1. NAME OF THE MEDICINAL PRODUCT
Epirubicin Hydrochloride solution for injection or infusion USP 2mg/ml Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains

Epirubicin hydrochloride USP              2mg
Sodium chloride                                    9mg
Water for Injection                                 q.s.

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM
Solution for injection or infusion
A clear red solution

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Epirubicin is used in the treatment of a range of neoplastic conditions including;

  • Carcinoma of the breast
  • Gastric cancer

When administered intravesically, epirubicin has been shown to be beneficial in the treatment of

  • Papillary transitional cell carcinoma of the bladder
  • Carcinoma-in-situ of the bladder.
  • Prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection

4.2  Posology and method of administration
Epirubicin is for intravenous or intravesical use only.

The safety and efficacy of epirubicin in children has not been established

Intravenous administration
It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation (see section 4.4). In case of extravasation, administration should be stopped immediately.

Conventional dose
When epirubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area. Epirubicin should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient’s haematomedullary status.

If signs of toxicity, including severe neutropenia/neutropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required.

High dose
Epirubicin as a single agent for the high dose treatment of lung cancer should be administered according to the following regimens:

  • Small cell lung cancer (previously untreated): 120 mg/m2day 1, every 3 weeks.

For high dose treatment, epirubicin may be given as an intravenous bolus over 3-5 minutes or as an infusion of up to 30 minutes duration.

Breast Cancer
In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin ranging from 100 mg/m2 (as a single dose on day 1) to 120 mg/m2 (in two divided doses on days 1 and 8) every 3-4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen (in accordance with local guidelines) are recommended.

Lower doses (60-75 mg/m2 for conventional treatment and 105-120 mg/m2 for high dose treatment) are recommended for patients whose bone marrow function has been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone marrow infiltration. The total dose per cycle may be divided over 2-3 successive days.

The following doses of epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

Epirubicin Dose (mg/m2 )a
Cancer IndicationMonotherapyCombination

Therapy

Ovarian cancer60–9050–100
Gastric cancer60–9050
SCLC120120
Bladder cancer50 mg/50 ml or 80 mg/50 ml (carcinoma in situ)

Prophylaxis:

50 mg/50 ml weekly for 4 weeks then monthly for 11months

aDoses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

Combination therapy
If epirubicin is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above. In establishing the maximal cumulative doses of Epirubicin (usually: 720 – 1000 mg/m2), any concomitant therapy with potentially cardiotoxic drugs should be taken into account.

 

Impaired liver function
The major route of elimination of epirubicin is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Serum BilirubinAST*Dose Reduction
1.4 – 3 mg/100 ml50%
> 3 mg/100 ml> 4 times upper normal limit75%

*AST – aspartate aminotransferase

Impaired renal function
Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450µmol/l).

Intravesical administration
Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall, systemic therapy or surgery is more appropriate in these situations (see section 4.3). Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity is observed: A dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ: Up to 80 mg/50 ml (depending on individual tolerability of the patient)

For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

Dose Epirubicin requiredVolume of 2 mg/ml epirubicin hydrochloride injectionVolume of diluent sterile water for injection or 0.9% sterile salineTotal volume for bladder installation
30 mg15 ml35 ml50 ml
50 mg25 ml25 ml50 ml
80 mg40 ml10 ml50 ml

The solution should be retained intravesically for 1- 2 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.

4.3 Contraindications
Epirubicin is contraindicated in:

  • Patients who have demonstrated hypersensitivity to the active substance or to any of the excipients.
  • Patients with marked myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy to the mediastinal pericardial area and/or who are under medical treatment with potentially cardiotoxic medicinal products (see section 4.5).
  • Patients treated with maximal cumulative doses of other anthracyclines such as doxorubicin or daunorubicin.
  • Patients with current or previous history of cardiac impairment and myocardial infraction.
  • Acute systemic infections.
  • Sever liver impairment.
  • Severe arrhythmias
  • Unstable angina pectoris
  • Severe mucositis of the mouth, pharynx, oeasophagus, and gastro-intestinal tract.
  • Breast-feeding.

Epirubicin is contraindicated for intravesical administration in case of:

  • Urinary tract infections.
  • Invasive tumours penetrating the bladder.
  • Catheterisation problems.
  • Vesicular inflammation.
  • Large volume of residual urine.
  • Contracted bladder.

