Fold 2

A GUIDE FOR HOSPITAL STAFF

090177e183a9ec5b\Final\Final On: 15-Oct-2012 11:34

Fold 5

Fold 4

Fold 5

Fold 3

Fold 5

Fold 4

Fold 5

Pharmorubicin®

Solution for Injection 2 mg/ml Solution for Injection or Infusion

epirubicin hydrochloride

_Pharmacia

IMPORTANT:

Refer to Summary of Product Characteristics before prescribing,

Presentation:

Sterile, red, mobile solution

containing 10 mg, 20 mg, 50 mg and

200 mg of epirubicin hydrochloride as a 2 mg/mi solution in

0,9% sodium chloride solution,

Uses:

Pharmorubicin has produced responses in a wide range of neoplastic conditions including breast, ovarian, gastric, lung and colorectal carcinomas, malignant lymphomas, leukaemias and multiple myeloma.

Intravesical administration of epirubicin has been found to be beneficial in the treatment of superficial bladder cancer, carcinoma-in-situ and the prophylaxis of recurrences after transurethral resection,

Dosage and administration:

Intravenous administration:

Pharmorubicin is not active when given orally and should not be injected intramuscularly or intrathecaily,

Pharmorubicin solution should be administered only under the supervision of a qualified physician experienced in antibiastic and cytotoxic therapy. Treatment with high dose Pharmorubicin in particular requires the availability of facilities for the care of possible clinical complications due to profound myeiosuppression.

It is advisable to give the drug via a freely-running i.v. saline infusion after checking that the needle is well placed in the vein, This method minimises the risk of drug extravasation and makes sure that the vein is flushed with saline after the administration of the drug, Extravasation of Pharmorubicin from the vein during injection may give rise to severe tissue lesions, even necrosis, Venous sclerosis may result from injection into small vessels or repeated injections into the same vein, Conventional doses:

When Pharmorubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area; the drug should be injected i.v. over 3-5 minutes and, depending on the patient’s haematomeduilary status, the dose should be repeated at 21-day intervals,

Dose modification (reduction) following signs of toxicity (specifically severe neutropaenia/neutropaenic fever and thrombocytopaenia, which could persist on Day 21 after the first dose) could be required or the following dose could be delayed, as in cases of liver impairment,

High doses:

Pharmorubicin as a single agent for the treatment of lung cancer at high doses should be administered according to the following regimens:

*    small ceil lung cancer (previously untreated): 120 mg/m² day 1, every 3 weeks.

*    non-smaii ceil lung cancer (squamous, large ceil, and adenocarcinoma previously untreated): 135 mg/m² day 1 or 45 mg/m² days 1,2,3, every 3 weeks.

*    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-fluorouraci! and oral tamoxifen, are recommended.

The drug should be given as an i.v. bolus over 3-5 minutes or as an infusion up to 30 minutes. Lower doses (60-75 mg/m² for conventional treatment and 105-120 mg/m² for high dose schedules) are recommended for patients whose bone marrow function has already been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone marrow infiltration, The total dosage per cycle may be divided over 2-3 successive days.

When the drug is used in combination with other antitumour agents, the doses need to be adequately reduced. Since the

major route of elimination of Pharmorubicin is the hepatobiliary system, the dosage should be reduced in patients with impaired liver function, in order to avoid an increase in overall toxicity. Moderate liver impairment (bilirubin: 1.4-3 mg/100 ml) requires a 50% reduction of dose, while severe impairment (bilirubin >3 mg/100 mi) necessitates a dose reduction of 75%,

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Pharmorubicin excreted by this route.

Intravesical administration:

Pharmorubicin may be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ, It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin has also been successfully used intravesica I ly as a prophylactic agent after transurethral resection of superficial bladder tumours in order to prevent recurrences.

While many regimens have been used, the following may be helpful as a guide: for therapy, 8 x weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water), In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg/50 mi is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg/50 ml, For prophylaxis, 4 x weekly administrations of 50 mg/50 mi followed by 11 x monthly instillations at the same dosage, is the schedule most commonly used.

The solution should be retained intravesica I ly for 1 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 instillation, the patient should be rotated occasionally and should be instructed to void at the end of the instillation time, Contraindications:

Hypersensitivity to epirubicin or any other component of the product, other anthracyclines or anthracenediones,

*    Lactation Intravenous use:

*    persistent myeiosuppression

*    severe hepatic impairment

*    severe myocardial insufficiency

*    recent myocardial infarction

*    severe arrhythmias

*    previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones (see section 4.4)

*    patients with acute systemic infections

*    unstable angina pectoris

*    myocardiopathy Intravesical use:

*    urinary tract infections

*    inflammation of the bladder

*    haematuria

*    invasive tumours penetrating the bladder

*    catheterisation problems

Warnings & Precautions

(refer to the SPC, section 4.4 - special warnings & precautions for use, for further information)

General

Epirubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy, Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

While treatment with high doses of epirubicin (e.g., > 90 mg/m² every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (< 90 mg/m² every 3 to 4 weeks), the severity of the neutropenia and stomatitis/mucositis may be increased. Treatment with high doses of epirubicin does require special attention for possible clinical complications due to profound myeiosuppression.

Cardiac function - Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e,, acute) or late (i.e., delayed) events,

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 - pharmacodynamic properties, clinical studies), 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,

Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m² epirubicin should be exceeded only with extreme caution.

