Idamycin (Idarubicin)

IDAMYCIN®

Pharmacia & Upjohn

Idarubicin HCl

Antineoplastic

Action And Clinical Pharmacology: Idarubicin, either as a single agent or in combination, has been shown to be a potent antileukemic agent capable of inducing complete remission in previously untreated and in relapsed and refractory acute non-lymphocytic leukemia (ANLL) including resistant patients, and in adult and pediatric relapsed patients with acute lymphoblastic leukemia (ALL).

Idarubicin is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The modification, in 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.

Idarubicin has been shown to have a higher potency than daunorubicin and to be an effective agent against murine leukemias and lymphomas. In vitro studies on human and murine anthracycline-resistant cells have revealed a lower degree of cross-resistance for idarubicin in comparison with doxorubicin and daunorubicin.

Seven pharmacokinetic studies were carried out in 49 patients. The plasma concentrations of idarubicin fit a 2 or 3 compartment open model. After i.v. administration to patients with normal renal and hepatic function, idarubicin is eliminated from systemic circulation with a terminal plasma half-life ranging between 11 to 25 hours and is extensively metabolized to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma half-life ranging between 41 to 69 hours. The drug is eliminated by biliary and renal excretion, mostly in the form of idarubicinol.

Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemic patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Idarubicin and idarubicinol concentrations 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.

Protein binding was studied in vitro by equilibrium dialysis at concentrations of idarubicin and idarubicinol similar to the maximum plasma level obtained in the pharmacokinetic studies. The percent of idarubicin and idarubicinol bound to human plasma proteins at the concentration of 100 ng/mL plasma is on the average 97% and 94% respectively.

Indications And Clinical Uses: In acute nonlymphocytic leukemia (ANLL) in adults for remission induction as front-line therapy or for remission induction in relapsed or refractory patients.

Also indicated in acute lymphocytic leukemia (ALL) as second-line treatment in adults and children.

Contra-Indications: In patients with a history of allergic reactions to idarubicin.

Manufacturers’ Warnings In Clinical States: Caution: Idarubicin is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs (see Precautions). Blood counts and hepatic function tests should be performed regularly. Cardiac monitoring is advised especially in those patients who have received mediastinal radiotherapy, patients with pre-existing cardiac disease or previous therapy with anthracyclines or anthracenes at high cumulative doses.

Idarubicin is intended for use under the direction of physicians experienced in leukemia chemotherapy.

Idarubicin should not be given to patients with pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.

Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or other potentially cardiotoxic agents are co-factors for increased risk of idarubicin-induced cardiac toxicity and the benefit to risk ratio of idarubicin therapy in such patients should be weighed before starting treatment with idarubicin.

Like most other cytotoxic agents, idarubicin has mutagenic properties and it is carcinogenic in rats.

Idarubicin is a potent bone marrow suppressant. Myelosuppression, primarily of leukocytes, will therefore occur in all patients given a therapeutic dose of this agent and careful hematologic monitoring including granulocytes, red cells and platelets is required. Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection.

Cardiac toxicity of the type described for other anthracycline compounds, manifested by clinically evident congestive heart failure or by a decrease in left ventricular ejection fraction may occur during therapy or several weeks after termination of therapy. Discontinuation of idarubicin and treatment with vasodilators, digitalis, diuretics, sodium restriction and bed-rest is indicated.

Although a cumulative dose limit cannot yet be defined, available data on patients treated with idarubicin capsules indicate that total cumulative doses up to 400 mg/mhave a low probability of cardiotoxicity.

Acute life-threatening arrhythmias have been occasionally observed during therapy.

The risk of such myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal pericardial area or treatment with other potentially cardiotoxic agents or in patients with clinical situations in which the cardiac reserve is compromised (anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis).

Available evidence appears to indicate that cardiotoxicity is cumulative across members of the anthracycline and anthracene class of drugs. Patients who have previously received daunorubicin, doxorubicin or epirubicin are at particular risk for possible cardiotoxic effects of idarubicin at a lower total dose than previously untreated patients and, therefore, should be carefully monitored.

