Daunorubicin

Registered South African indications:

• Acute leukaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to any anthracyclines
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Recent exposure to, or currently with existing, chickenpox or herpes zoster
• Persistent myelosuppression
• Severe infection
• Myocardial insufficiency
• Recent myocardial infarction
• Severe arrhythmias
• Intramuscular administration
• Cumulative highest dose of daunorubicin hydrochloride (500-600mg/m² in adults, 300mg/m² in children ≥2 years, 10mg/kg in children <2 years)
• Previous administration of another cardiotoxic anthracycline

Cautions

• Pregnancy
• Males and females of reproductive potential
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• All contact with skin and mucous membranes when handling daunorubicin
• Contact with patients' excrement and vomit
• Pregnant health care professionals
• High-grade pancytopenia (relative contraindication - see additional prescribing points)
• Isolated leuko-/thrombo-cytopenia (relative contraindication - see additional prescribing points)
• Poor general condition (relative contraindication - see additional prescribing points)
• History of cardiac disease (relative contraindication - see additional prescribing points)
• Uncontrolled infections, especially viral diseases (Herpes zoster)
• Preceding, concurrent or planned radiotherapy
• Acute toxicities of prior cytotoxic treatment
• Risk factors for cardiac toxicity
  - Active or dormant cardiovascular disease
  - Prior or concomitant radiotherapy to the mediastinal/pericardial area
  - Prior therapy with other anthracyclines
  - Prior therapy with anthracenediones
  - Use of agents with the ability to suppress cardiac contractility
  - Use of cardiotoxic agents e.g. trastuzumab
  - Total cumulative dose of >400mg/m² 
• Manifest arterial hypertension
• Thoracic irradiation
• High cumulative doses
• Children and adolescents
• Administration into small vessels or repeated administration into the same vein
• Immunocompromised patients or patients at risk of infection
• Neutrophil count <1500/mm³
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Acute myeloblastic leukaemia (additional agent required)
• Acute lymphoblastic leukaemia (additional agent required)

Consult specialist for dosages and regimens

No information available for children in South Africa

Used for the treatment of 

• Acute lymphocytic leukaemia (additional agent/s required)
• Acute myloid leukaemia (additional agent/s required) 

Consult specialist for dosages and regimens

Pregnancy

• Caution; not recommended
• Daunorubicin crosses the placenta and experiments in animals have shown it to be mutagenic, carcinogenic and teratogenic
• There are no or limited amount of data from the use of daunorubicin in pregnant women, although a few women who received daunorubicin during the second and third trimesters of pregnancy have delivered apparently normal infants
• According to experimental data, daunorubicin must be considered as a potential cause of foetal malformations when administered to a pregnant woman
• Daunorubicin should not be used during pregnancy unless the clinical condition of the woman requires treatment with daunorubicin and justifies the potential risk to the foetus. Women of childbearing potential who have to undergo daunorubicin therapy should be apprised of the potential hazard to the foetus and should be advised to avoid becoming pregnant during treatment. If daunorubicin is used during pregnancy, or if the patient becomes pregnant while receiving treatment, the woman should be informed of the potential hazard to the foetus. The possibility of genetic counselling should also be utilized. In any case, cardiologic examination and a blood count are recommended in foetuses and newborns born to mothers who received treatment with daunorubicin during pregnancy
• Men undergoing treatment with daunorubicin should use effective contraception methods during and up to 6 months after treatment

Breastfeeding

• Contraindicated
• It is unknown whether daunorubicin/metabolites are excreted in human milk; other anthracyclines are excreted in breast milk. Daunorubicin is contraindicated during breastfeeding

Fertility

• Daunorubicin inhibits fertility. Amenorrhea and azoospermia may occur. The severity is dose-dependent. Irreversible disorders of fertility are possible
• Daunorubicin could induce chromosomal damage in human spermatozoa. Men should receive counselling on sperm conservation before the start of daunorubicin treatment because of the possibility of irreversible infertility

Renal Impairment

• Mild to moderate: Caution; dose adjustment recommended
• Severe: Contraindicated

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
• Severe: Contraindicated

Elderly            

• Caution; dose adjustment recommended
  Daunorubicin should be used with care in patients with inadequate bone marrow reserves due to old age

