Idarubicin Hydrochloride: An Effective Medicine to Treat Acute Myeloid Leukemia

Overview

Idarubicin, classified as an anthracycline anticancer medication, received FDA (Food and Drug Administration) approval on February 17, 1997, for treating acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Idarubicin is administered intravenously and is utilized in both adults and children to treat acute non-lymphoblastic leukemia, also known as acute myeloid leukemia. Additionally, it serves as a second-line therapy for relapsed acute lymphoblastic leukemia in adults and children. Its mechanism involves impeding the growth of cancer cells within the body.

Clinical Efficacy and Safety of Idarubicin Hydrochloride

Idarubicin hydrochloride is deemed safe and effective for treating acute myeloid leukemia (AML), showing better efficacy compared to Daunorubicin combined with Cytarabine (DA) in a meta-analysis. It resulted in higher rates of complete remission and better overall survival, with no significant difference in adverse events. Thus, idarubicin hydrochloride is recommended as the preferred induction regimen for AML patients.

How Does Idarubicin Hydrochloride Work?

Idarubicin fights cancer by attacking and killing rapidly multiplying cells in the body, often found in cancerous tumors. This action helps to slow down or stop the growth of cancer.

For Patients:

What Is Idarubicin Hydrochloride?

Idarubicin, a chemotherapy drug, serves as a treatment option for acute myeloid leukemia (AML) and recurrent acute lymphoblastic leukemia (ALL) in cases where prior treatment with another chemotherapy drug has occurred. It may be prescribed either as a standalone treatment or combined with other chemotherapy drugs.

What Is Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is a type of cancer that originates in the bone marrow, where new blood cells are produced. It swiftly spreads into the bloodstream and can potentially affect other parts of the body, such as the lymph nodes, liver, spleen, central nervous system, and testicles. AML primarily arises from immature white blood cells, though it can develop from other blood-forming cells as well. Various names, including acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia, also know about this condition.

How Should the Patient Take Idarubicin Hydrochloride?

Idarubicin may be administered in capsule form or as an intravenous drip directly into the bloodstream. Through intravenous administration, a long plastic tube is typically inserted into a large vein in the chest. This tube, which remains in place for the duration of treatment, can be referred to as a central line, PICC line, or portacath. Alternatively, without a central line, treatment may involve using a thin, short tube called a cannula inserted into a vein in the arm prior to each treatment session.

Idarubicin is taken orally as capsules, which are swallowed whole with water. The number of capsules needed daily is determined by the doctor based on specific requirements. It is advisable to consume the capsules with a light meal. Follow the instructions provided by the doctor or pharmacist strictly. Ensure to take the prescribed dosage, neither more nor less.

Before discontinuing any cancer medication, consult the specialist or advice line.

What Are the Things to Inform the Doctor Before Taking Idarubicin Hydrochloride?

• Before taking Idarubicin hydrochloride, inform the doctor if there are any allergies to Idarubicin hydrochloride or similar cancer medicines such as Daunorubicin, Doxorubicin, Epirubicin, or Mitoxantrone.

• Inform the doctor if experiencing symptoms of an allergic reaction to Idarubicin hydrochloride, such as shortness of breath, wheezing, difficulty breathing, swelling of the face, lips, tongue, or other parts of the body, or rash, itching, or hives on the skin.

• Avoid taking Idarubicin hydrochloride if there are severe kidney, liver, or heart problems, including heart failure (inability of the heart to pump enough blood to meet the body's needs), abnormal heartbeat, or recent heart attack (damage to the heart muscle due to a lack of blood supply)

• Avoid taking Idarubicin hydrochloride if there is a severe infection with symptoms like fever, severe chills, sore throat, or mouth ulcers.

• Avoid taking Idarubicin hydrochloride if there is a reduced number of red or white blood cells or platelets.

• Avoid taking Idarubicin hydrochloride if previously completed a full course of treatment with the maximum dose of Idarubicin or similar medicines.

• Avoid taking Idarubicin hydrochloride if pregnant, trying to become pregnant, or if the partner is trying to conceive. This medication may cause birth defects.

• Avoid breastfeeding during treatment with idarubicin hydrochloride and for at least 14 days after the last dose. Consult with a doctor or midwife if there are concerns about breastfeeding during this period.

What Are the Side Effects of Idarubicin Hydrochloride?

Frequent adverse effects associated with idarubicin hydrochloride include:

• Nausea.

• Vomiting.

• Abdominal or stomach cramps.

• Diarrhea.

• Headache.

• Facial flushing during administration.

• Eye irritation or tearing.

• Darkening of the nail beds and skin folds.