While there is no reliable method for predicting acute congestive heart failure, cardiac function should be carefully monitored during treatment in order to minimize the risk of cardiac toxicity. Cardiomyopathy induced by anthracyclines is usually associated with persistent QRS voltage reduction, increase beyond normal limits of the systolic time interval (PEP/LVET) and decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values. An electrocardiogram or echocardiogram and a determination of left ventricular ejection fraction by echocardiogram or by radionuclide cineangiography (MUGA scan) should be performed prior to starting therapy and during treatment with idarubicin. Early clinical diagnosis of drug-induced myocardial damage appears to influence the response to symptomatic therapy.

Idarubicin therapy should not be administered in patients with severe renal and liver impairment or in patients with uncontrolled infections unless the benefit outweighs the risk.

Since hepatic and/or renal function impairment can affect the disposition of idarubicin, liver and kidney function should be evaluated prior to, and during treatment. In a number of Phase III clinical trials, treatment was not given if bilirubin and/or creatinine serum levels exceeded 2 mg%. With other anthracyclines a 50% dose reduction is generally employed if either bilirubin levels are greater than 40 mol/L (2.35 mg%) or creatinine levels are greater than 200 mol/L (2.25 mg%).

Idarubicin must not be administered by i.m. or s.c. injection.

Extravasation of idarubicin during i.v. administration can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle (see Dosage). If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein.

Idarubicin may impart a red color to the urine for 1 to 2 days after administration and patients should be advised that this is no cause for alarm.

Pregnancy and Lactation: There is no conclusive information about idarubicin adversely affecting human fertility, or causing teratogenesis; however, in rats (but not rabbits) it is teratogenic and embryotoxic. Therefore, women of childbearing potential should be prescribed effective contraceptive methods and counselled on the risks of pregnancy.

If idarubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be informed of the potential hazard to the fetus. Mothers should be advised not to breast-feed while undergoing chemotherapy with idarubicin.

Precautions: Therapy with idarubicin requires close observation of the patient and laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced: blood uric acid levels should be monitored and appropriate therapy initiated if hyperuricemia develops. Appropriate measures must be taken to control any systemic infection before beginning therapy.

Extravasation of idarubicin at the site of i.v. injection can cause severe local tissue necrosis. The risk of thrombophlebitis at the injection site may be minimized by following the recommended procedure for administration.

Adverse Reactions: Severe myelosuppression and cardiac toxicity are the 2 major adverse effects. Other adverse reactions include: reversible alopecia in most patients; acute nausea and vomiting; mucositis, usually involving the oral mucosa and appearing 3 to 10 days after starting treatment; esophagitis and diarrhea, fever, chills, skin rash, elevation of liver enzymes and bilirubin in about 20 to 30% of cases and 10 to 20% of cases after i.v. and oral administration, respectively. Severe and sometimes fatal infections have been associated with idarubicin alone or in combination with cytarabine. Acute toxicities such as nausea and vomiting, mucositis, diarrhea and liver dysfunction are comparable to those of daunorubicin.

Idarubicin appears to have a cardiac toxicity potential which is similar to that of daunorubicin.

The cardiotoxicity of idarubicin, taking into consideration the high risk population of leukemic patients treated, is low. Overall, the incidence of serious cardiac events has been 2.0% out of 1 204 patients receiving idarubicin via i.v. administration. If patients previously treated with anthracyclines are excluded, the overall incidence is 1.58%. When idarubicin was administered orally, the incidence of serious cardiac events (grade 3 only) was 3.2%.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within 1 or 2 weeks. Treatment should aim to support the patient during this period and should utilize such measures as blood transfusions and reverse-barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to several months after the overdose. Patients should be observed carefully and if signs of cardiac failure arise, should be treated along conventional lines.