Epirubicin can have genotoxic effects. Therefore male patients treated with epirubicin are advised not to take part in conception during and up to 6 months after treatment and to seek advise regarding conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin. Female patients should not become pregnant during treatment with epirubicin. Male and female should use an effective method of contraception during treatment and for 6 months thereafter.

Patients must have adequately recovered from severe stomatitis or mucositis, before starting treatment with epirubicin.

4.4 Special Warnings and precautions for use
Epirubicin should only be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of epirubicin.

Haematologic Toxicity As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopoenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin 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.

Secondary Leukaemia – Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. 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. (See section 5.1).

Gastrointestinal – Epirubicin is emetigenic. Mucositis/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.

Epirubicin can have genotoxic effects. Therefore male patients treated with epirubicin are advised not to take part in conception during and up to 6 months after treatment and to seek advise regarding conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin.

Female patients should not become pregnant during treatment with epirubicin. Male and female should use an effective method of contraception during treatment and for 6 months thereafter.

Extravasation of epirubicin from the vein during injection may cause severe tissue lesions and necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

Careful baseline monitoring of various laboratory parameters and cardiac function should precede initial treatment with epirubicin.

During treatment with epirubicin, red blood cell, white blood cell, neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. Leucopenia and neutropenia are usually transient with conventional and high-dose schedules, reaching a nadir between the 10th and 14th day, values should return to normal by the 21st day; they are more severe with high dose schedules.

Thrombocytopenia (< 100,000 platelets/mm3) is experienced in very few patients, even following high doses of epirubicin.

Patients must have adequately recovered from severe stomatitis or mucositis, before starting treatment with epirubicin.

In establishing the maximal cumulative dose of epirubicin, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs. A cumulative dose of 900-1000 mg/m2 should only be exceeded with extreme caution with both conventional and high doses of epirubicin. Above this level the risk of irreversible congestive heart failure increases greatly. An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the T-wave, depression of the S-T segment, or the onset of arrhythmias, generally transient and reversible, need not necessarily be taken as indications to discontinue treatment. With cumulative doses <900 mg/m2, there is evidence that cardiac toxicity rarely occurs. However, cardiac function must be carefully monitored during treatment to minimise the risk of heart failure of the type described for other anthracyclines.

Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving epirubicin treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques such as ECG, echocardiography and, if necessary, measurement of ejection fraction by radionuclide angiography.

Heart failure may appear several weeks after discontinuing therapy with epirubicin and may be unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial area and/or who are in a medical treatment with potential cardiotoxic agents (see section 4.5).

Cardiac Function – 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 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 treatment.

Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin 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 in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution (see section 5.1).

Cardiac function should be assessed before patients undergo treatment with epirubicin 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 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 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, and concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab) (see section 4.5).

Before commencing therapy with epirubicin, and if possible during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin). (see section 4.2) For patients with reduced renal function serum creatinine levels should be checked regularly prior to and during treatment. For patients with increased serum creatinine (>450µmol/l) a dose reduction should be considered (see section 4.2 and 5.2). Patients with severe hepatic impairment should not receive epirubicin (see section 4.3).

As with other cytotoxic agents, epirubicin may induce hyperuricaemia as a result of rapid lysis of neoplastic cells. Blood uric acid levels should therefore be checked so that this phenomenon may be recognised and properly managed.

Epirubicin may impart a red colour to the urine for one or two days after administration.

Tumor-Lysis Syndrome – Epirubicin 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.

Immunosuppressant Effects/Increased Susceptibility to Infections- Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. (see section 4.5).

Intravesical route – Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumours).

Intra-arterial route – Intra-arterial administration of epirubicin (transcatheter arterial embolisation for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of epirubicin) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.

4.5 Interaction with other medicinal products and other forms of interaction
Epirubicin can be used in combination with other antic-cancer agents but patients should be monitored for additive toxicity, especially myelotoxicity and gastrointestinal toxicity. Concomitant use of other medicinal products that may be cardiotoxic or affect cardiac function should be monitored throughout treatment. Paclitaxel has been show to increase plasma concentrations of epirubicin when paclitaxel is administered before epirubicin. When paclitaxel is administered after epiribucin no detectable changes in epirubicin plasma concentrations have been observed. With concomitant use, the latter administration schedule is therefore recommended.

