Epirubicin

Epirubicin is a cytotoxic anthracycline. The SmPC notes that the exact mechanisms of its cytotoxic and antiproliferative properties are not fully worked out. It is cytotoxic in vitro to established mouse and human cell lines and to primary cultures of human tumours, and active in vivo against several mouse tumours and human xenografts in athymic mice, including breast tumours.

Mechanism of Action

• DNA intercalation: it forms a complex with DNA by inserting its planar rings between nucleotide base pairs, which inhibits the synthesis of nucleic acids (DNA and RNA) and of proteins.
• Topoisomerase II: the intercalation triggers DNA cleavage by topoisomerase II, which gives the cell-killing activity. It stabilises the DNA–topoisomerase II complex and prevents the DNA from being re-joined.
• DNA helicase: it inhibits helicase activity, which prevents the enzymatic separation of double-stranded DNA and disturbs replication and transcription.
• Free radicals: it takes part in oxidation and reduction reactions that generate cytotoxic free radicals.
• Cell cycle: anthracyclines are not specific to one phase of the cell cycle.

Pharmacokinetics

• Linearity: linear over 60–150 mg/m²; plasma clearance (about 65–83 L/h) is not affected by the duration of the infusion or the schedule.
• Distribution: after intravenous administration it spreads quickly and widely into tissues. About 77% is bound to plasma proteins (mainly albumin), independent of concentration. It concentrates in red blood cells, so whole-blood concentration is about twice the plasma concentration. It does not cross the blood–brain barrier.
• Metabolism: extensive and rapid, in the liver and also in other organs and cells, including red blood cells. The four main routes are reduction of the C-13 keto group to the 13(S)-dihydro derivative epirubicinol; glucuronide conjugation of the unchanged drug and of epirubicinol; loss of the amino sugar by hydrolysis (doxorubicin and doxorubicinol aglycones); and loss of the amino sugar by a redox process (7-deoxy aglycones). Epirubicinol has about one tenth of the in vitro cytotoxic activity of epirubicin and is unlikely to reach cytotoxic concentrations in vivo. No significant activity or toxicity was seen with the other metabolites.
• Elimination: mainly biliary excretion and, to a lesser extent, urinary excretion. In a mass-balance study in one patient about 60% of the radioactive dose was recovered, 34% in faeces and 27% in urine. The three phases of decline have half-lives of about 3 minutes, 2.5 hours and 33 hours.
• Intravesical use: systemic absorption after instillation into the bladder is minimal.
• Hepatic impairment: patients with raised bilirubin or AST may have lower clearance and higher overall toxicity (see Administration and Dosage).

The Spanish SmPC introduces the indications as neoplastic diseases such as:

• Breast carcinoma.
• Soft-tissue sarcoma.
• Gastric carcinoma.
• Small-cell lung carcinoma.
• Advanced ovarian carcinoma.
• Superficial bladder tumours (Ta/T1 and carcinoma in situ), and prophylaxis of recurrence of superficial bladder tumours after complete transurethral resection. The intravesical route is the one described for these uses.

Epirubicin can be used as a single agent or as part of different combination chemotherapy regimens.

• Hypersensitivity to epirubicin, to any of the excipients, or to other anthracyclines or anthracenediones.
• Breastfeeding.
• Intravenous use is also contraindicated in: persistent myelosuppression; severe hepatic impairment; severe heart failure; recent myocardial infarction; severe arrhythmias; previous treatment with maximum cumulative doses of epirubicin and/or other anthracyclines or anthracenediones; acute systemic infections; unstable angina pectoris; cardiomyopathy.
• Intravesical use is also contraindicated in: urinary tract infections; bladder inflammation; haematuria; invasive tumours that have penetrated the bladder wall; problems with catheterisation.

The table in the SmPC covers reactions seen in clinical trials at standard and high doses and in post-marketing use. Bone-marrow suppression, gastrointestinal effects, alopecia and cardiotoxicity are the main ones.

Very common (≥1/10): infection, conjunctivitis; anaemia, leukopenia, neutropenia, thrombocytopenia, granulocytopenia, febrile neutropenia; keratitis; hot flush, phlebitis; nausea, vomiting, stomatitis, mucosal inflammation, diarrhoea; alopecia, skin toxicity; chromaturia (red urine for 1 to 2 days after a dose); amenorrhoea; malaise, pyrexia; abnormal transaminases.

