Daunorubicin

Daunorubicin is an antineoplastic anthracycline that kills dividing cells by interfering with several biological and biochemical functions in target cells. The exact mechanism is not fully known. The SmPC also attributes antibacterial and immunosuppressive properties to it.

Mechanism of Action

• DNA binding: it appears to inhibit mainly DNA synthesis and DNA-dependent RNA synthesis, by forming a complex with DNA through intercalation between base pairs and unwinding of the helix.
• Topoisomerase II: it stabilises the DNA–topoisomerase II complex and prevents the religation step the enzyme normally completes. It may also affect polymerase activity and the regulation of gene expression.
• Free radicals and oxidative stress: oxidation–reduction reactions generate highly reactive, toxic free radicals, which may add to cell death.
• Cell membrane: a direct interaction with the cell membrane, altering the cell-surface bilayer, has also been proposed.
• Cell cycle: cytotoxicity is greatest in the S phase, but daunorubicin has no specificity for a phase or cycle.
• Children: no controlled paediatric studies have been done. The literature describes its use in leukaemia regimens that include children, and published studies suggest that safety is similar in children and adults.

Pharmacokinetics

• Absorption: it is not absorbed from the gastrointestinal tract. Because it is extremely irritant to tissues it is given intravenously, where absorption is expected to be complete unless extravasation occurs.
• Distribution: widely distributed in body tissues, with the highest levels in the spleen, kidneys, lungs and heart. It enters cells and binds cellular components, particularly nucleic acids. There is no evidence that it crosses the blood–brain barrier, but it apparently crosses the placenta.
• Metabolism: rapid and extensive, in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases. One hour after a dose the main form in plasma is the active metabolite daunorubicinol (13-OH daunorubicin). Further breakdown of the sugar link gives aglycones with little or no antiproliferative activity, which are demethylated and conjugated by sulfation and glucuronidation.
• Elimination: after a rapid intravenous injection, total plasma levels of daunorubicin and its metabolites fall in three phases, and unchanged daunorubicin in two. The half-life averages 45 minutes in the initial phase and 18.5 hours in the terminal phase; daunorubicinol has a half-life above 24 hours. Excretion is in urine and bile (about 40% of the dose); urinary excretion of the drug and its metabolites is reported as 14–23% of the dose, mostly within 3 days. After the first 24 hours the urine contains mainly daunorubicinol.
• Special populations: raised bilirubin slows clearance and increases overall toxicity (see Administration and Dosage).

The Spanish SmPC of Daunoblastina lists these indications; other national SmPCs may differ.

• Adults: to induce remission in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), given alone or in combination with other antineoplastic medicines.
• Children: as part of combination treatment of AML and ALL.

• Hypersensitivity to daunorubicin or to any of the excipients, and hypersensitivity to other anthracyclines or anthracenediones.
• Persistent myelosuppression.
• Severe infections.
• Severe hepatic impairment (Child-Pugh grade C, score 10–15) or severe renal impairment (GFR below 10 mL/min or serum creatinine above 7.9 mg/dL).
• Heart failure, recent myocardial infarction or severe arrhythmias.
• Earlier treatment with the maximum cumulative doses of daunorubicin (500–600 mg/m² in adults, 300 mg/m² in children aged 2 years or older, 10 mg/kg in children under 2 years) or of other cardiotoxic anthracyclines, which markedly raises the risk of life-threatening heart damage.
• Pregnancy and breastfeeding.

Bone marrow suppression, heart toxicity, gastrointestinal reactions, hair loss and local tissue damage are the main concerns. Reactions below follow the SmPC table by frequency.

Very common (≥1/10): sepsis/septicaemia and infection (sometimes fatal); bone marrow failure, leucopenia, granulocytopenia, neutropenia, thrombocytopenia, anaemia; cardiomyopathy (shown clinically by dyspnoea, cyanosis, peripheral oedema, enlarged liver, ascites, pleural effusion and overt congestive heart failure); haemorrhage; nausea and vomiting, diarrhoea, oesophagitis, mucositis/stomatitis; alopecia, erythema, rash; fever, pain; raised serum bilirubin, AST and alkaline phosphatase.

Common (≥1/100 to <1/10): abdominal pain; phlebitis at the infusion site; abnormal electrocardiogram (ST-T changes, abnormal QRS complex, abnormal T waves).

Uncommon (≥1/1,000 to <1/100): acute myeloid leukaemia (secondary); myocardial infarction.