Drug interactions with epirubicin have been observed with cimetidine, dexverapamil, dexrazoxane, docetaxel, interferon α2b, paclitaxel and quinine.

Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.

Prior to administration of higher doses (900 mg/m2 and 1200 mg/m2) of dexrazoxane may increase the systemic clearance of epirubicin and result in a decrease in AUC.

One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites, when administered immediately after epirubicin.

The co-administration of interferon α2b may cause a reduction in both the terminal half life and the total clearance of epirubicin.

Paclitaxel may affect the pharmacokinetics of epirubicin and its metabolite, epirubicinol. In one study, haemotolgical toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin. One study has shown that paclitaxel clearance is reduced by epirubicin.

Quinine may accelerate the initial distribution of epirubicin from blood in to the tissues and may have an influence on the red blood cells partitioning of epirubicin.

Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m2 every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter p<0.05). The AUC of the 7-deoxy-doxorubicinol aglycone and liver blood flow were not reduced, so results are not explained by reduced cytochrome P-450 activity. Epirubicin used in combination with other cytotoxic agencts may result in additive myelotoxicity.

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.

This combination may be used if using staggered administration between the two agents. Infusion of epirubicin and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.

The possibility of a marked disturbance of haematopiesis needs to be kept in mind with a (pre-) treatment with agents which influence the bone marrow (i.e. cytostatic agents, sulphonamide, cloramphenicol, diphenylhydantoin, amidopyrinedervatives, antiretroviral agents)

The potential risk of cardiotoxicity may increase in patients, who have received concomitant cardiotoxic agents (e.g. 5-fluorouracil, cyclophosphamide, cisplatin, taxanes) or concomitant (or prior) radiotherapy to the mediastinal area.

If epirubicin is used concomitant with other agents that may cause heart failure, e.g. calcium channel blockers, the cardiac function must be monitored throughout the course of treatment.

Epirubicin is mainly metabolised in the liver; each concomitant agent, which affects hepatic function can also affect the metabolisation or the pharmacokinetics of epirubicin and consequently it’s efficacy and/or toxicity.

This medicinal product is generally not recommended in combination with live, attenuated vaccines.

4.6 Pregnancy and lactation
There is no conclusive information as to whether epirubicin may adversely affect human fertility or cause teratogenesis. Experimental data, however, suggest that epirubicin may harm the foetus. Like most other anti-cancer agents, epirubicin has shown mutagenic and carcinogenic properties in animals. Both men and women receiving epirubicin should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during epirubicin therapy.

In cancer chemotherapy, epirubicin should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Epirubicin may cause amenorrhea or premature menopause in premenopausal women.

Epirubicin should not normally be administered to patients who are breast-feeding.

It is unknown whether epirubicin is excreted in human breastmilk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with epirubicin.

4.7 Effects on ability to drive and use machines
There have been no reports of particular adverse events relating to the effects on ability to drive and to use machines. Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of the ability to drive or operate machines.

4.8 Undesirable Effects
The estimation of frequency: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000) not known (cannot be estimated from the available data).

Investigations
Rare: Increased transaminase levels.

Cardiac disorders
Rare: Cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (dyspnoea, oedemea, enlargement of the liver, ascites, pulmonary oedema, pleural effusion, gallop rhythm), ventricular tachycardia, bradycardia, AV block, bundle-branch block) (see section 4.4).

Blood and lymphatic system disorder
Frequency unknown: Myelosuppression (leukopenia, granulcytopenia, neutropenia, febril neutropenia, thrombocytopenia, anaemia), Hemorrhagia and tissue hypoxia (as a result of myelosuppression) may occur.

High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse events which are no different from those seen at conventional doses with the exception of reversible severe neutropenia (< 500 neutrophils/mm3 for < 7 days) which occurred in the majority of patients. Only few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.

Very common: Alopecia, normally reversible, appears in 60-90% of treated cases; it is accompanied by lack of beard growth in males.

Uncommon: Hyperpigmentation of skin and nails. Skin reddening.

Rare: Urticaria.

Metabolism and nutrition disorders
Common: Anorexia, dehydration.

