Colcin 0,5 mg Tablets

COLCIN is indicated for the relief of acute attacks of gout in cases of emergency.

Posology
In acute gout the initial dose is 0,5 mg to 1 mg (1 to 2 tablets) immediately, followed by 0,5 mg (1 tablet) every 2 hours until pain is relieved or vomiting or diarrhoea intervenes. A maximum total treatment course of 6 mg (12 tablets) should not be exceeded. The course should not be repeated within 3 days, but preferably 7 days should elapse between courses of gout treatment with COLCIN to avoid cumulative toxicity. COLCIN is not an analgesic medicine and should not be used to treat pain from other causes.
Special populations
Elderly
COLCIN should be given with caution to the elderly (see section 4.4).
Paediatric population
There are no data available.
Method of administration
For oral use.

• Patients with known hypersensitivity to colchicine or any of the other ingredients of COLCIN (see section 6.1).
• Patients with blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anaemia.
• Patients with severe renal insufficiency (creatinine clearance < 30 ml/min).
• Patients undergoing haemodialysis since it cannot be removed by dialysis or exchange transfusion.
• Patients with severe hepatic insufficiency.
• Patients with renal or hepatic impairment who are taking P-glycoprotein (P-gp) inhibitors or potent CYP3A4 inhibitors (see section 4.5). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine as in COLCIN in therapeutic doses (see section 4.8).
• Combination with macrolide antibiotics and pristinamycin (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• Women of childbearing potential unless they are using effective contraceptive measures.

Fatal overdoses
COLCIN is potentially toxic so it is important not to exceed the recommended dose as prescribed by a healthcare provider with the necessary knowledge and experience (see section 4.2). Colchicine, as contained in COLCIN, has a narrow therapeutic window.
The administration should be discontinued if toxic symptoms such as nausea, vomiting, abdominal pain, diarrhoea occur (see sections 4.2 and 4.8). COLCIN should be withdrawn, or the dose reduced if adverse gastrointestinal effects occur. Fatal overdoses have been reported with colchicine, as contained in COLCIN, in adults and children. Keep COLCIN away from children.
COLCIN should be given with great care to elderly or debilitated patients who may be particularly susceptible to cumulative toxicity and to those patients with cardiac, hepatic, renal or gastrointestinal disease. Patients with liver or renal impairment should be carefully monitored for adverse effects of colchicine as in COLCIN.
Blood dyscrasias
COLCIN should be avoided in patients with blood disorders (see section 4.3). Colchicine, as contained in COLCIN, may cause severe bone marrow depression (agranulocytosis, aplastic anaemia, thrombocytopenia). The change in blood counts may be gradual or very sudden. Aplastic anaemia in particular has a high mortality rate. Periodic checks of the blood picture are essential. If patients develop signs or symptoms that could indicate a blood cell dyscrasia, such as fever, stomatitis, sore throat, prolonged bleeding, bruising or skin disorders, treatment with COLCIN should be immediately discontinued and a full haematological investigation should be conducted straight away.
Hepatic and renal impairment
The dose should be reduced in patients with mild to moderate renal impairment. Patients with liver or renal impairment should be carefully monitored for adverse effects of COLCIN and if present, consider temporary interruption or discontinuation of COLCIN (see section 4.3).
Elderly population
COLCIN should be given with care to old and debilitated patients and to those with cardiac, hepatic, renal or gastrointestinal disease.
P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors
Co-administration of COLCIN with P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors will increase the exposure to COLCIN, which may lead to COLCIN induced toxicity, including fatalities. If treatment with a P-gp inhibitor or a moderate or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, a reduction in COLCIN dosage or interruption of COLCIN treatment is recommended (see section 4.5).
Excipients
COLCIN contains lactose. Patients with rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take COLCIN.