Common (≥1/100 to <1/10): decreased appetite, dehydration; ventricular tachycardia, atrioventricular block, bilateral bundle branch block, bradycardia, congestive heart failure (reported together with dyspnoea, oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusion and gallop rhythm); haemorrhage, flushing; oesophagitis, gastrointestinal pain, erosion and ulcer; rash or pruritus, nail pigmentation, skin disorder, skin hyperpigmentation; pollakiuria and burning sensation (after intravesical use); infusion site erythema, chills; decreased ejection fraction.

Uncommon (≥1/1,000 to <1/100): sepsis, pneumonia; acute myeloid leukaemia, acute lymphocytic leukaemia; embolism, thrombophlebitis, arterial embolism; pulmonary embolism; gastrointestinal haemorrhage; urticaria, erythema; asthenia.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction (with rash, itching, fever, chills), hypersensitivity (after intravesical use); hyperuricaemia; cardiotoxicity (for example ECG abnormalities, arrhythmias, cardiomyopathy); azoospermia; dizziness.

Not known: septic shock, cellulitis; shock, phlebosclerosis; hypoxia (as a result of myelosuppression); abdominal discomfort, oral pigmentation; photosensitivity reaction; soft-tissue necrosis (after accidental paravenous injection), pain; radiation recall (hypersensitivity of irradiated skin).

After intravesical use, serious systemic and allergic reactions are rare because little drug is absorbed. Local reactions such as burning and frequent urination are reported frequently, and bacterial or chemical cystitis occasionally; most of these are reversible. Dose-limiting cumulative heart damage, severe myelosuppression with infection or sepsis, secondary leukaemia and tissue necrosis after extravasation are the most serious reactions (see Special Instructions).

• Other cytotoxic medicines: epirubicin is mainly used in combination, and additive toxicities may occur, chiefly on the bone marrow (blood counts) and the gut.
• Cardiotoxic or cardioactive medicines: cardiac function must be monitored with other potentially cardiotoxic chemotherapy (for example 5-fluorouracil, cyclophosphamide, taxanes, cisplatin) and with cardioactive medicines such as calcium channel blockers. Anthracyclines should not be combined with other cardiotoxic agents unless cardiac function is closely monitored.
• Trastuzumab: given before an anthracycline, it can raise the risk of cardiotoxicity, especially because of its long half-life. See Special Instructions.
• Liver function: epirubicin is largely metabolised in the liver, so changes in liver function caused by other treatments can alter its metabolism, pharmacokinetics, efficacy and/or toxicity.
• Vaccines: live virus vaccines must not be given. Killed or inactivated vaccines can be given, but the response may be reduced.
• Cimetidine: it raises epirubicin AUC by 50%, so cimetidine should be stopped during epirubicin treatment.
• Taxanes: paclitaxel given before epirubicin can raise plasma concentrations of epirubicin and its metabolites (the metabolites are neither toxic nor active). Paclitaxel or docetaxel given after epirubicin does not change epirubicin pharmacokinetics.
• Food and fluids: drink plenty of fluids; a higher fluid intake raises urine output and uric acid excretion.
• Section 4.5 of the SmPC is the full reference for interactions.

Epirubicin hydrochloride is given by intravenous injection (infusion) or through an intravesical catheter. It is not active by mouth and must not be given intramuscularly or intrathecally. It should be given only under the supervision of doctors experienced in cytotoxic therapy, with diagnostic and treatment facilities available for myelosuppression and its complications, especially after high doses. Patients must have recovered from acute toxicity of earlier cytotoxic treatment (stomatitis, neutropenia, thrombocytopenia, generalised infections) before starting.

Intravenous Administration

• Technique: give through a running intravenous infusion of 0.9% sodium chloride, after checking that the needle is correctly in the vein. Usual infusion times are 3 to 20 minutes depending on dose and volume, to lower the risk of thrombosis or extravasation. Bolus injection is not recommended because of the risk of extravasation, which can occur even when blood return is good.
• Conventional dose: as a single agent in adults, 60–90 mg/m² body surface area per cycle. In combination for breast carcinoma with positive axillary nodes, 100–120 mg/m². The total starting dose per cycle can be given as one dose or divided over 2–3 consecutive days. If recovery from drug-induced toxicity (especially myelosuppression and stomatitis) is normal, cycles can be repeated every 3 or 4 weeks. With other cytotoxic agents whose toxicity overlaps, the dose per cycle should be reduced.
• High dose (breast and lung cancer): as a single agent, up to 135 mg/m² on day 1 or divided over days 1, 2 and 3, every 3 or 4 weeks. In combination, up to 120 mg/m² on day 1 every 3 or 4 weeks. As a single agent in previously untreated small-cell lung cancer, 120 mg/m² on day 1 every 3 weeks.