Rare: Hyperuricaemia (as a result of rapid lysis of neoplastic cells) (see section 4.4).

Infections and infestations
Frequency unknown: Fever, infections, pneumonia, sepsis and septic shock may occur as a result of myelosuppression.

Injury, poisoning and procedural complications
Common: Chemical cystitis, in some cases haemorrhagic, is observed following intravesical administration (see section 4.4).

Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare: Acute lymphocytic leukaemia, Secondary acute myeloid leukaemia with or without a pre-leukaemic phase in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents. These leukemia’s have short (1-3 years) latency.

Vascular disorders
Common: Hot flashes, Hot flushes.

Uncommon: Phlebitis, Thrombophlebitis.

Frequency unknown: Shock, Coincidental cases of thromboembolic events (including pulmonary embolism (in isolated cases with fatal outcome)) have occurred.

General disorders and administration site conditions
Common: Redness along the infusion vein. Phlebosclerosis, Local pain and tissue necrosis may occur (following accidental paravenous injection).

Uncommon: Headache.

Rare: Fever, chills, hyperpyrexia, malaise, asthenia, weakness.

Nervous system disorders
Rare: Dizziness

Eye disorders
Not known: Conjunctivitis, keratitis

Gastrointestinal disorders
Common: Mucositis may appear 5-10 days after the start of treatment and usually involves stomatitis with areas of painful erosions, ulceration and bleedings, mainly along the side of the tongue and the sublingual mucosa, esophagitis, vomiting, diarrhoea, nausea

Immune system disorders
Common: Allergic reactions after intravesical administration.

Uncommon: Photosensitivity or hypersensitivity in case of radiotherapy (“recall phenomenon”).

Rare: Anaphylaxis (anaphylaxis/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills).

Reproductive system and breast disorders
Rare: Amenorrhea, azoospermi.

4.9 Overdose
Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) within 10-14 days.

Treatment should aim to support the patient during this period and should utilise such measures as blood transfusion and reverse barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to 6 months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines. Epirubicin is not dialyzable.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anthracylines and related substances

The mechanism of action of epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

5.2 Pharmacokinetic properties
In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m2 of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.

In a pharmacokinetic study of patients with carcinoma in situ in the bladder the plasma levels of epirubicin after intravesical administration are typically low (<10 ng/ml). A significant systemic resorption is therefore not presumed. In patients with mucous membrane lesions in the bladder (e.g. tumour, cystitis, operations) an increased resorption rate may be expected.

The 4′-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged drug.

Epirubicin is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution.

Urinary excretion accounts for approximately 9-10% of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier

5.3 Preclinical safety data
Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs.

Epirubicin was also cardiotoxic in the rat, rabbit and dog.

Epirubicin, like other anthracyclines, was genotoxic, embryotoxic and carcinogenic in rats.

No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Sodium Chloride
Hydrochloric acid (For pH adjustment)
Water for Injections

6.2 Incompatibilities
Prolonged contact of the medicinal product with any solution of alkaline pH (including sodium bicarbonate solutions) should be avoided; this will result in hydrolysis (degradation) of the active substance. Only the diluents detailed in section 6.6 should be used.

Neither the injection nor any diluted solution should be mixed with any other drugs. A physical incompatibility with heparin has been reported.

Epirubicin should not be mixed with other drugs.

6.3  Shelf life
Shelf life of the product as package for sale:
2 year.

Shelf life after first opening the container:
The vials are for single use only and any unused portion must be discarded after use. From a microbiological point of view, the product should be used immediately after the first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.

Shelf life after dilution of the solution for injection:
Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted, under aseptic conditions, in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage after dilution, see section 6.3.

6.5 Nature and contents of container
5 and 10 ml vials: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white seal.

25 ml vial: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white / royal blue seal.

50 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off royal blue seal.

100 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white / royal blue seal.

Pack size: 1 vial.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling
Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. For information on the stability of the infusion solutions, please refer to section 6.3.

The solution for injection or infusion contains no preservative and any unused portion of the vial should be discarded immediately in accordance with local requirements.

