INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
FARMORUBICIN® RD

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FARMORUBICIN® RD

FARMORUBICIN® RD 10 (injection)
FARMORUBICIN® RD 50 (injection)

COMPOSITION:
Each vial contains:-
FARMORUBICIN RD 10: Epirubicin HCl 10 mg with lactose and methylparaben 2 mg
FARMORUBICIN RD 50: Epirubicin HCl 50 mg with lactose and methylparaben 10 mg

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
FARMORUBICIN RD is an anthracycline antibiotic with antineoplastic activity. This mechanism of action is related to its ability to bind to DNA.
Cell culture studies have shown rapid cell penetration, localization in the nucleus and inhibition of nucleic acid synthesis and mitosis.
In patients with normal hepatic and renal function, plasma levels after I.V. injection of 75 - 90 mg/m² of the medicine 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. Plasma levels of the drug's main metabolite, the 13-0H derivative, are constantly lower and virtually parallel to those of the unchanged medicine.
FARMORUBICIN RD, is eliminated mainly through the liver: high plasma clearance values (0,9 L/min) indicated that this slow elimination is due to extensive tissue distribution. The medicine does not cross the blood-brain barrier.

INDICATIONS:
FARMORUBICIN RD administered as a single agent, may produce regression in a broad spectrum of tumours including mammary carcinoma, malignant lymphomas, soft tissue sarcomas and gastric cancer. Other clinical studies indicate that the medicine may have anti-tumour activity in malignant melanoma and in advanced colorectal carcinoma. When administered in combination with other antineoplastic drugs, FARMORUBICIN RD has induced a therapeutic response in lung and ovarian cancer.

CONTRA-INDICATIONS:
Sensitivity to epirubicin HCl or any related substance. FARMORUBICIN RD is contra-indicated in patients with myelo-suppression induced by previous treatments with other anti-tumour agents or by radiotherapy and in patients already treated with maximal cumulative doses of other anthracyclines such as doxorubicin or daunorubicin.
Doses should not be repeated in the presence of buccal ulceration. This is sometimes preceded by a premonitary buccal burning sensation and the repetition of FARMORUBICIN RD therapy in the presence of this symptom is not advised.
The medicine is contra-indicated in patients with a current or previous history of cardiac impairment.
Pregnancy, especially during the first trimester, and to mothers who are breast feeding.

WARNINGS:

1.	Patients are advised not to conceive. Contraception is advised.
2.	FARMORUBICIN RD should be administered only under the supervision of a qualified physician experienced in cancer chemotherapy.
3.	Initial treatment calls for careful baseline monitoring of various laboratory parameters and cardiac function.

DOSAGE AND DIRECTIONS FOR USE:
FARMORUBICIN RD should be administered only by intravenous injection. It is not active when given orally and should not be injected intramuscularly or intrathecally.
When FARMORUBICIN RD is used as a single agent, the recommended dosage in adults is 60 - 90 mg/m² body area; the medicine should be injected I.V. in 3 - 5 minutes and, depending on the patient's haematological status, the dose should be repeated at 21 day intervals.
Doses up to 135 mg/m² as single agent and 120 mg/m² in combination, every 3 - 4 weeks may be used in the treatment of advanced breast cancer.
Lower doses, 60 - 75 mg/m² are recommended for patients whose bone marrow function has already been impaired by earlier chemotherapy or radiotherapy, by age, or by bone marrow neoplastic infiltrations. The total dosage per cycle may be divided over 2 - 3 successive days. When the medicine is used in association with other anti-tumour agents, the doses need to be adequately reduced.
Since the major route of elimination of FARMORUBICIN RD is the hepatobiliary system the dosage should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. The dosage should be adjusted as follows:

(a)	Moderate liver impairment - Bilirubin: 24 - 51,3 mmol/L (1,4 - 3 mg/100 mL) or BSP retention: 9 - 15% - requires a 50% reduction of dose.
(b)	Severe liver impairment - Bilirubin: >51,3 mmol/L (>3 mg/100 mL) or BSP retention: >15% -necessitates a dose reduction of 75%.

