Idamycin (Idarubicin) is an anthracycline antileukemic medicine that has potent bone marrow suppressant properties. It is used in conjunction with other drugs to treat acute leukemia.

Idamycin (Idarubicin) Uses:

• Acute myeloid leukemia:

  • Used for treatment of acute myeloid leukemia (AML) in adults (in combination with other approved chemotherapy agents).

Idamycin (Idarubicin) Dose in Adults:

• There is moderate emetic potential associated with idarubicin and antiemetics are therefore recommended for prevention of nausea and vomiting.

Idamycin (Idarubicin) Dose in the treatment of Acute myeloid leukemia (AML): 

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

• Indication-specific dosing:

  • AML, relapsed/ refractory:

    • FLAG-IDA regimen:
      • 10 mg/m²/day for 3 days (in combination with fludarabine, cytarabine, and filgrastim)
      • 2nd course was given for consolidation upon hematologic recovery.

Idamycin (Idarubicin) Dose in the treatment of Acute promyelocytic leukemia (APL):

• LPA 2005 (high-risk patients):

  • Induction (all patients):
    • 12 mg/m²/day, given on days 2, 4, 6, and 8 (day 8 dose was omitted in patients >70 years of age) in combination with ATRA (tretinoin).
  • Consolidation (patients ≤60 years of age):
    • 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).

• APML4 protocol:

  • Induction (age-adjusted dosing):

    • Age <60 years of age:
      • 12 mg/m²/day, given on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)
    • Age 61 to 70 years:
      • 9 mg/m²/day, given on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)
    • Age >70 years of age:
      • 6 mg/m²/day, given on days 2, 4, 6, and 8 (in combination with ATRA [tretinoin] and arsenic trioxide)

Idamycin (Idarubicin) Dose in Childrens:

Note:

• Depending upon treatment protocol and/or treatment phase, dose, frequency, number of doses, and start date may vary; refer to specific protocols.
• There is a moderate emetic potential associated with the use of Idarubicin; antiemetics are therefore recommended for the prevention of nausea and vomiting.

Idamycin (Idarubicin) Dose in the treatment of Acute myeloid leukemia (AML):

• Infants, Children, and Adolescents:

  • New diagnosis (CCG-2961):

    • Induction: IV: IdaDCTER:
      • Idarubicin 5 mg/m²/dose daily for 4 days on days 0 to 3, given in combination with cytarabine, etoposide, thioguanine, and dexamethasone
    • Consolidation: IV:
      • IdaDCTER: Idarubicin 5 mg/m²/dose daily for 4 days on days 0 to 3, given in combination with cytarabine, etoposide, thioguanine, and dexamethasone
      • OR
    • Idarubicin 12 mg/m²/dose daily for 3 days on days 0 to 2, given in combination with fludarabine and cytarabine

Relapsed/ refractory: IV:

• Children and Adolescents:

  • 12 mg/m² once daily for 3 days, given in combination with fludarabine and cytarabine.

Idamycin (Idarubicin) Pregnancy Risk Category: D

• Unstable events were reported in animal reproduction studies.
• A case report involving second-trimester exposure of a pregnant woman was reported with fetal death.
• The European Society for Medical Oncology's Guidelines for the Diagnosis, Treatment, and Follow-Up of Cancer During Pregnancy (ESMO) recommends that an anthracycline agent, other than idarubicin, be used (in combination with cytarabine), for induction treatment for acute myeloid leukemia.
• These guidelines recommend that you refer to a facility with expertise on cancer during pregnancy.
• A multidisciplinary team (obstetrician-neonatalian, oncologist, etc.) is also encouraged (Peccatori 2013,
• According to the manufacturer, women with reproductive potential should not get pregnant while undergoing treatment.

Use of Idarubicin while breastfeeding

• It is unknown if breast milk contains idarubicin.
• Manufacturers do not recommend breastfeeding due to the risk of serious adverse reactions in infants who are breastfed.

Idamycin (Idarubicin) Dose in Kidney Disease:

No dosage adjustments have been provided in the manufacturer's labeling; however, it does recommend that dosage reductions be made.

• The following adjustments have been recommended (Aronoff 2007):

  • CrCl >50 mL/minute:
    • Dose adjustment is not necessary.
  • CrCl 10 to 50 mL/minute:
    • Administer 75% of the dose.
  • CrCl <10 mL/minute:
    • Administer 50% of the dose.
  • Hemodialysis:
    • Supplemental dose not needed.
  • Continuous ambulatory peritoneal dialysis (CAPD):
    • Supplemental dose not needed.

Idamycin (Idarubicin) Dose in Liver Disease:

• Bilirubin 2.6 to 5 mg/dL:
  • Administer 50% of the dose.
• Bilirubin >5 mg/dL: 
  • Use should be avoided.

• The relative cardiotoxicity of idarubicin as compared to doxorubicin is not clear.
• Some investigators have reported no increase in cardiac toxicity for adults at cumulative oral idarubicin doses up to 540 mg/m²
• Other reports have suggested a maximum cumulative intravenous dose of 150 mg/m².