Guidelines for the safe handling and disposal of antineoplastic agents:

  1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.
  2. Preparation of an infusion solution should be performed in a designated aseptic area.
  3. Adequate protective disposable gloves, goggles, gown and mask should be worn.
  4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9% sodium chloride solution. Then seek medical evaluation by a physician.
  5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.
  6. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.
  7. Pregnant staff should not handle the cytotoxic preparation.
  8. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Epirubicin Hydrochloride solution for injection or infusion USP 2mg/ml Taj Pharma

Package leaflet: Information for the patient

Epirubicin Hydrochloride solution for injection or infusion USP 2mg/ml Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4).

What is in this leaflet
1. What Epirubicin Hydrochloride Injection is and what it is used for
2. What you need to know before you take Epirubicin Hydrochloride Injection
3. How to take Epirubicin Hydrochloride Injection
4. Possible side effects
5. How to store Epirubicin Hydrochloride Injection
6. Contents of the pack and other information

1. WHAT EPIRUBICIN HYDROCHLORIDE INJECTION IS AND WHAT IT IS USED FOR
The name of your medicine is ‘Epirubicin Hydrochloride 2 mg/ml solution for injection or infusion’ but in the rest of the leaflet it will be called ‘Epirubicin Hydrochloride Injection’.

What Epirubicin Hydrochloride Injection is
Epirubicin Hydrochloride Injection is an anti-cancer medicine. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy. Epirubicin Hydrochloride Injection is part of a group of medicines called anthracyclines. These act upon cells that are actively growing, to slow or stop their growth and increase the chance that the cells die.

What Epirubicin Hydrochloride Injection is used for
Epirubicin Hydrochloride Injection is used to treat a variety of cancers, either alone or in combination with other drugs. The way in which it is used depends upon the type of cancer that is being treated.
Epirubicin Hydrochloride Injection is used in the treatment of cancers of the breast, and stomach.
When injected into the bladder through a tube, Epirubicin Hydrochloride Injection is used to treat abnormal cells or cancers of the bladder wall. It can also be used after other treatments for prevention of such cells from growing again.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE EPIRUBICIN HYDROCHLORIDE INJECTION
Do not use Epirubicin Hydrochloride Injection if you
· are allergic (hypersensitive) to epirubicin hydrochloride or any of the other ingredients of Epirubicin Hydrochloride Injection (a list of ingredients can be found in Section 6).
·  are aware that your blood counts are low, as Epirubicin Hydrochloride Injection can lower them further.
· suffer with or have suffered with severe heart failure in the past or are presently receiving treatment for this.
· have previously been treated with Epirubicin Hydrochloride Injection or similar chemotherapy drugs as previous treatment with these medicines can increase the risk of side effects.
·  suffer from an acute severe infection.
· have severe inflammation in the mouth, pharynx, oesophagus and gastro-intestinal tract.
· are breast-feeding.
· have severe liver problems.

Tell your doctor or hospital pharmacist if any of the above applies to you. In any of the above cases, you should not be given Epirubicin Injection.

Epirubicin Hydrochloride Injection should not be injected into the bladder if:
– you suffer from urinary infection – there are tumours which penetrate the bladder wall
– your doctor has problems inserting a catheter (tube) into your bladder
– you have an inflammation of the bladder
– you have large volume of urine left in your bladder after you attempt to empty

Take special care with Epirubicin Hydrochloride Injection

Tell your doctor if:
·  you have some kidney or liver problems. You should inform your doctor before treatment, as he/she needs to take special care.
·  you have had or you are due to have any vaccination.

Your doctor will also be making regular checks
·  so that your blood cell counts will not be too low
· to control the levels of uric acid in the blood
· to see that your heart and liver are working normally
· if you have or are to have radiotherapy to the area around the heart.

You should inform your doctor in case you experience swelling and pain in your mouth or mucous membrane.

It is possible that the urine will have a red colour for one or two days after administration.

Using other medicines
Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Especially:
– Cimetidine (a drug usually used to reduce the acid in the stomach and heartburn). Cimetidine can make the effects of Epirubicin Hydrochloride Injection stronger.
– Paclitaxel and docetaxel (used in some cancers).
– Calcium channel blockers (medicines for the heart).
– Interferon alfa-2b (used in some cancers and lymphoma and for some yellow fever).
– Quinine (used for treatment of malaria and for leg cramps).
– Antibiotics such as sulphonamide and chloramphenicol.
– Antiretroviral (drugs used to treat infection by HIV).
– Diphenylhydantoin (a drug used to treat epilepsy).
– Painkillers such as amidopyrin derivatives.
– Dexrazoxane (sometimes used with doxorubicin in order to decrease the risk of heart problems).
– Dexverapamil (used to treat some heart conditions).
– Other medicines that may affect your liver and/or heart.