Moderate renal impairment does not appear to call for a dose reduction in view of the limited amount of FARMORUBICIN RD excreted via this route.
It is advisable to administer the drug via the tubing of a freely-running saline I.V. infusion after checking that the needle is well placed in the vein. This method minimizes the risk of medicine extravasation and makes sure the vein is flushed with saline after the administration of the medicine. Extravasation of FARMORUBICIN RD 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 within the same vein.
FARMORUBICIN RD is dissolved in sterile water for injection or 0,9% Sodium chloride solution as indicated in the table below:-

FREEZE-DRIED PREP	DILUENT ADDED	FINAL CONCENTRATION
10 mg	5 mL	2 mg/mL
50 mg	25 mL	2 mg/mL

After adding the diluent, shake the vial until the medicine has completely dissolved. The reconstituted solution is stable for 24 hours at room temperature and for 48 hours in a refrigerator (2 - 8°C). It should be protected from light.
As this is a single dose preparation, any unused portion must be discarded.
N.B.: A designated area, preferably under laminar flow system, should be defined for reconstitution. The work surface should be protected with a disposable plastic-backed absorbent paper. All items used for reconstitution should be placed in high-risk, waste-disposable bags for high temperature incineration. It is advisable that personnel handling this medicine should wear gloves. Accidental contact of FARMORUBICIN RD powder or solution with skin or mucosae should be treated immediately by copious lavage with soap and water. The conjunctiva should be washed with saline solution.
FARMORUBICIN RD should not be mixed with heparin as the two substances are chemically incompatible and in certain ratios may precipitate.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
FARMORUBICIN RD causes pronounced bone-marrow depression with leucopenia, reaching a nadir between the 10th and 14th day, but returning to normal values by the 21st day.
Anaemia, thrombocytopenia, bleeding and an immunosuppressant effect involving both antibody and cell-mediated immunity may occur.
Gastro-intestinal disturbances such as anorexia, nausea, vomiting, diarrhoea, abdominal pain, haemorrhage and intestinal ulceration and perforation have been reported. Buccal ulceration, stomatitis, oesophagitis, and facial flushing, conjunctivitis and lachrymation may occur.
Mucositis may appear 5-10 days after treatment starts and usually involves stomatitis with areas of painful erosions, mainly along the sides of the tongue and on the sublingual mucosa.
Allergic reactions include skin rashes, pruritus and erythema, often of areas previously irradiated.
Fever, headache, hypotension, malaise and weakness.
Anaphylaxis has been reported. Wound healing may be delayed.
Treatment may lead to suppression of ovarian and testicular function resulting in amenorrhoea and the inhibition of spermatogenesis. Gynaecomastia has been reported.
FARMORUBICIN RD may induce hyperuricemia and acute renal failure due to uric acid nephropathy as a result of rapid lysis of neoplastic cells. Nephrotoxicity may also occur. Blood uric acid levels should thus be monitored.
FARMORUBICIN RD may impart a red colouration to the urine for 1-2 days after administration. Alopecia, normally reversible, occurs in the majority of patients.
FARMORUBICIN RD is very irritant and thrombophlebitis has been reported following injection. The directions under “Dosage and directions for use”must be followed to minimise this effect.
FARMORUBICIN RD is cardiotoxic and may present both as an acute, usually transient disturbance of cardiac function, and as a delayed, sometimes fatal, chronic congestive heart failure. It is more likely in adults receiving total cumulative doses greater than 550 mg/m² of body area and may occur up to 6 months after administration. Left-ventricular failure may occur particularly in patients who have received more than 1 g/m².
Cardiac monitoring of patients receiving FARMORUBICIN RD 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.
It is recommended that an ECG be performed 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 arrythmias, need not necessarily be taken as indications to discontinue treatment. Cardiomyopathy, induced by anthracyclines, is associated with a persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction.
The advantages of continuing a treatment exceeding this cumulative dose should be carefully evaluated against the possibility of increasing the risk of heart failure.
In the case of concomitant or previous radiation of the mediastinal-pericardial area, the maximal cumulative dose should be lowered to 400 - 450 mg/m² body area.
During the first cycles of treatment with FARMORUBICIN RD patients must be carefully and frequently monitored. White and red blood cell and platelet counts should be carefully monitored.
FARMORUBICIN RD should be given with great care in reduced doses to elderly patients and those with hepatic impairment. Before commencing treatment and, if possible, during treatment, liver function should be evaluated (SGOT, SGPT, alkaline phosphatase, bilirubin, BSF).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Refer to “Side-effects and special precautions”. Treatment is supportive and symptomatic.

IDENTIFICATION:
Porous red freeze-dried cake or mass.

PRESENTATION:
Vials of 10 mg and 50 mg.

STORAGE INSTRUCTIONS:
Store the freeze-dried product in a dry place below 25°C. Protect from light. The reconstituted solution is stable for 24 hours at room temperature and for 48 hours in a refrigerator (2 to 8°C).
Single dose preparation - discard any unused portion. Keep out of reach of children.

REGISTRATION NUMBERS:
FARMORUBICIN® RD 10: Y/26/397
FARMORUBICIN® RD 50: Y/26/398

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
Midrand
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
11 June 1999

New addition to this site: February 2005
Source: Pharmaceutical Industry



SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2005