Intravesical Administration

• Technique: the solution is instilled through a catheter and kept in the bladder for one hour, after which the patient empties the bladder. During instillation the patient is turned to give maximum contact with the bladder mucosa. To avoid unwanted dilution by urine, the patient should drink no fluid in the 12 hours before the instillation.
• Single instillation: 80–100 mg immediately after transurethral resection.
• Course of 4 to 8 weeks followed by monthly instillations: 8 weekly instillations of 50 mg (in 25–50 mL saline), starting 2 to 7 days after resection. If local toxicity (chemical cystitis) occurs, the dose is reduced to 30 mg. Alternatively, 4 weekly instillations of 50 mg followed by 11 monthly instillations of the same dose.
• Intravesical epirubicin is not recommended for invasive tumours that have penetrated the muscle layer of the bladder wall.

Dose Adjustments

• Hepatic impairment: moderate (bilirubin 1.2–3 mg/100 mL or AST 2 to 4 times the upper limit of normal), reduce the dose by 50%. Significant (bilirubin above 3 mg/100 mL or AST above 4 times the upper limit), reduce by 75%. Severe hepatic impairment: do not treat.
• Renal impairment: because little is excreted by the kidneys, moderate impairment does not seem to need a reduction. Data are limited; reduce the starting dose in severe impairment (serum creatinine above 5 mg/100 mL).
• Impaired bone-marrow function (from earlier chemotherapy or radiotherapy, or tumour infiltration of the marrow): lower doses (60–75 mg/m² for conventional and 105–120 mg/m² for high-dose regimens) or a longer interval between cycles.
• Elderly: standard starting doses and regimens have been used.
• Children and adolescents: there are no data on efficacy and safety below 18 years.

Cardiotoxicity and Cumulative Dose

• Early (acute) effects: mainly sinus tachycardia and/or ECG changes (non-specific ST-T changes), with tachyarrhythmias, premature ventricular contractions, ventricular tachycardia, bradycardia, atrioventricular block and bundle branch block reported. They do not predict later cardiotoxicity, are rarely clinically relevant, are usually transient and reversible, and do not require stopping.
• Late (delayed) effects: cardiomyopathy develops late in treatment or within 2–3 months afterwards, although effects months to years later have been reported. It shows as reduced left ventricular ejection fraction (LVEF) and/or signs of congestive heart failure: dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Life-threatening heart failure is the most severe form and is the cumulative dose-limiting toxicity.
• Cumulative dose: the risk of heart failure rises considerably when the total cumulative dose of epirubicin hydrochloride exceeds 900 mg/m². Do not exceed this dose except with extreme caution. Cardiotoxicity can also occur at lower cumulative doses, with or without cardiac risk factors.
• Monitoring: assess cardiac function before treatment (ECG and either MUGA scan or echocardiography, especially in higher-risk patients) and throughout, with regular LVEF checks using the same technique each time, particularly at high cumulative doses. Stop epirubicin at the first sign of impaired cardiac function.
• Risk factors: active or latent cardiovascular disease; previous or concurrent radiotherapy to the mediastinal or pericardial area; earlier anthracyclines or anthracenediones; concurrent medicines that suppress cardiac contractility or are cardiotoxic (for example trastuzumab); older age. The toxicity of epirubicin and other anthracyclines or anthracenediones is likely to be additive.
• Trastuzumab: heart failure (NYHA class II–IV), sometimes fatal, has occurred with trastuzumab alone or with anthracyclines. Trastuzumab and anthracyclines should not be combined except in well-controlled clinical studies with cardiac monitoring. Trastuzumab can stay in the blood for up to 7 months, so where possible anthracycline therapy should be avoided for up to 7 months after it stops; otherwise cardiac function must be monitored carefully.
• Sporadic foetal and neonatal cardiotoxic events, including foetal death, have been reported after in-utero exposure.

Haematological Toxicity

Blood counts (red cells, leukocytes, neutrophils, platelets) must be checked before and during each cycle. Dose-dependent, reversible leukopenia and neutropenia are the main manifestations and the most common acute dose-limiting toxicity. They are worse at high doses, peak between days 10 and 14 and usually recover by about day 21. Thrombocytopenia and anaemia may also occur. Severe myelosuppression can cause fever, infection, sepsis, septic shock, haemorrhage, tissue hypoxia or death.