Not known: septic shock (sometimes fatal); myelodysplastic syndrome; anaphylactic/anaphylactoid reactions; dehydration; acute hyperuricaemia (with possible renal impairment, especially when the white cell count is high before treatment); myocardial ischaemia (angina), endomyocardial fibrosis, pericarditis/myocarditis, supraventricular tachyarrhythmias (sinus tachycardia, ventricular extrasystoles, atrioventricular block); flushing, shock, thrombophlebitis, venous sclerosis; hypoxia; colitis; hepatitis, hepatic failure; contact dermatitis, pruritus, hyperpigmentation of skin and nails, urticaria; red urine for 1–2 days after administration; amenorrhoea, azoospermia; death, hyperpyrexia, chills; extravasation at the infusion site (pain or burning, cellulitis, skin ulcer, necrosis).

Heart toxicity, severe myelosuppression with fatal infection or bleeding, extravasation necrosis and secondary leukaemia are the most important serious reactions (see Special Instructions).

Daunorubicin is used mainly with other cytotoxic medicines, so additive toxicity can occur, especially on the bone marrow and the gastrointestinal tract.

• Other cytotoxics (for example cytarabine, cyclophosphamide): the toxic effects of daunorubicin may be increased.
• Medicines acting on the bone marrow (cytostatics, sulfonamides, chloramphenicol, phenytoin, amidopyrine derivatives, antiretrovirals): the possibility of important changes in blood-cell production should be considered, and the daunorubicin dose adjusted if needed.
• Cardiotoxic agents and mediastinal radiotherapy: raise the cardiotoxicity of daunorubicin. Other medicines acting on the heart (for example calcium channel blockers) call for cardiac monitoring throughout treatment.
• Trastuzumab: it can stay in the blood for up to 7 months after treatment. Where possible, anthracyclines should not be given until 7 months after trastuzumab; if they are, cardiac function is monitored closely.
• Hepatotoxic medicines (for example methotrexate): may change the liver metabolism and biliary excretion of daunorubicin and so raise its toxicity. Medicines that affect liver function can also change its pharmacokinetics.
• Medicines that delay uric acid excretion (sulfonamides, some diuretics): can increase hyperuricaemia.
• Antiplatelet agents (acetylsalicylic acid): in patients with low platelets, the bleeding risk is further increased.
• Live vaccines: must not be given during treatment (see Special Instructions).
• Oral medicines: their absorption can be markedly affected by oral and gastrointestinal mucositis during intensive chemotherapy.

Treatment is started and supervised by physicians experienced in cancer treatment, and patients are monitored carefully and often. Hospital admission is recommended at least for the first phase of treatment. The dose is generally based on body surface area (mg/m²); for children under 2 years (or with a body surface area below 0.5 m²) calculation by body weight (kg) is suggested. The dose per cycle varies with whether daunorubicin is used alone, with other cytotoxic medicines or with radiotherapy, with the patient’s age, and with tolerance, clinical situation and response.

Adults

• As a single agent: for the first remission-induction cycle in AML or ALL, 60 mg/m² daily on 3 successive days. Later induction cycles, given every 3 to 4 weeks according to bone marrow and haematological status, use the same daily dose for 2 consecutive days only.
• In combination: in standard combination regimens, 45 mg/m² daily on the same schedule.
• Elderly (over 65 years): the dose may need reducing to 45 mg/m² as a single agent and 30 mg/m² in combination regimens.

Children

• In children over 2 years the dose is usually calculated by body surface area and adjusted to clinical response and haematological status. Cycles may be repeated after 3 to 6 weeks. Current protocols and specialist guidelines should be consulted for the regimen.
• Maximum cumulative dose: 300 mg/m² in children over 2 years; 10 mg/kg in children under 2 years (or below 0.5 m²).

Hepatic and Renal Impairment

• Severe hepatic impairment (Child-Pugh grade C): daunorubicin must not be given.
• Mild or moderate hepatic impairment (Child-Pugh A, score 5–6, or B, score 7–9): the dose is reduced according to serum bilirubin. For bilirubin of 1.2 to 3 mg/dL the dose is half the recommended starting dose; above 3 mg/dL it is a quarter.
• Moderate renal impairment (GFR 10 to 20 mL/min, or serum creatinine about 3.4 to 7.9 mg/dL): the dose is halved. Severe renal impairment is a contraindication.

Method of Administration

• Intravenous only. Daunorubicin is not active by mouth and must not be given intramuscularly, subcutaneously or intrathecally.
• The recommended technique is to inject into the tubing of a running intravenous infusion of 0.9% sodium chloride or 5% dextrose, after making sure the needle is correctly placed in the vein. This lowers the risk of extravasation and flushes the vein at the end. The injection can last from 2–3 minutes to 30–45 minutes, depending on the dose and the calibre of the vein.
• Direct intravenous injection is not recommended, because extravasation can occur even when blood returns freely on aspiration.
• Reconstitution and handling are described in section 6.6 of the SmPC.
• Missed dose: the SmPC gives no rule; doses follow the treating physician’s schedule.

