SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Colchicine Tablets BP 500 mcg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Colchicine BP 0.50 mg

3    PHARMACEUTICAL FORM

White or faintly yellow biconvex uncoated tablets. Engraved Evans 126 on one side, plain on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adults

Colchicine is used for the treatment of acute gout. Colchicine is also used for the prophylaxis of recurrent gout and to prevent acute attacks during the initial treatment with allopurinol or uricosuric drugs.

Paediatric population

Colchicine is indicated in Familial Mediterranean Fever for prophylaxis of attacks and prevention of amyloidosis.

4.2    Posology and method of administration

Posology

Adults

Treatment for acute gout 1 mg initially, followed by 500 mcg every 4 hours until relief of pain is obtained or vomiting or diarrhoea occurs, or until a total dose of 6 mg has been reached. The course should not be repeated within 3 days.

Prophylaxis

500 mcg weekly or up to 2-3 times daily.

Prophylaxis of recurrent gout and prevention of acute attacks during initial treatment with allopurinol or uricosuric drugs, 500 mcg 2-3 times daily. Administration in Elderly

The adult dose should apply, but with caution in patients with renal impairment, where the dosage should be reduced by up to 50%.

Paediatric population Familial Mediterranean fever

For paediatric use, colchicine should only be prescribed under the supervision of a medical specialist with the necessary knowledge and experience.

A starting dose should be administered orally based on age:

•    0.5mg/day in children less than 5 years of age

•    1mg/day in children from 5 to 10 years of age

•    1.5mg/ day in children over 10 years,

The dose could be given as a single dose or doses higher than 1mg/day could be divided and given twice daily.

Colchicine dosage should be increased in a stepwise fashion (eg, 0.25mg/step) up to a maximum of 2mg/day to control disease in patients who do not clinically respond to the standard dosage. Any increase of the daily dose should be monitored closely for adverse effects.

In children with amyloid nephropathy, higher daily doses up to 2mg/day might be needed.

Careful monitoring is needed in the presence of impaired renal or liver function. For these patients, the starting dose should be reduced by 50% (e.g. < 1mg/day).

Method of administration

Oral route

Tablet should be swallowed with a glass of water

4.3 Contraindications

Hypersensitivity to Colchicine, serious gastro-intestinal, renal, hepatic, cardiac disorders, and blood dyscrasias.

Colchicine is potentially toxic so it is important not to exceed the dose prescribed by a medical specialist with the necessary knowledge and experience.

Colchicine should be given with great care to elderly or debilitated patients and those with cardiac, hepatic, renal or gastro-intestinal disease. Colchicine has adversely affected spermatogenesis in humans under certain conditions of therapy. Periodic blood counts should be done in patients receiving long term therapy. Notify physician if skin rash, sore throat, fever, unusual bleeding, bruising, tiredness or weakness, numbness or tingling occurs. Discontinue medication as soon as gout pain is relieved or at the first sign of nausea, vomiting, stomach pain, or diarrhoea. If symptoms persist, notify physician.

4.5 Interaction with other medicinal products and other forms of interaction

Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Colchicine may impair the absorption of fat, sodium, potassium, nitrogen, xylose and other actively transported sugars. This may lead to decreased serum cholesterol and carotene concentrations.

Colchicine is inhibited by acidifying agents but is potentiated by alkalinizing agents.

Colchicine may increase sensitivity to CNS depressants and enhance the response to sympathomimetic agents.

Colchicine may cause false-positive results when testing urine for RBC or haemoglobin.

Colchicine may react with cyclosporin leading to an increased risk of nephrotoxicity and increased plasma-cyclosporin concentration.

Colchicine has been reported to interfere with urinary determinations of 17-hydroxycorticoids using the Reddy, Jenkins and Thorn procedure.

Concomitant use with clarithromycin may lead to colchicine toxicity. Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity.

Concomitant use with erythromycin may also lead to colchicine toxicity.

Colchicine has been shown to be teratogenic in animals and there is a risk of teratogenicity or of foetal chromosomal damage in humans. Colchicine should not be used during the first trimester of pregnancy and only used in late stages of pregnancy where the risk/benefit ratio has been considered as Colchicine may be excreted in breast milk. It should not be given to lactating mother because of the risk of cytotoxic effects.

4.7 Effects on ability to drive and use machines

No specific statement.

4.8 Undesirable effects

Colchicine therapy may cause elevated alkaline phosphatase and SGOT values.

Decreased thrombocyte values may be obtained during therapy.

Bone marrow depression with aplastic anaemic, agranulocytosis, leukopenia or thrombocytopenia may occur in patients receiving long term therapy. Loss of hair, rashes, vesicular dermatitis, peripheral neuritis or neuropathy, myopathy, anuria, renal damage, haematuria and purpura have been reported with prolonged administration of colchicine.