Common Side Effects of Idamycin (Idarubicin):

• Cardiovascular:

  • Cardiac Failure
  • ECG Abnormalities

• Central Nervous System:

  • Headache

• Dermatologic:

  • Alopecia
  • Skin Rash
  • Urticaria

• Gastrointestinal:

  • Vomiting
  • Gastrointestinal Hemorrhage
  • Diarrhea
  • Stomatitis
  • Nausea

• Genitourinary:

  • Urine Discoloration

• Hematologic & Oncologic:

  • Anemia
  • Bone Marrow Suppression
  • Thrombocytopenia

• Hepatic:

  • Increased Serum Bilirubin
  • Increased Serum Transaminases

• Miscellaneous:

  • Radiation Recall Phenomenon

Less Common Side Effects of Idamycin (Idarubicin):

• Central nervous system:

  • Peripheral neuropathy
  • Seizure

Contraindications to Idamycin (Idarubicin):

• The manufacturer's labeling does not contain any contraindications.

Canadian labeling: Additional contraindications not in the US labeling

• Patients with hypersensitivity to idarubicin or any other anthracyclines, anthracenediones, or any component of the formulation are contraindicated
• Uncontrolled infections
• Recent MI, severe myocardial dysfunction, severe arrhythmia, history of severe heart disease
• Therapy with the maximum cumulative doses of idarubicin or doxorubicin and/or epirubicin.
• Myelosuppression resulting from persistent use of drugs
• Hepatic impairment severe
• Grave renal impairment
• There is not much evidence of cross-reactivity between drugs within this class and allergenic substances. 
• Cross-sensitivity is possible due to similarities in chemical structure or pharmacologic activities.

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • When administered in therapeutic doses, can cause severe myelosuppression.
  • The risk of infection and bleeding from neutropenia or thrombocytopenia (can be fatal) is possible.
  • It is important to monitor blood counts regularly.
  • Patients with bone marrow suppression should not be treated unless the benefits outweigh the risks.

• Cardiomyopathy [US Boxed Warning]

  • It can cause myocardial toxicities, which could lead to heart failure. 
  • Patients who have had anthracyclines in the past or have existing cardiac disease are more likely to experience cardiotoxicity.
  • Patients with prior mediastinal/pericardial radiation, anemia, bone-marrow depression, infections or myocarditis are at greater risk.
  • Cardiotoxicity is also a concern for patients with active or dormant heart disease.
  • It can lead to potentially fatal heart failure, severe arrhythmias (may cause death), and other cardiomyopathies.
  • It is important to monitor left ventricular efficacy (LVEF) regularly, especially for patients with impaired cardiac function or cardiac risk factors.
  • It is important to consider the half-life of cardiotoxic agents.
  • Anthracycline-based therapy should not be used for more than 5 half-lives following discontinuation. Idarubicin should be avoided for 7 months after discontinuation.
  • During treatment, it is important to monitor your cardiac function.
  • ASCO has created guidelines to monitor and prevent cardiac dysfunction in adult cancer survivors.
  • The following guidelines indicate that there is an increased risk of developing cardiac dysfunction:
    • High-dose anthracycline treatment (eg, epirubicin >=600mg/m2 and doxorubicin>=250 mg/m2)
    • High-dose radiotherapy (>=30 Gy), with the heart in treatment field
    • Lower-dose anthracycline (eg doxorubicin 250 mg/m2, epirubicin 600 mg/m2) when combined with lower-dose radiotherapy (30 Gy) with the heart in treatment field
    • Low-dose anthracycline (eg doxorubicin at 250 mg/m2, epirubicin at 600 mg/m2), or trastuzumab by itself AND any of these risk factors:
      • Multiple cardiovascular risk factors (>=2 factors), such as smoking, hypertension and diabetes, obesity (during or following treatment), or older age (>=60) during or after treatment for cancer, or impaired cardiac function (eg borderline low LVEF [50%-555%], history MI, or moderate or greater valvular disease) prior to or during treatment
      • Tratuzumab (sequential treatment) is followed by lower-dose anthracycline.
      • Anthracycline-induced cardiotoxicity can also be caused by age above 60 years at the time of treatment, and any other cardiovascular risk factors such as smoking, diabetes, hypertension or obesity during or after treatment.
  • ASCO guidelines recommend a thorough assessment of patients with cancer.
  • This includes a history, physical exam, screening for cardiovascular disease risk factors like hypertension, diabetes and dyslipidemia.
  • Before you start potentially cardiotoxic therapies, have an echocardiogram taken.
  • Before initiating potentially dangerous therapies, it is important to manage modifiable risk factors such as smoking, diabetes, hypertension, and obesity.
  • Patients who will likely be receiving high-dose anthracycline therapy should consider cardioprotectants such as dexrazoxane or continuous infusions.
  • An echocardiogram is recommended to diagnose patients with signs/symptoms of heart dysfunction after therapy.
  • If an echocardiogram is not possible or available, a cardiac MRI or MUGA scan can be used. A referral to a cardiologist is recommended if you are interested in serum cardiac biomarkers.