Secondary Leukaemia

Secondary leukaemia, with or without a pre-leukaemic phase, has been reported with anthracyclines. It is more frequent when they are combined with DNA-damaging antineoplastic agents or radiotherapy, after intensive cytotoxic pre-treatment or at escalated anthracycline doses. The latency period is 1 to 3 years.

Gastrointestinal, Liver and Kidney Effects

• Gastrointestinal: epirubicin is emetogenic. Mucositis or stomatitis appears early and, if severe, may progress to mucosal ulceration within days; most patients recover by the third week.
• Liver: the hepatobiliary system is the main route of elimination, so total bilirubin and AST should be measured before and during treatment. Raised values can reduce clearance and increase toxicity, so lower doses are advised.
• Kidney: serum creatinine should be measured before and during therapy, with dose adjustment when it exceeds 5 mg/100 mL.

Extravasation and Injection Site

Extravasation during intravenous injection can cause local pain, severe tissue damage (blistering, severe cellulitis) and necrosis. The infusion must be stopped immediately at the first signs. Prompt specific treatment, for example dexrazoxane (see its SmPC), can prevent or reduce the damage. Local pain can be eased by cooling the area and keeping it cool, and by hyaluronic acid and dimethyl sulfoxide. Patients need close follow-up because necrosis may appear weeks later, and a plastic surgeon should be consulted. Injection into a small vessel or repeated injection into the same vein can cause phlebosclerosis; following the recommended technique lowers the risk of phlebitis and thrombophlebitis.

Thromboembolism and Tumour Lysis Syndrome

• Thromboembolism: thrombophlebitis and thromboembolic events, including pulmonary embolism (in some cases fatal), have been reported.
• Tumour lysis syndrome: rapid tumour cell breakdown can cause hyperuricaemia. Blood levels of uric acid, potassium, calcium phosphate and creatinine should be checked after the first treatment. Hydration, urine alkalinisation and allopurinol prophylaxis can minimise complications.

Immunosuppression and Live Vaccines

Live or live-attenuated vaccines in patients made immunocompromised by chemotherapy, including epirubicin, can cause serious or fatal infections. Live vaccines must not be given during treatment. Killed or inactivated vaccines can be given, but the response may be reduced.

Intravesical Use

Instillation can cause chemical cystitis (dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is needed with catheterisation problems, for example ureteral obstruction due to tumour masses in the bladder.

Pregnancy, Breastfeeding, Fertility and Contraception

• Pregnancy: data are limited, and animal studies show reproductive toxicity. Epirubicin may cause foetal harm, and its use in the first trimester should be avoided. Human data from the second and third trimesters do not show whether major malformations or miscarriage are related to it. Sporadic transient foetal and neonatal ventricular hypokinesia, transient rises in cardiac enzymes and foetal death from presumed anthracycline cardiotoxicity have been reported after in-utero exposure; the foetus or newborn should be monitored for cardiotoxicity. A woman who receives epirubicin in pregnancy or becomes pregnant during treatment should be told of the risk to the foetus, and genetic counselling considered. It should be given in pregnancy only if the benefit justifies the risk to the foetus.
• Breastfeeding: contraindicated. It is not known whether epirubicin passes into human milk; women should not breastfeed during treatment and for at least 7 days after the last dose.
• Fertility: epirubicin can cause chromosomal damage in human sperm and can cause amenorrhoea or premature menopause in premenopausal women. Animal studies suggest male and female fertility may be irreversibly impaired. Men and women should be strongly encouraged to discuss fertility preservation before treatment.
• Contraception: women of childbearing potential should avoid becoming pregnant and use effective contraception during treatment and for at least 6.5 months after the last dose. Men should use effective contraception during treatment and for at least 3.5 months after the last dose. Epirubicin may be genotoxic, and genetic counselling is advised for patients who want children after treatment.

Excipients

Each vial of Farmorubicina powder contains 250 mg anhydrous lactose and 10 mg methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm. The medicine may be prepared with sodium-containing solutions, and this should be counted in the patient’s total sodium intake.

Effect on Driving

The effect on the ability to drive and use machines has not been systematically evaluated. Nausea and vomiting may temporarily impair it.

Farmorubicina powder needs no special storage conditions. After reconstitution, the solution should be used immediately. The vial is clear glass with a rubber stopper.

4 years. After reconstitution of the powder, use the solution immediately.

Prescription only (Rx), for use under the supervision of doctors experienced in cytotoxic therapy. Epirubicin is given by healthcare professionals as an intravenous infusion or as a bladder instillation through a catheter, so it is supplied to the hospital or clinic that administers it.