1. Name Of The Medicinal Product
Procarbazine 50mg Capsules
2. Qualitative And Quantitative Composition
Each capsule contains 58.3mg Procarbazine hydrochloride (equivalent to 50mg of Procarbazine).
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Capsules with white opaque cap and body. Marked 'CL 50' on cap.
4. Clinical Particulars
4.1 Therapeutic Indications
The main indication is Hodgkin's disease (lymphadenoma).
Procarbazine may also be useful in other advanced lymphomata and a variety of solid tumours which have proved resistant to other forms of therapy.
4.2 Posology And Method Of Administration
In combination chemotherapeutic regimens:
Procarbazine is usually administered concomitantly with other appropriate cytostatic drugs in repeated four- to six-weekly cycles. In most such combination chemotherapy regimens currently in use (eg. the so-called MOPP schedule with mustine, Vincristine and Prednisone) Procarbazine is given daily on the first 10 - 14 days of each cycle in a dosage of 100mg per sq. metre of body surface (to nearest 50mg).
As sole therapeutic agent: Adults:
Treatment should begin with small doses which are increased gradually up to a maximum daily dose of 250 or 300mg divided as evenly as possible throughout the day.
Initial dosage scheme
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Further procedure:
Treatment should be continued with 250 or 300mg daily until the greatest possible remission has been obtained, after which a maintenance dose is given.
Maintenance dose:
50 -150mg daily. Treatment should be continued until a total dose of at least 6g has been given. Otherwise, a negative result is not significant.
Elderly:
Procarbazine should be used with caution in the elderly. Patients in this group should be observed very closely for signs of early failure or intolerance of treatment.
Children:
If, on the recommendation of a physician, a children's dosage is required, 50mg daily should be given for the first week. Daily dosage should then be maintained at 100mg per sq. metre of body surface (to nearest 50mg) until leucopenia or thrombocytopenia occurs or maximum response is obtained.
Procarbazine capsules are for oral administration.
4.3 Contraindications
Pre-existing severe leucopenia or thrombocytopenia from any cause; severe hepatic or renal damage.
Procarbazine should not be used in the management of non-malignant disease.
Procarbazine is contraindicated during breast-feeding.
Hypersensitivity to the active substance (Procarbazine) or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Procarbazine should be given only under the supervision of a physician who is experienced in cancer chemotherapy and having facilities for regular monitoring of clinical and haematological effects during and after administration.
Introduction of therapy should only be effected under hospital conditions.
Caution is advisable in patients with hepatic or renal dysfunction and Procarbazine should be avoided in patients with severe hepatic or renal disease. Its use should be avoided if creatinine clearance is less than 10mL/min. Caution is also advised in cardiovascular or cerebrovascular disease, phaeochromocytoma, or epilepsy.
Regular blood counts are of great importance. If during the initial treatment the total white cell count falls to 3,000 per mm3 or the platelet count to 80,000 per mm3, treatment should be suspended temporarily until the leucocyte and/or platelet levels recover, when therapy with the maintenance dose may be resumed.
Treatment should be interrupted on the appearance of allergic skin reactions.
Procarbazine has been shown to be carcinogenic in animals. The increased risk of carcinogenicity in man should be borne in mind when long-term management of patients is proposed.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Procarbazine is a weak MAO inhibitor and therefore interactions with certain foodstuffs and drugs, although very rare, must be borne in mind. Thus, owing to possible potentiation of the effect of barbiturates, narcotic analgesics (especially Pethidine), drugs with anticholinergic effects (including phenothiazine derivatives and tricyclic antidepressants), other central nervous system depressants (including anaesthetic agents) and anti-hypertensive agents, these drugs should be given concurrently with caution and in low doses.
Cytotoxics may reduce the absorption of phenytoin and cardiac glycosides.
Concomitant use of clozapine may increase the risk of agranulocytosis. Use with enzyme-inducing antiepileptics is associated with an increased risk of hypersensitivity reactions to procarbazine.
Intolerance to alcohol (Disulfiram-like reaction) may occur.
4.6 Pregnancy And Lactation
Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown. There are no adequate data from the use of Procarbazine in pregnant women, however isolated human foetal malformations have been reported following MOPP combination therapy.
Procarbazine is contraindicated during breast-feeding.
4.7 Effects On Ability To Drive And Use Machines
Procarbazine has no influence on the ability to drive and use machines.
4.8 Undesirable Effects
Potential adverse effects are listed below. The incidence of adverse effects is provided where known, however for some effects the incidence cannot be accurately estimated from the available data.
Blood and lymphatic systems disorders:
Procarbazine causes leucopenia and thrombocytopenia. These haematological changes are almost always reversible and seldom require complete cessation of therapy.
Gastrointestinal system disorders:
Loss of appetite and nausea, sometimes with vomiting occur in >1/10 patients treated. These symptoms are usually confined to the first few days of treatment and then tend to disappear.
Hepatobiliary disorders:
Hepatic complications including jaundice and abnormal liver function tests have been reported. The incidence of such reactions is not known.
Reproductive system and breast disorders:
Procarbazine has been reported to cause azoospermia and ovarian failure, which may be irreversible. It is extremely important that the patient is provided with appropriate information and advice, particularly as men may wish to have semen saved for use after Procarbazine treatment.
Skin and subcutaneous tissue disorders:
Allergic skin reactions have been reported.
4.9 Overdose
Signs of overdosage include severe nausea and vomiting, dizziness, hallucinations, depression and convulsions; hypotension or tachycardia may occur.
Gastric lavage and general supportive treatment should be performed, with prophylactic treatment against possible infection, and frequent blood counts.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Methylhydrazines, ATC Code: L01XB01
Procarbazine, a methylhydrazine derivative, is a cytostatic agent with weak MAO inhibitor properties. Its exact mode of action on tumour cells is unknown. It may be effective in patients who have become resistant to radiation therapy and other cytostatic agents.
5.2 Pharmacokinetic Properties
Procarbazine is readily absorbed from the gastrointestinal tract. It is rapidly metabolised, the primary circulating metabolite is the azo derivative while the major urinary metabolite has been shown to be N-isopropyl-terephthalamic acid.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, other that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Mannitol
Maize starch
Talc
Magnesium stearate
Capsule shell components:
Gelatin
Titanium dioxide E171
Ink components:
IMS 74
Shellac
Soya lethicin
n-Butyl alcohol
Antifoam DC 1510
Black iron oxide E172
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
Three years.
6.4 Special Precautions For Storage
Store in a dry place. Do not store above 25°C
6.5 Nature And Contents Of Container
Blister packs of 50 capsules.
6.6 Special Precautions For Disposal And Other Handling
Handling guidelines:
Undamaged capsules present minimal risk of contamination, but in accordance with good hygiene requirements, direct handling should be avoided. As with all cytotoxics, precautions should be taken to avoid exposing staff during pregnancy.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Alliance Pharmaceuticals Ltd
Avonbridge House
2 Bath Road
Chippenham
Wiltshire,
SN15 2BB
UK
Trading as: Cambridge Laboratories, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB, UK
8. Marketing Authorisation Number(S)
PL 16853/0114
9. Date Of First Authorisation/Renewal Of The Authorisation
30/08/2006
10. Date Of Revision Of The Text
16th March 2011
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