1. Name Of The Medicinal Product
Pharmorubicin Rapid Dissolution 10mg, 20mg, 50mg and 150mg
2. Qualitative And Quantitative Composition
Epirubicin hydrochloride HSE 10.0 mg
Epimbicin hydrochloride HSE 20.0 mg
Epirubicin hydrochloride HSE 50.0 mg
Epirubicin hydrochloride HSE 150.0 mg
3. Pharmaceutical Form
Red, freeze-dried powder for injection containing 10mg, 20mg, 50mg and 150mg epirubicin hydrochloride.
4. Clinical Particulars
4.1 Therapeutic Indications
Pharmorubicin has produced responses in a wide range of neoplastic conditions, including breast ovarian, gastric, lung and colorectal carcinomas, malignant lymphoma, leukaemias and multiple myelomas.
Intravesical administration of Pharmorubicin has been found to be beneficial in the treatment of superficial bladder cancer, carcinoma-in-situ and in the prophylaxis of recurrences after transurethral resection.
4.2 Posology And Method Of Administration
Intravenous Administration:
Pharmorubicin is not active when given orally and should not be injected intramuscularly or intrathecally.
It is advisable to give the drug via the tubing of a freely-running iv. 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 patients' haematomedullary status, the dose should be repeated at 21-day intervals.
Dose modification (reduction) following signs of toxicity (specifically severe neutropaenia/neutopaenic 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 the case 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 cell lung cancer (previously untreated): 120 mg/m2 day 1, every 3 weeks.
• Non-small cell lung cancer (squamous, large cell, and adaenocarcinoma previously untreated): 135 mg/m2 day 1 or 45 mg/m2 day 1, 2. 3 every 3 weeks.
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 dose 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 of 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 ml) necessitates a dose reduction of 75%.
Moderate renal impairment does nor appear to require a dose reduction in view of the limited amount of Pharmorubicin excreted by this route.
Intravesical Administration:
Pharmorubicin can 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 intravesically as a prophylactic agent after transurethral resection of superficial 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 ml 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 followed by 11 x monthly instillations of the same dosage, is the schedule most commonly used.
The solution should be retained intravesically 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.
4.3 Contraindications
Pharmorubicin Rapid Dissolution is contraindicated in patients with marked myelosuppression induced by previous treatment with other antitumour agents or by radiotherapy and in patients already treated with maximal cumulative doses of other anthracyclines such as Doxorubicin or Daunorubicin.
The drug is contraindicated in patients with current or previous history of cardiac impairment.
4.4 Special Warnings And Precautions For Use
Pharmorubicin Rapid Dissolution should be administered only under supervision of qualified physicians experienced in antiblastic and cytotoxic therapy. Treatment with high dose Pharmorubicin in particular requires the availability of facilities for the care of possible clinical complications due to myelosuppression.
Initial treatment calls for a careful baseline monitoring of various laboratory parameters and cardiac function.
During each cycle of treatment with Pharmorubicin Rapid Dissolution, patients must be carefully and frequently monitored. Red and white blood cells, neutrophils and platelet counts should be carefully assessed both before and during each cycle of therapy. Leukopenia and neutropenia are usually transient with conventional and high-dose schedules, reaching a nadir between the 10th and 14th day and returning to normal values by the 21st day; they are more severe with high dose schedules. Very few patients, even receiving high doses, experience thrombocytopenia (<100,000 platelets/mm3).
Before starting therapy and if possible during treatment, liver function should be evaluated (SGOT, SGPT, alkaline phosphatase, bilirubin). A cumulative dose of 900-1000 mg/m2 should only be exceeded with extreme caution with both conventional and high doses.
Above this level the risk of irreversible congestive cardiac failure increases greatly. There is objective evidence that cardiac toxicity may occur rarely below this range. However, cardiac function must be carefully monitored during treatment to minimise the risk of heart failure of the type described for other anthracyclines.
Heart failure can appear even several weeks after discontinuing treatment, and may prove 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.