Supervision and Monitoring

Daunorubicin is given under the supervision of physicians experienced in cytotoxic therapy. Before it starts, patients should have recovered from the acute toxic effects of earlier cytotoxic treatment (stomatitis, neutropenia, thrombocytopenia, generalised infection). Blood counts and liver and kidney function are checked before each treatment. Severe pancytopenia or isolated leucopenia/thrombocytopenia, serious arrhythmias (in particular ventricular tachycardia), overt heart failure (including a history of it), myocardial infarction, severe kidney or liver disorders, pregnancy and a poor general condition all count against treatment; the doctor weighs benefit and risk case by case.

Bone Marrow Suppression and Infections

Every patient develops myelosuppression at a therapeutic dose. It is reversible and dose-dependent, mainly leucopenia, neutropenia and thrombocytopenia; anaemia is less common. The lowest counts occur between days 8 and 10 after the start, and counts usually return to pre-treatment values in the second to third week after the last injection. Blood counts are monitored closely before and during each cycle. Severe myelosuppression can lead to fever, infection, sepsis, septic shock, haemorrhage and tissue hypoxia, and can be fatal; serious infection or bleeding needs rapid, effective treatment, and intensive supportive care may be needed. Because daunorubicin is immunosuppressive, uncontrolled infections, especially viral ones such as herpes zoster, can worsen and become life-threatening.

Cardiotoxicity

Cardiotoxicity is one of the most important risks and can be early (acute) or late (delayed).

• Acute effects do not depend on the dose: supraventricular arrhythmias (sinus tachycardia, premature ventricular contractions, atrioventricular block) and/or non-specific ECG changes. Angina, myocardial infarction, endomyocardial fibrosis and pericarditis/myocarditis have also been reported. They do not usually predict later cardiotoxicity, rarely matter clinically and are generally not a reason to stop treatment.
• Delayed effects: congestive cardiomyopathy that can appear during treatment but often months or years after it ends, with heart failure that can occasionally be fatal. Signs include a fall in left ventricular ejection fraction, dyspnoea, pulmonary or peripheral oedema, an enlarged heart or liver, oliguria, ascites, pleural effusion and gallop rhythm. Severity and frequency depend on the cumulative dose, which is the limiting toxicity.
• Monitoring: cardiac function is assessed before treatment, with an ECG and either a MUGA scan or echocardiography, especially in higher-risk patients, and monitored throughout and after treatment. The ejection fraction is measured repeatedly by the same method, particularly at high cumulative anthracycline doses. Daunorubicin is stopped at the first sign of impaired function.
• Cumulative dose: without other cardiac risk factors, the risk of congestive heart failure rises above 550 mg/m² in adults, 300 mg/m² in children over 2 years and 10 mg/kg in children under 2 years.
• Risk factors: active or latent cardiovascular disease; earlier or concurrent radiotherapy of the pericardial or mediastinal area; earlier anthracyclines or anthracenediones; and cardiotoxic or contractility-suppressing medicines such as trastuzumab. Elderly patients, those with heart disease or hypertension, chest irradiation and children are more susceptible; in these settings the total cumulative dose in adults should not exceed 400 mg/m². Children need long-term follow-up of cardiac function, because congestive cardiomyopathy can develop after a latency of many years. The toxicity of daunorubicin and other anthracyclines is probably additive.

Secondary Leukaemia

Secondary leukaemia, with or without a pre-leukaemic phase, has been reported with anthracyclines including daunorubicin. It is more frequent with DNA-damaging antineoplastic agents or radiotherapy, in heavily pretreated patients and with escalated anthracycline doses. The latency can be 1 to 3 years.

Liver, Kidney and Tumour Lysis

The liver is the main route of elimination, with biliary excretion, so total serum bilirubin is checked before and during treatment; raised bilirubin slows clearance and increases toxicity, and the dose is reduced. Kidney function is evaluated before treatment, because impairment increases toxicity. Massive death of leukaemic cells can cause hyperuricaemia and uric acid nephropathy, especially when the white cell count is high before treatment, and a nephrotic syndrome can develop. Prophylactic allopurinol is necessary in the treatment of acute leukaemia (first cycle). Uric acid, potassium, calcium phosphate and creatinine are checked after the first treatment; hydration, urine alkalinisation and allopurinol minimise the complications of tumour lysis syndrome.

