 75 mg/m2 orally on Days 1 to 14
• Epirubicin: 60 mg/m2 IV on Days 1 and 8
• 5-Fluorouracil: 500 mg/m2 IV on Days 1 and 8

• 5-Fluorouracil: 500 mg/m2 IV on Day 1
• Epirubicin: 100 mg/m2 IV on Day 1
• Cyclophosphamide: 500 mg/m2 IV on Day 1

• For starting doses of 100 to 120 mg/m2, give the infusion over 15 to 20 minutes.
• For patients who require lower starting doses due to organ dysfunction or who require modification of doses during therapy, the infusion time may be proportionally decreased, but should not be less than 3 minutes to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis.
• A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

• Doses are manufacturer suggested. Consult local protocol.
• Consider use of antiemetics when given in conjunction with other emetogenic drugs.
• Patients administered the 120 mg/m2 regimen should receive prophylactic antibiotics.

Renal Dose Adjustments

Mild to moderate renal impairment: No adjustment recommended.
Severe renal impairment (CrCl greater than 5 mg/dL): Consider lower doses.

Liver Dose Adjustments

In patients with elevated serum AST or serum total bilirubin concentrations reduce the dose as follows:

• Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal (ULN): Administer 50% of the recommended starting dose.
• Bilirubin greater than 3 mg/dL or AST greater than 4 x ULN: Administer 25% of the recommended starting dose.
• Do not administer this drug in patients with severe hepatic impairment.

Dose Adjustments

Dose adjustments for hematologic and nonhematologic toxicities within a cycle of treatment is based on nadir platelet counts less than 50,000/mm3, absolute neutrophil counts (ANC) less than 250/mm3, neutropenic fever, or Grade 3 or 4 nonhematologic toxicity.

• Reduce the Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle.
• Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are 100,000/mm3 or greater, ANC 1500/mm3 or greater, and nonhematologic toxicities have recovered to Grade 1 or less.

• Discontinue this drug in patients who develop cardiomyopathy.

• Consider administering a lower starting dose (75 to 90 mg/m2) for heavily pretreated patients, patients with preexisting bone marrow depression, or in the presence of neoplastic bone marrow infiltration.
• For patients receiving a divided dose (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000 to 100,000/mm3 and ANC is 1000 to 1499/mm3.
• If Day 8 platelet counts are less than 75,000/mm3, ANC less than 1000/mm3, or Grade 3 or 4 nonhematologic toxicity has occurred, omit the Day 8 dose.

Precautions

US BOXED WARNINGS:
CARDIAC TOXICITY:

• Myocardial damage, including acute left ventricular failure, has been reported.
• The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2.
• The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy.

• Assess left ventricular ejection fraction (LVEF) before and regularly during and after therapy.

• Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines.

• Extravasation of this drug can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting.

• Immediately terminate therapy and apply ice to the affected area.

• Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur.

• Hypersensitivity to the active component or any of the ingredients
• Hypersensitivity to other anthracyclines or anthracenediones
• Severe myocardial insufficiency
• Recent myocardial infarction or severe arrhythmias, or previous treatment with maximum cumulative dose of anthracyclines
• Severe persistent drug-induced myelosuppression Severe hepatic impairment (Child-Pugh C)
• Serum bilirubin level greater than 5 mg/dL

Dialysis

Data not available

Other Comments

Administration advice:

• When possible, to reduce the risk of developing cardiotoxicity in patients receiving this drug after stopping treatment with other cardiotoxic agents, especially those with long half-lives, delay this drug until the other agents have cleared from circulation.
• Antiemetics may reduce nausea and vomiting; consider use of antiemetics before administration of this drug or when clinically indicated, particularly when given in conjunction with other emetogenic drugs.
• Administer this drug into the tubing of a freely flowing IV infusion (0.9% sodium chloride or 5% glucose solution).

• Store refrigerated between 2C and 8C (36F and 46F). Do not freeze.
• Protect from light.
• Storage of the solution at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15C to 25C).
• Solution for injection should be used within 24 hours after removal from refrigeration.

• Sodium chloride 0.9%
• Glucose solution 5%
• Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of this drug.
• Do not mix this drug with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.
• This drug can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

• This drug is cytotoxic; follow applicable special handling and disposal procedures.

• Cardiac function
• Hematologic
• Renal function
• Hepatic function