In establishing the maximal cumulative doses of Pharmorubicin, any concomitant therapy with potential cardiotoxic drugs should be taken into account
It is recommended that an ECG before and after each treatment cycle should be carried out Alterations in the EGG tracing, such as flattening or invasion 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.
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. Cardiac monitoring of patients receiving Pharmorubicin 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.
Like other cytotoxic agents, Pharmorubicin may induce hyperuricemia as a result of rapid lysis of neoplastic cells. Blood uric acid levels should therefore be carefully checked so that this phenomenon may be controlled pharmacologically.
Pharmorubicin Rapid Dissolution may impart a red color to the urine for 1-2 days after administration.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
It is not recommended that Pharmorubicin Rapid Dissolution be mixed with other drugs. But Pharmorubicin can be used in combination with other anticancer drugs.
Cimetidine increases the formation of the active metabolite of epirubicin and the exposure of the unchanged epirubicin by pharmacokinetic interaction.
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. This product should not normally be administered to patients who are pregnant or to mothers who are breast-feeding. Like most other anti-cancer agents, epirubicin has shown mutagenic and carcinogenic properties in animals.
4.7 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.
4.8 Undesirable Effects
Apart from myelosuppression and cardiotoxicity, the following adverse reactions have been described:
• Alopecia, normally reversible, appears in 60-90% of treated cases; it is accompanied by lack of beard growth in males
• Mucositis may appear 5-10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, mainly along the side of the tongue and the sublingual mucosa.
• Gastro-intestinal disturbances, such as nausea, vomiting and diarrhoea.
• Hyperpyrexia
Fever, chills and urticaria have been rarely reported; anaphylaxis may occur.
High doses of Pharmorubicin have been safely administered in a large number of untreated patients having various solid tumours and has 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.
During intravesical administration, as drug absorption is minimal, systemic side effects are rare; more frequently chemical cystitis, sometimes haemorrhagic, has been observed.
Haematological:
The occurrence of secondary acute mycloid leukaemia with or without a pre-leukaemic phase has been reported rarely in patients concurrently treated with epirubicin in association withDNA-damaging antineoplastic agents Such cases could have a short (1-3 year) latency period.
4.9 Overdose
Very high single doses of epirubucin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
The mechanism of action of Pharmorubicin 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 mytosis. Pharmorubicin has proved to be active on a wide spectrum of experimental tumours including L 1210 and P 388 leukemias, sarcomas SA 180 (solid and ascitic forms), B 16 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 i.v. 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.
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 constantly lower and virtually parallel those of the unchanged drug.
Pharmorubicin is eliminated mainly through the liver high plasma clearance values (0.9 l/mm) 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. When Pharmorubicin is administered intravesically the systemic absorption is minimal
5.3 Preclinical Safety Data
No further information is given.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Methyl hydroxybenzoate Ph. Eur.
Lactose monohydrate Ph. Eur.
Water for Injections Ph. Eur.
6.2 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.
6.3 Shelf Life
The shelf-life shall not exceed 36 months from the time of manufacture.
6.4 Special Precautions For Storage
No special precautions
6.5 Nature And Contents Of Container
Colourless glass vial Type III with chlorobutyl rubber bung and aluminium snap cap.
6.6 Special Precautions For Disposal And Other Handling
and Disposal
The following protective recommendations are given due to the toxic nature of this
substance:
• Personnel should be trained in good technique for reconstitution and handling.
• Pregnant staff should be excluded from working with this drug.
• Personnel handling Pharmorubicin Rapid Dissolution should wear protective clothing goggles, gowns and disposable gloves and masks.
• A designated area should be defined for reconstitution (preferably under laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper.
•All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration
Spillage ar 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.
The drug should be used within 24 hours of first penetration of the rubber stopper Discard any unused solution.
7. Marketing Authorisation Holder
Farmitalia Carlo Erba Limited
Davy Avenue
Milton Keynes
MK5 8PH
United Kingdom
8. Marketing Authorisation Number(S)
PL 03433/0082
9. Date Of First Authorisation/Renewal Of The Authorisation
14 December 1984/16 January 1995
10. Date Of Revision Of The Text
12th April 2001
Legal Category
POM
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