Extravasation and Vein Reactions

Extravasation during intravenous injection can cause local pain, serious tissue lesions (severe cellulitis, painful ulceration) and tissue necrosis; some cases need surgery and the damage can be irreversible. If signs of paravenous administration appear, the infusion is stopped immediately. Local phlebitis, thrombophlebitis and/or venous sclerosis can occur, especially when a small vessel is used or the same vein is injected repeatedly. Following the recommended administration procedure keeps the risk low.

Radiotherapy and Vaccines

• Particular care is needed in patients who have had, are having or will have radiotherapy, because the risk of local reactions in the irradiated area (radiation recall reaction) increases. Earlier radiotherapy of the mediastinum raises the cardiotoxicity of daunorubicin.
• Immunosuppression raises susceptibility to infection. Live or attenuated virus vaccines can cause serious or fatal infections in patients made immunocompromised by chemotherapy and must not be given during daunorubicin treatment. Killed or inactivated vaccines may be given, but the response may be reduced.

Other Reactions

• Nausea, vomiting and mucositis: severe vomiting can cause dehydration, and appropriate antiemetic treatment prevents or relieves it. Mucositis (mainly stomatitis, less often oesophagitis) appears soon after the dose, can progress to ulceration within days, and most patients recover by the third week.
• Alopecia: complete hair loss, including beard, scalp, axillary and pubic hair, occurs almost always at full doses. It is usually reversible, with regrowth about two to three months after treatment ends.
• Posterior reversible encephalopathy syndrome (PRES): reported when daunorubicin is combined with chemotherapy. It can cause headache, convulsions, lethargy, confusion, blindness and other visual or neurological disorders, with mild to severe hypertension. MRI confirms the diagnosis, and stopping daunorubicin should be considered.

Handling

Skin and mucous membrane contact must be avoided. Because of the mutagenic and carcinogenic potential of daunorubicin, doctors and nurses take extra safety measures when handling it. Special care is needed with patients’ faeces and vomit, which may contain daunorubicin or an active metabolite. Pregnant healthcare staff must not come into contact with cytostatics.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated (see above). Daunorubicin was embryotoxic, teratogenic, mutagenic and carcinogenic in animals and must be regarded as a potential cause of foetal malformations. There are no adequate studies in pregnant women, although some women who received it in the second and third trimesters bore apparently normal children. As a general rule it is not given to pregnant patients, and the SmPC adds that it should not be used in pregnancy unless the woman’s clinical situation requires it and justifies the potential risk to the foetus. If it is used, or pregnancy occurs during treatment, the woman is told of the risk; genetic counselling is recommended, and a cardiological examination and blood counts are recommended in foetuses and newborns.
• Breastfeeding: contraindicated. It is not known whether daunorubicin passes into human milk, but many medicines, including other anthracyclines, do, and it could cause serious reactions in infants. Women should not breastfeed during treatment or for at least 6 days after the last dose.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 27 weeks after the last dose; male patients should do so during treatment and for at least 14 weeks after the last dose.
• Fertility: daunorubicin can be genotoxic and inhibit fertility; amenorrhoea and azoospermia can occur, depending on the dose, and fertility disorders can be irreversible. It could cause chromosomal damage in human sperm, so sperm preservation counselling is recommended before treatment; women who wish to become pregnant afterwards should receive genetic counselling and counselling on preserving fertility.

Sodium

The reconstituted solution contains less than 1 mmol (23 mg) of sodium per mL, essentially sodium-free.

Effect on Driving

Daunorubicin can cause nausea and vomiting that in some cases impair the ability to drive and use machines. There are no specific reports of an effect on driving.

The unopened powder vial needs no special storage conditions. The pack holds one colourless type I glass vial with a rubber stopper and aluminium cap, and one ampoule containing 10 mL of solvent. For storage after reconstitution, see Shelf Life. Keep out of the sight and reach of children.

• Unopened vial: 3 years.
• Reconstituted solution: to reduce the risk of microbiological contamination, use it immediately after reconstitution or opening of the vial. If it is not used immediately, storage times and conditions are the responsibility of the user. Tests with the solution reconstituted in sodium chloride 0.9% showed chemical and physical in-use stability for 24 hours at no more than 30 °C and for 48 hours in a refrigerator at 2–8 °C.

Prescription only (Rx). Daunorubicin is started and supervised by physicians experienced in cancer treatment and is given intravenously, with hospital admission recommended at least for the first phase of treatment. It is supplied to the hospital or clinic that administers it.