Chemical formula: C₂₇H₂₉NO₁₁ Molecular mass: 543.519 g/mol PubChem compound: 41867
Epirubicin interacts in the following cases:
Vaccination with a live vaccine should be avoided in patients receiving epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin hydrochloride,may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
The possibility of a marked disturbance of haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).
Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450µmol/l).
The major route of elimination of epirubicin hydrochloride is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin hydrochloride. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients.
In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:
| Serum Bilirubin | AST* | Dose Reduction |
|---|---|---|
| 1.4-3 mg/100 ml | 50% | |
| >3 mg/100 ml | >4 times upper normal limit | 75% |
* AST-aspartate aminotransferase
Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.
Epirubicin may cause amenorrhea or premature menopause in premenopausal women.
Cimetidine increased the AUC of epirubicin by 50% and should be discontinued during treatment with epirubicin hydrochloride.
Increase of myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.
One study found that docetaxel may increase the plasma concentrations of epirubicin hydrochloride metabolites, when administered immediately after epirubicin hydrochloride.
When given prior to epirubicin hydrochloride, paclitaxel can cause increased plasma concentrations of unchanged epirubicin hydrochloride and its metabolites, the latter being, however, neither toxic nor active. Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin hydrochloride when epirubicin hydrochloride was administered prior to the taxane.
This combination may be used if using staggered administration between the two agents. Infusion of epirubicin hydrochloride and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.
The co-administration of interferon α2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin hydrochloride.
Quinine may accelerate the initial distribution of epirubicin hydrochloride from blood in to the tissues and may have an influence on the red blood cells partitioning of epirubicin hydrochloride.
Anthracyclines including epirubicin hydrochloride should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of trastuzumab is approximately 28-38 days and may persist in the circulation for up to 27 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Epirubicin hydrochloride may induce hyperuricemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumour-lysis syndrome.
Epirubicin hydrochloride is emetigenic. Mucosal inflammation/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin hydrochloride.
As with other cytotoxic agents, epirubicin hydrochloride may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin hydrochloride, including differential white blood cell (WBC) counts.
A dose-dependent, reversible leucopoenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin hydrochloride haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopoenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.
Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events.
Early (i.e., Acute) Events: Early cardiotoxicity of epirubicin hydrochloride consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of epirubicin hydrochloride treatment.
Late (i.e., Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m²; this cumulative dose should only be exceeded with extreme caution.
Cardiac function should be assessed before patients undergo treatment with epirubicin hydrochloride and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin hydrochloride at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m² epirubicin hydrochloride should be exceeded only with extreme caution.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab) with an increased risk in the elderly.
Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzumab therapy alone or in combination with anthracyclines such as epirubicin hydrochloride. This may be moderate to severe and has been associated with death.
Trastuzumab and anthracyclines such as epirubicin should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of traztuzumab and anthracyclines.
Because the reported half-life of trastuzumab is approximately 28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as epirubicin after stopping trastuzumab may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin hydrochloride are used, the patient’s cardiac function should be monitored carefully.
If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin hydrochloride therapy, it should be treated with the standard medications for this purpose.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present. It is probable that the toxicity of epirubicin hydrochloride and other anthracyclines or anthracenediones is additive.
Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin hydrochloride. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemia’s can have a 1- to 3-year latency period.
Dexverapamil may alter the pharmacokinetics of epirubicin hydrochloride and possibly increase its bone marrow depressant effects.
Experimental data in animals suggest that epirubicin may cause fetal harm when administered to a pregnant woman. If epirubicin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
There are no studies in pregnant women. Epirubicin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether epirubicin is excreted in human breast milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin, mothers should discontinue nursing prior to taking this drug.
Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.
Epirubicin may cause amenorrhea or premature menopause in premenopausal women.
There have been no reports of particular adverse events relating to effects on ability to drive and to use machines.
Τhe following undesirable effects have been observed and reported during treatment with epirubicin with the following frequencies: Very Common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000, Very Rare <1/10,000, Frequency not known (cannot be estimated from the available data).
Very Common: Infection, Conjunctivitis
Uncommon: Sepsis,* Pneumonia*
Uncommon: Acute myeloid leukaemia, Acute lymphocytic leukaemia
Very Common: Anaemia, Leukopenia, Neutropenia, Thrombocytopenia, Febrile neutropenia
Rare: Anaphylactic reaction*
Common: Decreased appetite, Dehydration*
Rare: Hyperuricaemia*
Very Common: Keratitis
Common: Ventricular tachycardia, Atrioventricular block, Bundle branch block, Bradycardia, Cardiac failure congestive
Very Common: Hot flush, Phlebitis*
Common: Haemorrhage*, Flushing*
Uncommon: Embolism, Embolism arterial*, Thrombophlebitis*
Frequency not known: Shock*
Uncommon: Pulmonary embolism*
Very Common: Nausea, Vomiting, Stomatitis, Mucosal inflammation, Diarrhoea
Common: Gastrointestinal pain*, Gastrointestinal erosion*, Gastrointestinal ulcer*
Uncommon: Gastrointestinal haemorrhage*
Frequency not known: Abdominal discomfort, Pigmentation buccal*
Very Common: Alopecia, Skin toxicity
Common: Rash/Pruritus, Nail pigmentation*, Skin disorder, Skin hyperpigmentation*
Uncommon: Urticaria*, Erythema*
Frequency not known: Photosensitivity reaction*
Very Common: Chromaturia*†
Very Common: Amenorrhoea
Very Common: Malaise, Pyrexia*, mucosal inflammation
Common: Chills*
Uncommon: Asthenia
Very Common: Transaminases abnormal
Common: Ejection fraction decreased
Very Common: Chemical cystitis*§
Frequency not known: Recall phenomenon*Δ
* ADR identified post-marketing.
† Red coloration of urine for 1 to 2 days after administration.
§ Following intravesical administration.
Δ Hypersensitivity to irradiated skin (radiation-recall reaction).
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