Pregnancy and breast-feeding
Epirubicin Hydrochloride Injection may cause birth defects when used during pregnancy, it is important to tell your doctor if you are pregnant or if you become pregnant during treatment. You must not use Epirubicin Hydrochloride Injection during pregnancy unless clearly indicated by your doctor.

If you or your partner are being teated with Epirubicin Hydrochloride Injection effective birth control to prevent pregnancy during treatment and for 6 months after treatment is advised. If pregnancy occurs during treatment, genetic counsellation is recommended.

There is a risk of sterility due to therapy with Epirubicin Hydrochloride Injection and male patients should consider storage of sperm before treatment.

Epirubicin Hydrochloride Injection may be harmful to nursing infants, therefore women must stop breast-feeding before starting treatment with Epirubicin Hydrochloride Injection.

Driving and using machines
Epirubicin Hydrochloride Injection may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of the ability to drive or use machines.

Important information about some of the ingredients of Epirubicin Hydrochloride Injection
This medicinal contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium free’.

3. HOW TO TAKE EPIRUBICIN HYDROCHLORIDE INJECTION
Epirubicin Hydrochloride Injection will be given to you by a doctor or nurse, either into a vein or directly into your bladder.
Your doctor will decide the correct dose and number of days treatment you receive, this will depend on the type of cancer you have, your health, height, weight, how well your liver is working and any other treatment you may receive.

By injection or infusion into a vein
Epirubicin Hydrochloride Injection may be given as an injection into a vein over 3-5 minutes. It may also be diluted before it is infused slowly, usually via a drip into a vein over 30 minutes.

By being put into the bladder
If the injection is given into the bladder, you should not drink any fluids for 12 hours before treatment so that your urine will not dilute the drug too much. The solution should be kept in your bladder for 1-2 hours after installation. You will need to turn occasionally to make sure all parts of the bladder are exposed to the drug.

Care should be taken to ensure that the contents of the bladder, when emptied, do not come into contact with the skin. In case of skin contact, thoroughly wash the affected area with soap and water but do not scrub.

Your doctor will regularly check your blood for any unwanted effects. To detect any possible heart damage your doctor will also monitor your heart for several weeks after the treatment.

Regular checks by your doctor during Epirubicin Hydrochloride Injection treatment
During treatment your doctor will be making regular checks of your:

  • Blood – to check for low blood cell counts that may need treatment
    · Heart function – heart damage can occur when high doses of Epirubicin Hydrochloride Injection are given. This may not be detected for several weeks, so regular tests may be required during this period
    · Liver – using blood tests to check that this medicine is not affecting the way it functions in a harmful way
    · Blood uric acid levels – Epirubicin Hydrochloride Injection may increase uric acid levels in the blood which might cause gout. Another medicine may be given if your uric acid levels are too high.

If you receive more Epirubicin Hydrochloride Injection than you should:
High doses can worsen side effects like sores in the mouth or may decrease the number of white blood cells (which fight infection) and platelets (these help the blood to clot) in the blood. Should this happen, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to make them less uncomfortable as they heal. Please tell your doctor if you have any concerns.

4. POSSIBLE SIDE EFFECTS
Like all medicines, Epirubicin hydrochloride Injection can cause side effects, although not everybody gets them.
If any of the following side effects happen when epirubicin is given by infusion into a vein tell you doctor immediately, as these are very serious side effects. You may need urgent medical attention:
– redness, pain or swelling at the injection site; tissue damage may occur after accidental injection outside a vein
– symptoms of heart problems such as chest pain, shortness of breath, swelling of your ankles (these effects may occur up to several weeks after finishing treatment with epirubicin)
– severe allergic reaction, symptoms include faintness, skin rash, swelling of the face and difficulty in breathing or wheeze. In some cases collapse may occur.