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Posterior Reversible Encephalopathy Syndrome (also known as Reversible Posterior Leukoencephalopathy Syndrome)

Cardiovascular Disorders

• Cardiomyopathy
  - Dyspnoea
  - Cyanosis
  - Dependent oedema (peripheral, cardiac)
  - Hepatomegaly
  - Ascites
  - Pleural effusion
  - Overt congestive heart failure
• Endomyocardial fibrosis
• Myocardial ischaemia (angina)
• Myocardial infarction
• Pericarditis/myocarditis
• Supraventricular tachyarrhythmias
  - Sinus tachycardia
  - Premature ventricular contractions
  - Heart block
• Shock
• Haemorrhage
• Flushes
• ECG abnormalities
  - Non-specific ST-T wave changes
  - Low voltage QRS complex
  - T waves

Respiratory Disorders

• Tissue hypoxia

Gastrointestinal Disorders

• Mucositis/stomatitis
  - Pain, or burning sensation
  - Erythema
  - Erosions-ulcerations
  - Bleeding
  - Infections
• Oesophagitis
• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Colitis
  - Neutropenic enterocolitis (typhilitis)
  - Enterocolitis

Hepatobiliary Disorders

• Elevated serum bilirubin (transient)
• Elevated aspartate aminotransferase
• Elevated alkaline phosphatase

Genitourinary Disorders

• Nephrotic syndrome
• Uric acid nephropathy
• Red color of urine
• Amenorrhea
• Azoospermia

Endocrine and Metabolic Disorders

• Dehydration
• Tumour lysis syndrome
• Acute hyperuricaemia

Skin and Subcutaneous Tissue Disorders

• Alopecia (reversible)
• Contact dermatitis
• Erythema
• Hypersensitivity to irradiated skin ('radiation recall reaction')
• Pruritus
• Skin rash
• Skin and nail hyperpigmentation
• Urticaria
• Perivenous extravasation
  - Immediate local pain/burning sensation
  - Severe cellulitis
  - Painful ulceration
  - Tissue necrosis
• Venous sclerosis/phlebosclerosis
• Thrombophlebitis
• Local phlebitis

Immune, Blood and Lymphatic System Disorders

• Bone marrow failure
• Leucopenia
• Anaemia
• Granulocytopenia (neutropenia)
• Thrombocytopenia
• Febrile neutropenia (with fatal outcomes)
• Serious infections (with fatal outcomes)
  - Sepsis
  - Septic shock
  - Pneumonia
• Anaphylaxis
• Anaphylactoid reactions
• Secondary malignancies including leukaemia
• Fulminant hyperpyrexia
• Fever

Others

• Aplasia
• Death
• Pain

• Cardiotoxic substances
• Cardioactive substances
• Calcium antagonists
• Trastuzumab
• Agents influencing bone marrow function
• Cytostatics
• Cytarabine
• Cyclophosphamide  
• Sulfonamides
• Chloramphenicol
• Diphenylhydantoin
• Amidopyrine derivatives
• Antiretroviral agents
• Potentially hepatotoxic agents
• Methotrexate
• Agents leading to a delayed excretion of uric acid
• Certain diuretics
• Thrombocyte aggregation inhibitors
• Acetylsalicylic acid 
• Live vaccines

• Full blood count with differential
• Hepatic function
• ECG
• Left ventricular ejection fraction
• Renal function

Relative contraindications

• Relative contraindications are high-grade pancytopenia or isolated leuko-/thrombocytopenia
• Further relative contraindications are severe cardiac arrhythmias in particular ventricular tachycardias or arrhythmias with clinically relevant haemodynamic effects and clinically manifest heart failure - even in the history, myocardial infarction, severe disorders of the kidneys and liver, pregnancy and a poor general condition of the patient
• The treating physician should weigh the benefits and risks and decide, in each individual case, on the treatment

Daunorubicin is an anthracycline glycoside antibiotic and is a potent antileukaemic agent. It also has immunosuppressant effects. The exact mechanism of antineoplastic action is uncertain but may involve binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis by template disordering and steric obstruction. Daunorubicin is most active in the S-phase of cell division but is not cycle phase specific. Tumour cell cross-resistance has been observed between daunorubicin and doxorubicin.

Injection (per vial) 20mg

• Daunoblastin (Pfizer) originator