• Red-colored urine for one or two days post-dose.

• Temporary hair loss is also typical with Idarubicin. However, normal hair growth typically resumes after the treatment is completed.

For Doctors:

Indications: Idarubicin is prescribed for treating acute myeloid leukemia (AML) in adults, covering classifications M1 through M7 according to the French-American-British (FAB) system.

Dosage and Administration: For initial treatment in adult AML patients, the recommended dosage regimen is as follows:

• Idarubicin hydrochloride for injection at 12 mg/m2 (milligrams per square meter) daily for three days via slow (10 to 15 minute) intravenous injection in combination with Cytarabine is recommended.

• Cytarabine may be administered as 100 mg/m2 daily via continuous infusion for seven days or as a 25 mg/m2 intravenous bolus followed by Cytarabine 200 mg/m2 daily via continuous infusion for five days.

• Patients showing clear signs of leukemia after the first course of treatment may receive a second course, with administration delayed in those experiencing severe mucositis until recovery occurs. A 25 percent dose reduction is recommended.

• For patients with liver or kidney issues, a dose reduction should be considered. It should not be given if the bilirubin level exceeds five mg/L (milligrams per liter).

• The benefits of consolidation therapy in extending remission duration and survival have not been established. There is no consensus on recommended regimens for consolidation.

Clinical Pharmacology

1. Mechanism of Action: Idarubicin exhibits antimitotic and cytotoxic effects via several proposed mechanisms of action. It forms complexes with DNA (Deoxyribonucleic Acid) by intercalating between base pairs and inhibits the activity of topoisomerase II by stabilizing the DNA-topoisomerase II complex. This prevents the religation phase of the ligation-religation reaction catalyzed by topoisomerase II.

2. Pharmacodynamics: Idarubicin belongs to the anthracycline class of antineoplastics. These drugs interact with DNA in various ways, including intercalation, DNA strand breakage, and inhibition of the enzyme topoisomerase II. While most anthracyclines are derived from natural sources and antibiotics, they lack the specificity of antimicrobial antibiotics, leading to significant toxicity. Despite this, they remain crucial antitumor agents. Doxorubicin is commonly used for treating solid tumors, whereas Daunorubicin and Idarubicin are specifically used for leukemia. In addition to its primary mechanisms, idarubicin may inhibit polymerase activity, influence gene expression regulation, and cause free radical damage to DNA. It exhibits antitumor effects against a broad range of grafted and spontaneous tumors. Anthracyclines are not limited to specific phases of the cell cycle.

3. Pharmacokinetics: Idarubicin exhibits slow elimination in adult leukemia patients, with a mean terminal half-life of about 22 hours when used alone and 20 hours when combined with cytarabine. Its active metabolite, idarubicinol, has a longer half-life, sustaining plasma levels for over eight days.

• Distribution: Idarubicin rapidly distributes into tissues, with peak cellular concentrations exceeding plasma levels significantly. Idarubicinol's terminal half-life in cells is approximately 72 hours.

• Metabolism: The primary active metabolite is idarubicinol, contributing to Idarubicin's effects.

• Elimination: Idarubicin is mainly eliminated through bile and, to a lesser extent, urine, predominantly as idarubicinol.

4. Overdose: Overdosing may lead to severe myelosuppression and increased gastrointestinal toxicity, requiring supportive care. Acute overdose's impact on cardiac function is unclear, but severe arrhythmia occurred in one case. High doses may induce acute cardiac toxicity and increase the risk of delayed cardiac failure. Dialysis studies are lacking, but conventional methods are unlikely to significantly alter Idarubicin's efficacy or toxicity due to its unique pharmacokinetics.

What Are the Contraindications of Idarubicin Hydrochloride?

Contraindications to Idarubicin hydrochloride include the following:

• A history of hypersensitivity to Idarubicin, other anthracyclines, or anthracene diones, as well as total bilirubin levels exceeding 86 mcmol/L (micromoles per liter). Caution is advised in patients with existing or prior cardiovascular disease, recent myocardial infarction, severe arrhythmias, or those predisposed to cardiac toxicity due to factors such as prior or concomitant radiation to the thoracic area, use of other cardiotoxic agents like Trastuzumab, or previous therapy with anthracyclines or anthracene diones. Baseline electrocardiogram (ECG) and either multigated acquisition (MUGA) or echocardiogram (ECHO) are recommended, with the observation of maximum cumulative doses of anthracyclines or anthracene diones.

• Concomitant or prior radiation within two to three weeks before Idarubicin administration may increase myelosuppression risk. Patients over 60 years old with preexisting cardiac disease or using other cardiotoxic agents may experience more frequent asymptomatic declines in left ventricular ejection fraction (LVEF).