COLCIN is contraindicated in patients with renal or hepatic impairment who are taking a P-glycoprotein inhibitor (e.g. ciclosporin, verapamil or quinidine) or a strong CYP3A4 inhibitor (e.g. ritonavir, atazanavir, indinavir, clarithromycin, telithromycin, itraconazole or ketoconazole) (see section 4.3 and 4.4). Colchicine, as contained in COLCIN, is a substrate for both the transport protein P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4. In the presence of CYP3A4 or P-gp inhibitors, the concentrations of colchicine in the blood increase. Toxicity, including fatal cases, have been reported during concurrent use of CYP3A4 or P-gp inhibitors such as macrolides (clarithromycin, telithromycin and erythromycin, roxithromycin,), ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors (ritonavir, atazanavir), calcium channel blockers (verapamil and diltiazem) and disulfiram (see sections 4.3 and 4.4). A reduction in COLCIN dosage or an interruption of treatment is recommended in patients with normal renal or hepatic function if treatment with a P-gp inhibitor or strong CYP3A4 inhibitor is required. A 4-fold reduction in colchicine dosage is recommended when co-administered with a P-gp inhibitor (e.g., ciclosporin) and/or a strong CYP3A4 inhibitor (e.g., clarithromycin, ketoconazole, ritonavir). A 2-fold reduction in colchicine, as contained in COLCIN dosage is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., verapamil, diltiazem, grapefruit juice (see sections 4.3 and 4.4)). Such combinations should be avoided in patients with renal and hepatic impairment (see sections 4.3 and 4.4). Given the nature of the side effects, caution is advised with concomitant administration of medicine that can affect the blood count or have a negative effect on hepatic and/or renal function.
Pristinamycin
Concomitant administration may increase the side effects of COLCIN with potentially fatal consequences (see section 4.3).
Oral anticoagulants
Concomitant administration of COLCIN and oral anticoagulants may increase the effect of the oral anticoagulant and increase the risk of haemorrhage. More frequent INR checks are required. Possible modification of the dosage of the oral anticoagulant during treatment with COLCIN and for 8 days after its cessation may be required.
Thiazide diuretics
Thiazide diuretics may increase serum uric acid levels and interfere with the activity of COLCIN.
Cimetidine and tolbutamide
Cimetidine and tolbutamide reduce metabolism of colchicine and thus plasma levels of colchicine as contained in COLCIN increase.
Grapefruit juice
Grapefruit juice may increase plasma levels of colchicine, as grapefruit juice is a moderate inhibitor of CYP3A4. Grapefruit juice should therefore not be taken together with colchicine as in COLCIN.
Vitamin B12 (cyanocobalamin)
Reversible malabsorption of cyanocobalamin (vitamin B12) may be induced by an altered function of the intestinal mucosa.

Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment (see section 4.3).
Pregnancy
COLCIN is contraindicated in pregnancy due to animal teratogenicity and genotoxicity in vitro and in vivo and there are suggestions of a risk of foetal chromosome damage (see section 4.3).
Breastfeeding
Colchicine, as contained in COLCIN, is distributed into breastmilk. Therefore, COLCIN is contraindicated in women who are breastfeeding (see section 4.3).
Fertility
Colchicine administration in animals induces significant reductions in fertility.

COLCIN is not expected to have an influence; however patients should not drive, use machinery or perform any tasks that require concentration until they are certain that COLCIN does not adversely affect their ability to do so safely (see section 4.8).