• Extravasation: [US Boxed Warning]

  • Extravasation of Vesicant may cause severe tissue necrosis.
  • Only for IV administration; not to administer IM or SubQ.
  • Should be administered via an IV infusion line that flows freely
  • Before and during infusion, ensure proper placement of the needle or catheter
  • It is important to avoid extravasation.

• Gastrointestinal toxicities:

  • Idarubicin can cause mild emesis; antiemetics should be used to prevent nausea or vomiting.
  • Occasionally, abdominal pain, diarrhea, or mucositis can occur.
  • Rarely, severe enterocolitis has been associated with perforation.

• Hyperuricemia

  • The rapid lysis and engorgement of leukemic cell may lead to hyperuricemia.
  • You might consider hydration and anti-hyperuricemic treatment.

• Hepatic impairment: [US-Boxed Warning]

  • Patients with hepatic impairment should reduce their dosage.
  • If bilirubin is greater than 5 mg/dL, Idarubicin should be avoided.

• Infections

  • Before you start treatment, control systemic infections.

• Renal impairment: [US-Boxed Warning]

  • Patients with impaired renal function should be advised to reduce their dosage.

Idarubicin: Drug Interaction

Monitoring parameters:

• CBC is frequently monitored with differential and platelet count
• Cardiac function (LVEF) before and during treatment
• Electrolytes in serum
• Pre- and post-treatment, renal function (serum creatinine)
• Uric acid
• LFTs (ALT and AST, bilirubin, before and during treatment).
• Extravasation should be observed at the infusion site
• Examine your gastrointestinal for signs of toxicity or infection

Cardiovascular monitoring

• Before treatment can begin, a comprehensive assessment must be done.
• This includes a history, physical examination, screening for risk factors like hypertension, diabetes and dyslipidemia as well as screening for smoking.
• Before any treatment, an echocardiogram is recommended.
• A diagnostic echocardiogram should be performed for patients who experience signs/symptoms of heart dysfunction after therapy.
• If an echocardiogram is not possible or available, a cardiac MRI (preferred), or MUGA scan can be used to obtain serum cardiac biomarkers.

How to administer Idarubicin?

• Idarubicin has a moderate emetic potency. Therefore, antiemetics should be used to prevent nausea and vomiting.
• IV: For IV administration only.
• Not to be administered IM/SubQ
• Slowly administer the medication over 10 to 15 mins into an IV solution of D5W or NS.
• It is a vesicant. Proper needle or catheter placement should always be done prior to infusion. Extravasation should also be avoided.

Extravasation management

• Extravasation should be stopped immediately and disconnected (leave the needle/cannula in place).
• Gently aspirate the extravasated solution (do).NOTFlush the line
• You should remove the needle/cannula and elevate your extremity.
• Initiate antidote [dexrazoxane, dimethyl sulfate]
• For up to two days, apply dry cold compresses four times per day for 20 minutes.
• Begin cooling 15 minutes prior to dexrazoxane injection
• Keep the infusion going for at least 15 minutes.
• Topical DMSO should not be administered in conjunction with dexrazoxane. It may reduce dexrazoxane's efficacy.

• Dexrazoxane

  • 1,000 mg/m2 (maximum dosage: 2,000 mg) IV (administered in a large vein distant from the site of extravasation) for 1 to 2 hour days 1 and 2. Then 500 mg/m2 IV (maximum dosing: 1,000 mg) for 1 to 2 hour days 3;
  • Start within six hours after extravasation. Administer the Day 2 and Day 3 doses approximately at the same time (+-3 hrs) as the dose of day 1.
• Notice:Reduce the dose of dexrazoxane by half in patients suffering from moderate or severe renal impairment (CrCl 40mL/minute).
• DMSO should only be applied topically to a area twice as large as the affected region, every 8 hours for 7 days. It should be applied within 10 minutes of extravasation.

Mechanism of action of Idamycin (Idarubicin):

• Idarubicin can inhibit DNA and RNA synthesis through intercalation between DNA base pair pairs and steric obstruction.
• It is unclear what the mechanism of intercalation and inhibition of DNA-repair (topoisomerase II inhibitor) are, but it seems that DNA synthesis and DNA fragmentation can be blocked by binding to DNA.

Protein binding:

• 94% (idarubicinol) to 97% (idarubicin)

Metabolism:

• Hepatic to idarubicinol (active metabolite)

Half-life elimination:

• Children:
  • Children ≥1 year of age and adolescents: 17.6 ± 6.8 hours (range: 8.3 to 29.6 hours) (Reid 1990)
  • Adults: 22 hours (range: 4 to 48 hours); >45 hours (idarubicinol)

Excretion:

• Primarily biliary excretion
• Urine (8 to 10% as idarubicinol, ~2% to 5% as unchanged drug.

International Brands of Idarubicin:

• Idamycin PFS
• Idamycin
• Idaralem
• Ondarubin
• Zavedos
• Zavedos CS
• Zavel
• Zaverucin

Idarubicin Brand Names in Pakistan: