Idarubicin

Idarubicin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• diarrhea
• sores in the mouth and throat
• stomach pain
• headache
• joint pain
• hair loss
• rash
• redness and blisters on the palms and soles

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• seizures
• hives
• dizziness
• fainting
• pale skin
• difficulty urinating
• yellowing of the skin or eyes

Idarubicin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Mechanism of Action

Anthracycline; intercalates between DNA base pairs, inhibits topoisomerase II, which in turn inhibits DNA and RNA synthesis

Pharmacokinetics

Half-Life: 14-35 hr (PO); 12-27 hr (IV)

Bioavailability: 30%

Protein Bound: 94-97%

Vd: 64 L/kg

Peak plasma time: 1-5 hr

Metabolism: Liver

Metabolites: Idarubicinol

Clearance: 122.8 L/hr

Excretion: Urine (5-13%)

Mechanism Of Action

Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines.

Pharmacokinetics

Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic function following intravenous administration of 10 to 12 mg/m² of idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine. The plasma concentrations of idarubicin are best described by a two or three compartment open model. The elimination rate of idarubicin from plasma is slow with an estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when used in combination with cytarabine. The elimination of the primary active metabolite, idarubicinol, is considerably slower than that of the parent drug with an estimated mean terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days.

The disposition profile shows a rapid distributive phase with a very high volume of distribution presumably reflecting extensive tissue binding. Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Concentrations of idarubicin and idarubicinol in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin disappearance rates in plasma and cells were comparable with a terminal half-life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours. The extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7-and 2.3-fold, respectively, and suggests no change in kinetics following a daily x 3 regimen. The percentages of idarubicin and idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies. The binding is concentration independent. The plasma clearance is twice the expected hepatic plasma flow indicating extensive extrahepatic metabolism.

The primary active metabolite formed is idarubicinol. As idarubicinol has cytotoxic activity, it presumably contributes to the effects of idarubicin.

The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol.

Pharmacokinetics In Special Populations

Idarubicin studies in pediatric leukemia patients, at doses of 4.2 to 13.3 mg/m²/day x 3, suggest dose independent kinetics. There is no difference between the half-lives of the drug following daily x 3 or weekly x 3 administration. Cerebrospinal fluid (CSF) levels of idarubicin and idarubicinol were measured in pediatric leukemia patients treated intravenously. Idarubicin was detected in 2 of 21 CSF samples (0.14 and 1.57 ng/mL), while idarubicinol was detected in 20 of these 21 CSF samples obtained 18 to 30 hours after dosing (mean = 0.51 ng/mL; range, 0.22 to 1.05 ng/mL). The clinical relevance of these findings is unknown.

The pharmacokinetics of idarubicin have not been evaluated in leukemia patients with hepatic impairment. It is expected that in patients with moderate or severe hepatic dysfunction, the metabolism of idarubicin may be impaired and lead to higher systemic drug levels. The disposition of idarubicin may be also affected by renal impairment. Therefore, a dose reduction should be considered in patients with hepatic and/or renal impairment (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

No formal drug interactions studies have been performed.

Clinical Studies

Four prospective randomized studies, three U.S. and one Italian, have been conducted to compare the efficacy and safety of idarubicin (IDR) to that of daunorubicin (DNR), each in combination with cytarabine as induction therapy in previously untreated adult patients with acute myeloid leukemia (AML). These data are summarized in the following table and demonstrate significantly greater complete remission rates for the IDR regimen in two of the three U.S. studies and significantly longer overall survival for the IDR regimen in two of the three U.S. studies.

There is no consensus regarding optional regimens to be used for consolidation; however, the following consolidation regimens were used in U.S. controlled trials. Patients received the same anthracycline for consolidation as was used for induction.

Studies 1 and 3 utilized 2 courses of consolidation therapy consisting of idarubicin 12 or 13 mg/m² daily for 2 days, respectively (or DNR 50 or 45 mg/m² daily for 2 days), and cytarabine, either 25 mg/m² by IV bolus followed by 200 mg/m² daily by continuous infusion for 4 days (Study 1), or 100 mg/m² daily for 5 days by continuous infusion (Study 3). A rest period of 4 to 6 weeks was recommended prior to initiation of consolidation and between the courses. Hematologic recovery was mandatory prior to initiation of each consolidation course.

Study 2 utilized 3 consolidation courses, administered at intervals of 21 days or upon hematologic recovery. Each course consisted of idarubicin 15 mg/m² IV for 1 dose (or DNR 50 mg/m² IV for 1 dose), cytarabine 100 mg/m² every 12 hours for 10 doses and 6-thioguanine 100 mg/m² orally for 10 doses. If severe myelosuppression occurred, subsequent courses were given with 25% reduction in the doses of all drugs. In addition, this study included 4 courses of maintenance therapy (2 days of the same anthracycline as was used in induction and 5 days of cytarabine).

Toxicities and duration of aplasia were similar during induction on the 2 arms in the U.S. studies except for an increase in mucositis on the IDR arm in one study. During consolidation, duration of aplasia on the IDR arm was longer in all three studies and mucositis was more frequent in two studies. During consolidation, transfusion requirements were higher on the IDR arm in the two studies in which they were tabulated, and patients on the IDR arm in Study 3 spent more days on IV antibiotics (Study 3 used a higher dose of idarubicin).

The benefit of consolidation and maintenance therapy in prolonging the duration of remission and survival is not proven.

Intensive maintenance with IDAMYCIN (idarubicin hydrochloride for injection, USP) is not recommended in view of the considerable toxicity (including deaths in remission) experienced by patients during the maintenance phase of Study 2.

A higher induction death rate was noted in patients on the IDR arm in the Italian trial. Since this was not noted in patients of similar age in the U.S. trials, one may speculate that it was due to a difference in the level of supportive care.

Common side effects of idarubicin include:

• infection
• nausea
• vomiting
• hair loss
• stomach cramps
• diarrhea
• inflammation and sores in the mouth
• skin reactions
• fever
• headache

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of idarubicin, there are no specific foods that you must exclude from your diet.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if idarubicin crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using idarubicin.

Idarubicin is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Idarubicin is used to treat acute myeloid leukemia (AML), a type of blood cancer.

Idarubicin may also be used for purposes not listed in this medication guide.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Do not receive a "live" vaccine while using idarubicin, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Idarubicin Hydrochloride Injection, USP in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7.

Idarubicin Hydrochloride Injection, USP contains no preservative and is for single dose only.

REFRIGERATE AT:  2° to 8°C (36° to 46°F).
Protect from light (keep in outer carton).

The container closure is not made with natural rubber latex.

Possible impaired metabolism leading to higher systemic concentrations in patients with moderate and severe impairment; disposition may also be affected.

Idarubicin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Roila, 2010).

Acute myeloid leukemia (AML): IV:

Manufacturer labeling: Induction: 12 mg/m2/day for 3 days (in combination with cytarabine); a second induction cycle may be administered if necessary.

Indication-specific dosing:

AML, relapsed/refractory: FLAG-IDA regimen: 10 mg/m2/day for 3 days (in combination with fludarabine, cytarabine, and filgrastim); a second course was given for consolidation upon hematologic recovery (Parker, 1997)

Acute promyelocytic leukemia (APL):

LPA 2005 (high-risk patients; Sanz, 2010):

Induction (all patients): 12 mg/m2/day on days 2, 4, 6, and 8 (day 8 dose was omitted in patients >70 years) in combination with ATRA (tretinoin) (Sanz, 2010)

Consolidation (patients ≤60 years): 5 mg/m2/day for 4 days in consolidation cycle 1 and 12 mg/m2/day for 1 day in consolidation cycle 3 (in combination with ATRA [tretinoin] and cytarabine) (Sanz, 2010)

APML4 protocol (Iland, 2012): Induction (age-adjusted dosing):

Age <60 years: 12 mg/m2/day on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)

Age 61 to 70 years: 9 mg/m2/day on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)

Age >70 years: 6 mg/m2/day on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)

Idarubicin HCl should be given slowly into a freely flowing intravenous infusion; it must never be given intramuscularly or subcutaneously. Severe local tissue necrosis can occur if there is extravasation during administration.

As is the case with other anthracyclines, the use of idarubicin HCl can cause myocardial toxicity leading to heart failure. Cardiac toxicity is more common in patients who have received prior anthracyclines or who have preexisting cardiac disease.

As is usual with antileukemic agents, severe myelosuppression occurs when idarubicin HCl is used at effective therapeutic doses.

It is recommended that idarubicin HCl be administered only under the supervision of a physician who is experienced in leukemia chemotherapy and in facilities with laboratory and supportive resources adequate to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The physician and institution must be capable of responding rapidly and completely to severe hemorrhagic conditions and/or overwhelming infection.

Dosage should be reduced in patients with impaired hepatic function.

Dosage should be reduced in patients with impaired renal function.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or alopecia. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), severe skin irritation or pain at injection site, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of infection, severe nausea, vomiting, severe diarrhea, severe abdominal pain, loss of strength and energy, mood changes, mouth sore, or redness or irritation of the palm or soles of feet (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.