Summary of safety profile
Colchicine, contained in COLCIN, frequently causes nausea, vomiting, abdominal pain and diarrhoea.
Tabulated list of adverse reactions
Blood and the lymphatic system disorders
Frequency unknown: Bone marrow suppression with agranulocytosis, thrombocytopenia, aplastic anaemia, leukopenia, neutropenia*
Nervous system disorders
Frequency unknown: Peripheral neuritis, peripheral neuropathy
Vascular disorders
Frequency unknown: Hypotension
Gastrointestinal disorders
Frequent: Nausea, vomiting, abdominal pain and diarrhoea** (see section 4.4)
Less frequent: Burning of the throat
Frequency unknown: Profuse diarrhoea, gastrointestinal haemorrhage
Hepatobiliary disorders
Frequency unknown: Hepatic damage, hepatotoxicity
Skin and subcutaneous tissue disorders
Less frequent: Urticaria, morbilliform eruptions
Frequency unknown: Burning of the skin and skin rashes, alopecia
Musculoskeletal, connective tissue and bone disorders
Frequency unknown: Myopathy, rhabdomyolysis
Renal and urinary disorders
Frequency unknown: Renal damage and dehydration
Reproductive system and breast disorders
Frequency unknown: Amenorrhoea, dysmenorrhoea, oligospermia, reversible azoospermia
Description of selected adverse reactions
* Larger doses may cause profuse diarrhoea, gastrointestinal haemorrhage, skin rashes and renal damage. Bone marrow depression with agranulocytosis, thrombocytopenia and aplastic anaemia have occurred on prolonged treatment, as well as peripheral neuritis, myopathy, rashes and alopecia.
** COLCIN should be withdrawn or the dose reduced if gastrointestinal side effects occur.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Colchicine has a narrow therapeutic window and is extremely toxic in overdose, it has been associated with serious and fatal toxicity. Patients at particular risk of toxicity are those with renal or hepatic impairment, gastrointestinal or cardiac disease, and patients at extremes of age (very young and very old). Following colchicine overdose, all patients, even in the absence of early symptoms, should be referred for immediate medical assessment (see section 4.4).
Symptoms
There is often a delay of up to 6 hours before toxicity is apparent; some features may be delayed up to 1 week or longer. Early symptoms of acute overdosage may be delayed (which occur up to 1 day after ingestion but 3 hours on average): nausea, vomiting, abdominal pain, haemorrhagic gastroenteritis, volume depletion, electrolyte abnormalities, diarrhoea, electrolyte disturbances, hypovolaemic shock, leukocytosis, hypotension in severe cases.
The second phase with life-threatening complications develops 24 to 72 hours (7 days or longer) after medicine administration: hepatic impairment, hyperpyrexia, bone marrow depression with leukopenia followed by rebound leukocytosis, multisystem organ dysfunction, acute renal failure, confusion, coma, ascending peripheral motor and sensory neuropathy, myocardial depression (decreased cardiac output), pancytopenia, cardiac dysrhythmias, respiratory failure (respiratory distress), consumption coagulopathy. A toxic epidermal necrolysis-like reaction has also been reported. These can progress in severe cases to multiple organ damage with bone marrow aplasia, convulsions, coma, delirium, rhabdomyolysis, neuropathy, hepatocellular damage and ascending paralysis of the central nervous system, disseminated intravascular coagulation and death. 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. The lethal dose varies widely (7 mg to 65 mg single dose) for adults but is generally about 20 mg.
Treatment
No antidote is available. In acute overdosage, the value of gut decontamination is uncertain. Consider oral activated charcoal 50 g in adults who have ingested more than 0,1 mg/kg bodyweight within 1 hour of presentation and children who have ingested any amount of COLCIN within 1 hour may be given activated charcoal 1 g/kg. Doses may be repeated every 4 hours in both adults and children, for those who have ingested more than 300 u03bcg/kg, provided they are not vomiting. Haemodialysis and haemoperfusion has no efficacy (high apparent distribution volume) as they do not enhance COLCIN elimination; blood and urine concentrations are of no use diagnostically (see section 4.3). Close clinical and biological monitored are required in a hospital environment. Management is mainly symptomatic and supportive, with attention given to respiration, pulse, blood pressure and circulation, and cardiac rhythm; fluid and electrolyte imbalances should be corrected. In cases of overdosage or acute poisoning patients should be carefully monitored. Patients are monitored for at least 6 hours after ingestion, or 12 hours if they have taken more than 300 u03bcg/kg. Asymptomatic patients may then be discharged, with advice to return if gastrointestinal symptoms appear.