• Idarubicin may pose carcinogenic risks, potentially causing secondary leukemias, especially in combination with DNA-damaging antineoplastic agents, with a latency period of one to three years. It is also mutagenic and clastogenic in unspecified tests. Idarubicin is reported to be toxic to reproductive organs, inducing chromosomal damage to human spermatozoa. Men are advised to use appropriate contraceptive methods during treatment to prevent pregnancy.

• Regarding pregnancy, Idarubicin falls under FDA pregnancy category D, indicating positive evidence of fetal risk, but may be acceptable in life-threatening situations or serious diseases where safer drugs are ineffective. Breastfeeding is not recommended due to potential drug secretion into breast milk, with the parent drug and metabolite possibly requiring 10 days or longer for elimination.

What Are the Adverse Effects of Idarubicin Hydrochloride?

The adverse reactions to Idarubicin include:

• Myelosuppression: Severe myelosuppression is the primary toxicity associated with Idarubicin therapy, increasing the risk of infection and bleeding, which can be life-threatening.

• Gastrointestinal Effects: Common gastrointestinal effects include nausea, vomiting, mucositis, abdominal pain, and diarrhea. Severe enterocolitis with perforation is rare but possible, especially with instrumental intervention.

• Dermatologic Reactions: Alopecia (hair loss) is common, and dermatologic reactions such as generalized rash, urticaria, and bullous erythrodermatous rash of the palms and soles have occurred. Local reactions like hives at the injection site have also been reported.

• Hepatic and Renal Changes: Transient changes in hepatic and renal function tests may occur, particularly in sepsis and concurrent use of hepatotoxic and nephrotoxic agents.

• Cardiac Effects: Congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and declines in left ventricular ejection fraction (LVEF) have been reported, particularly during induction therapy for acute myeloid leukemia. These events are more frequent in patients over 60 years old and those with pre-existing cardiac conditions.

Warnings and Precautions:

Medications, Foods, and Beverages: Certain cancer drugs can interact with certain medications or herbal supplements. Inform the doctor or pharmacist about all medications currently taken, including vitamins, herbal supplements, and over-the-counter remedies.

Avoid Idarubicin if Trastuzumab (Herceptin) has been received within the last seven months, as it can affect heart function and persist in the body for approximately seven months after treatment. Since Idarubicin also impacts heart function, it is advisable to wait until Trastuzumab is fully eliminated from the system before using Idarubicin.

Fertility Concerns: Treatment with this drug may impact fertility, potentially affecting the ability to conceive or father a child. Discuss fertility preservation options with the doctor before initiating treatment if intending to have children in the future. Sperm banking for men and egg or ovarian tissue preservation for women may be options to consider, although availability varies by hospital.

Contraception and Pregnancy: Because this treatment can harm a developing fetus, it is crucial to avoid pregnancy or causing pregnancy during treatment and for several months afterward. Discuss reliable contraception methods with healthcare providers before starting treatment, and promptly notify them if pregnancy occurs during treatment.

Breastfeeding: Avoid breastfeeding while undergoing treatment, as the drug may pass into breast milk.

Other Medical Treatments: Inform healthcare providers about the cancer treatment when undergoing tests or treatment for other conditions, such as dental procedures.

Immunizations: Depending on the specific treatment regimen, avoid live vaccines during treatment and for up to 12 months afterward.

What Are the Drug Interactions of Idarubicin Hydrochloride?

The drug interactions of Idarubicin hydrochloride are not known.

Clinical Studies: According to clinical studies, Idarubicin shows superior complete remission rates compared to daunorubicin (DNR) in induction therapy for previously untreated adult patients with acute myeloid leukemia (AML). Specifically, two out of three U.S. (United States) studies indicate higher complete remission rates with the Idarubicin regimen, and two out of three U.S. studies demonstrate longer overall survival with IDR.

Consolidation regimens varied across studies, with different courses and doses of Idarubicin and cytarabine utilized. Toxicities during induction were generally similar between IDR and DNR arms, though mucositis was increased in one IDR study. However, during consolidation, IDR was associated with a longer duration of aplasia in all three studies and more frequent mucositis in two studies. In some instances, transfusion requirements were higher with IDR, and patients on IDR spent more days on IV antibiotics in one study.

Overall, the benefit of consolidation and maintenance therapy in extending remission and survival is not definitively established. Intensive maintenance with Idarubicin is not recommended due to the substantial toxicity observed during maintenance phases in certain studies. Additionally, a higher induction death rate was noted in patients receiving IDR in an Italian trial, potentially due to differing levels of supportive care compared to U.S. trials.