Heart failure (New York Heart Association [NYHA] class ll-IV) has been observed in patients receiving trastuzamab therapy alone or in combination with anthracyclines such as epirubicin, 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 weli-controlied 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 half-life of trastuzumab is approximately 4-5 weeks, trastuzumab may persist in the circulation for up to 20-25 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 25 weeks after stopping trastuzumab. If anthracyclines such as epirubicin are used, the patient’s cardiac function should be monitored carefully,

If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin therapy, it should be treated with the standard medications for this purpose.

(Please refer to the SPC, section 4.4 - special warnings & precautions for use, for further information)

Haematoiogic toxicity- As with other cytotoxic agents, epirubicin may produce myeiosuppression, Haematoiogic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. Secondary leukaemia - Secondary leukaemia, with or without a preieukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin.

Gastrointestinal- Epirubicin is emetigenic. Mucositis/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations,

Liver function - The major route of elimination of epirubicin is the hepatobiliary system, Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin, Lower doses of epirubicin are recommended in patients with elevated bilirubin or AST levels.

Renal function - Serum creatinine should be assessed before and during therapy.

Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL.

Effects at site of injection- Phieboscierosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phiebitis/thrombophlebitis at the injection site (see section 4.2).

Extravasation - Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis, The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g dexrazoxane (please refer to relevant labels for use). The patient’s pain may be relieved by cooling down the area and keeping it cool, using hyaluronic acid and DMSO. If extravasation occurs the patient should be monitored closely during the subsequent period of time, as tissue necrosis at the extravasation site may occur after several weeks from the extravasation episode,

Other- 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.

Tumour-lysis syndrome - Epirubicin may induce hyperuricemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic ceils (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).

2

PATIENT INFORMATION LEAFLET_ PlIMlMAClA

Pharmorubicin*

Solution for Injection 2 mg/ml Solution for Injection or Infusion

PFIZER (PERTH) PTY LIMITED, AUSTRALIA

Item Code

PAM658PE

2

BACK

090177e183a9ec5b\Final\Final On: 15-Oct-2012 11:34

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.

Reproductive system - Epirubicin can cause genotoxicity. Men and women treated with epirubicin should adopt appropriate contraceptives.

Intravesical 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.

Intra-arterial administration of epirubicin (transcatheter arterial embolization 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.

Epirubicin, powder for solution for injection, contains methyl parahydroxybenzoate. This may cause allergic reactions (which may occur after treatment), and in rare cases, respiratory difficulties.

For additional warnings and precautions for other routes of administration refer to the SPC section 4.4 - special warnings & precautions for use.

Interactions:

Epirubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/ haematologic and gastro-intestinal effects (see section 4.4). The use of epirubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment. Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy and/ or toxicity (see section 4.4).

Anthracyclines including epirubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored.

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.

Cimetidine increased the AUC of epirubicin by 50% and should be discontinued during treatment with epirubicin.

When given prior to epirubicin, paclitaxel can cause increased plasma concentrations of unchanged epirubicin and its metabolites, the latter being, however, neither toxic nor active. Increase of myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.

Refer to the SPC, section 4.5 - interaction with other medicinal products and other forms of interaction, for further information.

Adverse reactions:

The undesirable effects in the table below 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), not known (cannot be estimated from the available data).

More than 10% of treated patients can expect to develop undesirable effects. The most common undesirable effects are myelosuppression, gastrointestinal side effects, anorexia, alopecia, infection.

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.

Lactation

It is not known whether epirubicin is excreted in human 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.

Refer to SPC section 4.6 - pregnancy and lactation, for further information.

Effects on ability to drive and use machines

There have been no reports of particular adverse events relating to effects on ability to drive and to use machines. Overdosage:

Acute overdosage with epirubicin will result in severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications. Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment (see section 4.4). Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic. Epirubicin cannot be removed by dialysis. Pharmaceutical precautions:

The following protective recommendations are given due to the toxic nature of this substance:

•    Personnel should be trained in good technique for handling.

•    Pregnant staff should be excluded from working with this drug.

•    Personnel handling Pharmorubicin Solution should wear protective clothing: goggles, gowns, and disposable gloves and masks.

•    All items used for administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration.

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 indicated previously. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution; medical attention should be sought.

Discard any unused solution.

Incompatibilities

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Pharmorubicin should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.

Pharmorubicin can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs.

Shelf life

Glass vials - three years from time of manufacture. Polypropylene Cytosafe® vials - three years from time of manufacture.

Storage

The vials should be stored at between 2°C - 8°C (in the refrigerator).

Keep the container in outer carton.

Shelf life after first opening the container

From a microbiological point of view, the product should be used immediately after first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.

Vials are for single use only and any unused portion must be discarded after use.

Package quantities:

10 mg, 20 mg, 50 mg and 200 mg vials for intravenous or intravesicular use.

Impairment of fertility

Epirubicin could induce chromosomal damage in human spermatozoa.

Epirubicin may cause amenorrhoea or premature menopause in premenopausal women.

Pregnancy

Experimental data, however, suggest that epirubicin may harm the foetus.

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.

PL 0032/0275

This leaflet was prepared in 10/2012.

Further information is available to the medical and allied professions on request from:

Medical Information at Pfizer Limited, Walton Oaks, Tadworth, Surrey, KT20 7NS, UK.

Tel: 01304 616161.    PAM658PE

POM