If you experience any of the following tell your doctor as soon as possible:

Very common (these may affect at least 1 in 10 people):
· White blood cell counts (which fight infection) can drop, which increases the chance of infections and fever.
· A low red blood cell count (anaemia) that can leave you feeling tired and lethargic.
· Hair loss – may be quite severe. Beard growth may stop in men. Hair normally re-grows when your treatment course ends.
· Red discolouration of urine (which is normal and related to the colour of the medicine). You should inform your doctor if it does not stop in a few days or you think there is blood in your urine.

Common (these may affect between 1 in 100 and 1 in 10 people):
· Infections
· Allergic reactions,
· Feeling or being sick (nausea or vomiting),
· Diarrhoea (which can result in dehydration),
· Feeling thirsty (dehydration),
· Loss of appetite,
· Abdominal pain,
· Heartburn,
· Inflammation of the gullet (oesophagitis),
· High levels of pigments in the mouth,
· Swelling and pain in your mouth,
· Ulcers involving the lips and/or tongue and/or under the tongue, which may not appear until 3-10 days after treatment
· Hot flushes,
· Changes in blood cells causing bleeding,
· Fever .
· Pain, redness, burning or stinging sensation at injection site
· Irritation of the bladder or damage to the bladder wall (called necrosis)

Uncommon (these may affect between 1 in 10,000 and 1 in 100 people):
· Platelets (cells that help the blood to clot) can be affected which could make you bruise or bleed more easily. It  is important to seek medical advice if this happens,
· Swelling, redness, leg pain, which can be associated with blood clots.
· Vein inflammation including blood clotting (thrombophlebitis).

Rare (these may affect between 1 in 10,000 and 1 in 1,000 people):
· When given in combination with other anti-cancer drugs, some patients have developed a rare leukaemia (cancer of white blood cells) after completing treatment,
· Tiredness, weakness and feeling cold,
· Gasping for air, shortness of breath, swelling of abdomen, legs or ankles, fluid in lungs (signs of congestive  heart failure),
· ECG abnormalities, irregular heartbeat, heart muscle disease
· Hives (urticaria),
· Fever and/or chills,
· Dizziness,
· Absence of menstrual periods (amenorrhea),
· Low sperm count,
· Increase uric acid levels in the blood which might cause gout,
· Changes in heart or liver function.
· Fever with an extreme elevation of body temperature (hyperpyrexia)
· Feeling of general discomfort or uneasiness (malaise)

Not known (cannot be estimated from the available data)
· Blood infection,
· Pneumonia,
· Internal bleeding,
· Inflammation to the eye (conjunctivitis and keratitis),
· Shock,
· Discolouration of skin and nails,
· Sensitive to light,
· Blood clots, including a clot in the lungs which causes chest pain and breathlessness.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE EPIRUBICIN HYDROCHLORIDE INJECTION
Store in a refrigerator (2°C – 8°C) Do not freeze. Keep the vial in the outer carton in order to protect from light.
Always keep Epirubicin Hydrochloride Injection in a safe place and out of the reach and sight of children.
Do not use Epirubicin Hydrochloride Injection after the expiry date, which is printed on the label and carton after EXP. The expiry date refers to the last day of that month.
Do not use Epirubicin Hydrochloride Injection if you notice any visible signs of deterioration.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose medicines no longer required. These measures will help to protect the environment.

6. CONTENTS OF THE PACK AND FURTHER INFORMATION

What Epirubicin Hydrochloride Injection contain
The active ingredient in Epirubicin Injection is Epirubicin Hydrochloride.
Each ml contains
Epirubicin hydrochloride USP              2mg
Sodium chloride                                    9mg
Water for Injection                                 q.s.

Other ingredients include sodium chloride, hydrochloric acid and water for injection.

What Epirubicin Hydrochloride Injection look like and contents of the pack
Epirubicin Injection is a clear, red coloured solution.
Pack sizes:
1 x 5 ml vial (10 mg/5 ml)
1 x 10 ml vial (20 mg/10 ml)
1 x 25 ml vial (50 mg/25 ml)
1 x 50 ml vial (100 mg/ 50 ml)
1 x 100 ml vial (200 mg/100 ml)
5 and 10 ml vials: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white seal.
25 ml vial: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white/royal blue seal.
50 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off royal blue seal.
100 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white / royal blue seal.
Pack size: 1 vial.
Not all pack sizes may be marketed

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com