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

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FARMORUBICIN® CSV

FARMORUBICIN® CSV 10 mg/5 mL (injection)
FARMORUBICIN® CSV 20 mg/10 mL (injection)
FARMORUBICIN® CSV 50 mg/25 mL (injection)
FARMORUBICIN® CSV 200 mg/100 mL (injection)

COMPOSITION:
Each vial contains:-
FARMORUBICIN CSV 10 mg/5 mL: Epirubicin HCl 10 mg (2 mg/mL)
FARMORUBICIN CSV 20 mg/10 mL: Epirubicin HCl 20 mg (2 mg/mL)
FARMORUBICIN CSV 50 mg/25 mL: Epirubicin HCl 50 mg (2 mg/mL)
FARMORUBICIN CSV 200 mg/100 mL: Epirubicin HCl 200 mg (2 mg/mL)

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
FARMORUBICIN CSV 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 CSV 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 CSV, 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 CSV has induced a therapeutic response in lung and ovarian cancer.

CONTRA-INDICATIONS:
Sensitivity to Epirubicin HCl or any related substance. FARMORUBICIN CSV 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 CSV 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 CSV 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 CSV should be administered only by intravenous injection. It is not active when given orally and should not be injected intramuscularly or intrathecally.
When FARMORUBICIN CSV 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. over 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 CSV 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 CSV 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 CSV 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 CSV 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 CSV 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 and thrombocytopenia and 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 CSV 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 CSV may impart a red colouration to the urine for 1-2 days after administration. Alopecia, normally reversible, occurs in the majority of patients.
FARMORUBICIN CSV 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 CSV is cardiotoxic and may produce 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 1g/m².
Cardiac monitoring of patients receiving FARMORUBICIN 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 CSV patients must be carefully and frequently monitored. White and red blood cell and platelet counts should be carefully monitored.
FARMORUBICIN CSV 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:
Clear red solution practically free from particles.

PRESENTATION:
Vials of 10 mg, 20 mg, 50 mg and 200 mg.

STORAGE INSTRUCTIONS:
Store between 2 - 8°C. Protect from light. Do not freeze. Single dose preparation - discard any unused portion. Keep out of reach of children.

REGISTRATION NUMBERS:

FARMORUBICIN® CSV 10 mg/5 mL:	32/26/0600
FARMORUBICIN® CSV 20 mg/10 mL:	32/26/0601
FARMORUBICIN® CSV 50 mg/25 mL:	32/26/0602
FARMORUBICIN® CSV 200 mg/100 mL:	32/26/0603

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George St
MIDRAND 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
22 January 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