Vomiting, diarrhoea, abdominal pain and nausea may occur, especially when maximum doses are necessary for a therapeutic effect. These may be particularly troublesome in the presence of peptic ulcer or spastic colon.

At toxic doses colchicine may cause severe diarrhoea, generalised vascular damage and renal damage with haematuria and oliguria. To avoid more serious toxicity, discontinue use when these symptoms appear, regardless of whether joint pain has been relieved. Dermatoses have been reported; hypersensitivity reactions may occur infrequently.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme on the MHRA website (www.mhra.gov.uk/yellowcard).

4.9 Overdose

Colchicine has a narrow therapeutic window and is extremely toxic in overdose. Patients at particular risk of toxicity are those with renal or hepatic

impairment, gastrointestinal or cardiac disease, and patients at extremes of age.

Colchicine overdose is complex and specialist advice should be promptly obtained. There is often a delay of up to 6 hours before toxicity is apparent, and some features of toxicity may be delayed by 1 week or longer. Following colchicine overdose, all patients, even in the absence of early symptoms, should be referred for immediate medical assessment.

Clinical

Symptoms of acute overdosage may be delayed (3 hours on average): nausea, vomiting, abdominal pain, hemorrhagic gastroenteritis, volume depletion, electrolyte abnormalities, leukocytosis, hypotension in severe cases. The second phase with life threatening complications develops 24 to 72 hours after drug administration: multisystem organ dysfunction, acute renal failure, confusion, coma, ascending peripheral motor and sensory neuropathy, myocardial depression, pancytopenia, dysrhythmias, respiratory failure, consumption coagulopathy. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery may be accompanied by rebound leukocytosis and reversible alopecia starting about one week after the initial ingestion.

Treatment

No antidote is available.

Elimination of toxins by gastric lavage within one hour of acute poisoning. Consider oral activated charcoal in adults who have ingested more than 0.1mg/kg bodyweight within 1 hour of presentation and in children who have ingested any amount within 1 hour of presentation.

Haemodialysis has no efficacy (high apparent distribution volume)

Close clinical and biological monitoring in hospital environment. Symptomatic and supportive treatment: control of respiration, maintenance of blood pressure and circulation, correction of fluid and electrolytes imbalance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The exact mechanism of action of Colchicine in gout is not known. It is involved in leukocyte migration inhibition; reduction of lactic acid production by leukocytes which results in a decreased deposition of uric acid; interference with kinin formation and reduction of phagocytosis with inflammatory response abatement.

Colchicine apparently exerts its effect by reducing the inflammatory response to the deposited crystals and also by diminishing phagocytosis.

Colchicine diminishes lactic acid production by leukocytes directly and by diminishing phagocytosis and thereby interrupts the cycle of urate crystal deposition and inflammatory response that sustains the acute attack.

The oxidation of glucose in phagocytizing as well as in nonphagocytizing leukocytes in vitro is suppressed by Colchicine.

Colchicine is not an analgesic, although it relieves pain in acute attacks. It is not a uricosuric agent and will not prevent the progression of gout to chronic gouty arthritis. It has a prophylactic, suppressive effect which helps reduce the incidence of acute attacks and relieve the patients occasional residual pain and mild discomfort.

Colchicine can produce a temporary leukopenia which is followed by leukocytosis.

5.2 Pharmacokinetic properties

Paediatric population

No pharmacokinetics data are available in children.

Absorption

Readily absorbed after oral administration, peak concentrations in plasma after 2 hours.

Half life

Plasma half-life about 1 hour, but 60 hours in leucocytes, which is increased in renal function impairment and decreased in hepatic function impairment.

Distribution

Colchicine does not appear to be specifically localised in any tissues except the liver leucocytes, spleen and kidneys; it undergoes enterohepatic circulation.

Metabolic Reactions Deacetylated in the liver.

Excretion

Colchicine is mainly excreted in the faeces, with 10-20% in the urine. The percentage excreted in the urine rises in patients with hepatic disease.

Preclinical safety data

Colchicine has been shown to be teratogenic in animals and there is a risk of teratogenicity or of foetal damage in humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose BP Starch Maize BP Purified Water BP Magnesium Stearate BP

6.2 Incompatibilities

None stated

6.3 Shelf life

36 months

6.4 Special precautions for storage

Protect from light Store below 25^oC Keep well closed

6.5 Nature and contents of container

Pigmented polypropylene with tamper-evident closure of low density polyethylene.

Pack size 20, 28, 30, 50, 60 and 100.

Special precautions for disposal

As directed by physician.

7 MARKETING AUTHORISATION HOLDER

RPH Pharmaceuticals AB,

Lagervagen 7,

136 50 Jordbro,

Sweden

8    MARKETING AUTHORISATION NUMBER(S)

PL 36301/0044

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/05/2005

10 DATE OF REVISION OF THE TEXT

28/05/2015