Dosage And Administration: I.V.: Acute Nonlymphocytic Leukemia (ANLL): In adults, for remission induction as front-line therapy or for remission induction in relapsed or refractory patients, the following dose schedules are recommended: (a) 12 mg/mdaily by i.v. injection for 3 days in combination with cytarabine, or (b) 8 mg/mdaily by i.v. injection as a single agent for 5 days.

Acute Lymphocytic Leukemia (ALL): As a second-line treatment, the following dose schedules are recommended: (a) in adults, 12 mg/mdaily by i.v. injection for 3 days as a single agent, or (b) in children, 10 mg/mdaily by i.v. injection for 3 days as a single agent.

These dose schedules should, however, take into account the hematological status of the patient and the dosage of the other cytotoxic drugs when used in combination. In patients with hepatic impairment a dose reduction should be considered.

Preparation of the Solution: Caution in handling of the powder and preparation of the solution must be exercised as skin reaction associated with idarubicin may occur (refer to Guidelines for Safe Preparation and Handling).

Idarubicin 5 mg and 10 mg vials should be reconstituted with 5 mL and 10 mL respectively of either Water for Injection USP or 0.9% Sodium Chloride Injection USP to give a final concentration of 1 mg/mL of idarubicin HCl. Diluents containing bacteriostatic agents are not recommended.

The vial contents are under a negative pressure to minimize aerosol formation during reconstitution; therefore, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.

Stability and Storage of Solution: The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration at 2 to 8°C. The solution should be protected from exposure to direct light and any unused solution should be discarded.

Administration: Care in the administration of idarubicin will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On i.v. administration of idarubicin extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that s.c. extravasation has occurred it is recommended that intermittent ice packs (1/2 hour immediately, then 1/2 hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication. If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered.

Idarubicin should be slowly administered into the tubing of a freely running i.v. infusion of Sodium Chloride Injection USP (0.9%). The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein and the dosage. However, the dosage should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly.

Unless specific compatibility data are available, mixing idarubicin with other drugs is not recommended. Precipitation occurs with heparin. Prolonged contact with any solution of an alkaline pH will result in degradation of the drug.

Guidelines for Safe Preparation and Handling: Preparation and Handling: 1. Preparation of antineoplastic solutions should be done in a vertical laminar flow hood (Biological Safety Cabinet-Class II).

2. Personnel preparing idarubicin solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks. If idarubicin contacts the skin or mucosa, the area should be washed with soap and water immediately.

3. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.

Disposal: 1. Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.

2. All needles, syringes, vials and other materials that have come in contact with idarubicin should be segregated in plastic bags, sealed and marked as hazardous waste. Incinerate at 1 000°C or higher. Sealed containers may explode if a tight seal exists.

3. If incineration is not available, idarubicin may be detoxified by adding sodium hypochlorite solution (household bleach) to the vial, in sufficient quantity to decolorize the idarubicin, taking care to vent the vial to avoid a pressure build-up of the chlorine gas that is generated. Dispose detoxified vials in a safe manner.

Needles, Syringes, Disposable and Nondisposable Equipment: Rinse equipment with an appropriate quantity of sodium hypochlorite solution. Discard the solution in the sewer system with running water and discard disposable equipment in a safe manner. Thoroughly wash nondisposable equipment in soap and water.

Spillage/Contamination: Wear gloves, mask, protective clothing. Treat spilled powder or liquid with sodium hypochlorite solution. Carefully absorb solution with gauze or towels again and place in polyethylene bag; seal, double bag and mark as hazardous waste. Dispose waste by incineration or by other methods approved for hazardous materials. Personnel involved in clean-up should wash with soap and water.

Availability And Storage: 5 mg: Each vial contains: idarubicin HCl 5 mg. Also contains lactose NF 50 mg. Cartons of 1.

10 mg: Each vial contains: idarubicin HCl 10 mg. Also contains lactose NF 100 mg. Cartons of 1.

Store at 15 to 30°C and protect from light.

IDAMYCIN® Pharmacia & Upjohn Idarubicin HCl Antineoplastic

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