Treatment of acute attacks of gout and chronic gout, prophylaxis of acute attacks starting treatment with mobilizers of acid uric and periodic disease (familiar Mediterranean fever).
Name: Colchicine 0.5
Active ingredient: Colchicine
SUMMARY OF PRODUCT CHARACTERISTICS COLCHICINE SEID
1. NAME OF THE MEDICINAL PRODUCT
COLCHICINE SEID 0,5 mg TABLETS.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Colchicine ………………………0.5 mg
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of acute gout attacks and chronic gout, prophylaxis of acute attacks due to start of
treatment with uric acid mobilisers and periodic disease (familial Mediterranean fever).
4.2 Posology and method of administration
Colchicine has a narrow therapeutic window and is extremely toxic in the event of
overdose. The dose indicated below must never be exceeded as it may prove fatal.
The recommended dose depends on the age of the patient, renal and hepatic function and the concomitant use of other medicinal products (see sections 4.4 and 4.5)..
· Acute attack of gout:
The recommended dose is 2 tablets (1 mg) at the first sign of an acute attack. If pain relief is not achieved, one or two tablets more (0,5 to 1 mg) may be administered one or two hours after the first dose. Doses higher than 2 mg in 24 hours must not be administered. Doses higher than 2 mg per day have demonstrated increased adverse effects with no benefit in terms of efficacy.
This dosage regime may be administered for up to 4 consecutive days, with a total cumulative dose of 6 mg in 4 days. If necessary due to persistence of gout-related pain, the regime described above may be repeated after a three day treatment-free “wash-out” period
· Preventative treatment of gout attacks during initial therapy with allopurinol or
The recommended dose for preventive treatment of gout attacks is 0,5 mg per day one or
twice per day (one or two tablets one or twice per day).
· Periodic disease or familial Mediterranean fever:
The recommended dose is 1 to 2,5 mg per day. This may be divided into two daily doses or taken as a single dose.
· Treatment of chronic gout:
The recommended dose for the treatment of chronic gout is from 0,5 to 1 mg per day (one or two tablets one or twice per day).
Children and adolescents under 18 years of age.
· Acute gout attack, prevention of gout attacks and chronic gout:
There are insufficient data to establish recommendations in this age group.
· Periodic disease or familial Mediterranean fever:
The recommended dose in children over 12 years is 1 to 2 mg per day. This may be divided into two daily doses or taken as a single dose.
Although the presentation of this medicinal product does not allow for an appropriate dosage in children younger than 12 years, for information purposes the dose in children aged 4 to 6 years would be 0.3 to 1.8 mg per day and the dose in children aged 6 to 12 years would be 0.9 to 1.8 mg per day. These doses may be administered in a single dose or divided into two doses.
No dose adjustment is required in patients with mild renal failure (creatinine clearance 50-80 ml/min), although close monitoring is recommended due to the possible appearance of adverse effects (see sections 4.4 and 5.2). Should these appear, dose reduction may be necessary.
The dose may need to reduced by half and/or the interval between doses may need to be increased in patients with moderate renal failure (creatinine clearance 30-50 ml/min).
The use of colchicine is contraindicated in patients with severe renal failure (creatinine clearance < 30 ml/min) (see section 4.3).
No dose adjustment is required in patients with mild or moderate hepatic insufficiency, although close monitoring is recommended due to the possible appearance of adverse effects (see sections 4.4 and 5.2). Should these appear, dose reduction may be necessary.
Although a dose reduction is required in patients with severe hepatic insufficiency, the
presentation of this medicinal product does not allow this; therefore the use of colchicine would
be contraindicated in such patients (see section 4.3).
Elderly patients and special populations
Other alternative therapies should be used in elderly patients or in those with renal or hepatic disorders. If it is decided to administer colchicine in these patients, the cumulative dose must not exceed 3 mg in a four-day period instead of 6 mg in the adult population (see section 4.2).
- Hypersensitivity to the active substance or to any of the excipients of this medicinal
- Severe renal failure and patients undergoing haemodialysis.
- Severe hepatic insufficiency.
- Severe gastrointestinal disorders.
- Stomach ulcer.
- Heart disorders.
- Haematological disorders, such as blood dyscrasias.
- During the 14 days subsequent to the use of CYP3A4 and/or P glycoprotein inhibitors.
4.4. Special warnings and precautions for use
- In the event of diarrhoea, treatment must be discontinued or the dose reduced.
- Treatment with colchicine in the elderly, children and debilitated patients, or those who abuse alcohol, must be closely monitored due to the higher risk of cumulative toxicity in these populations.
- Leukopoenia, granulocytopoenia, pancytopoenia, aplastic anaemia and myelosuppression have all been associated with the use of colchicine at therapeutic doses, so possible side effects must be monitored and patients must undergo regular blood tests.
- A dose adjustment may be required in patients with hepatobiliary and renal impairment. Patients must be closely monitored during treatment of acute gout attacks due to the possibility of renal or hepatobiliary impairment.
- Colchicine is significantly excreted in the urine of healthy individuals. Colchicine clearance is diminished in patients with renal impairment. Total body clearance of colchicine is reduced by up to 75% in patients with renal disease undergoing dialysis (see section 5.2).
- As colchicine may not be cleared in patients undergoing dialysis, its use would be contraindicated (see section 4.3).
- Colchicine clearance may be significantly reduced and its plasma half-life increased in patients with hepatic insufficiency.
- Neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment at therapeutic doses. This risk may be increased in patients with renal failure and in the elderly (even those with no hepatic or renal impairment).
- Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, fenofibrate, fenofibric acid or bezafibrate (all of which are associated with myotoxicity), digoxin or cyclosporine with colchicine may promote the appearance of myopathies (see section 4.5). Once treatment with colchicine has been discontinued, the symptoms usually subside in a period of between one week and several months.
Warning about the excipients.
This medicinal product contains lactose. Patients with a hereditary galactose intolerance, Lapp lactase deficiency (deficiency observed in some towns in Lapland) or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains methylene casein. Patients who are allergic or intolerant to cow
milk protein must not take this medicinal product.
4.5. Interactions with other medicinal products and other forms of interaction
Monitoring should be increased when colchicine is associated with active substances that are metabolised by, or interact with, the cytochrome P450 system, particularly with isoenzyme CYP3A4 or P glycoprotein
- Anti-infective agents: colchicine toxicity increases when combining treatment with clarithromycin, erythromycin or telithromycin, CYP3A4 substrates and inhibitors, particularly in patients with pre-existing renal disorders. Other CYP3A4 inhibitors such as itraconazole, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir may increase colchicine toxicity.
- Calcium-channel antagonists: verapamil and diltiazem.
- Cyclosporine: colchicine must be used with caution together with cyclosporine due to the possible risk of increased nephrotoxicity and myotoxicity.
- -Vitamins: vitamin B12 absorption may be affected by chronic administration or high doses of colchicine. Vitamin requirements may be increased.
Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, fenofibrate, fenofibric acid or bezafibrate (all of which are associated with myotoxicity) may promote the appearance of myopathies. Once treatment with colchicine has been discontinued, the symptoms usually subside in a period of between one week and several months.
Colchicine treatment must not be combined with grapefruit juice intake (CYP3A4 inhibitor) as colchicine toxicity may be enhanced.
4.6. Fertility, pregnancy and lactation.
There are no data regarding the possible effects of colchicine on fertility.
No malformations or foetal/neonatal toxicity were observed after exposure of a limited number of pregnant women with familial Mediterranean fever to colchicine. However, studies with colchicine in animals have shown teratogenic effects. Therefore, as a precaution, and due to the lack of controlled studies in humans and its ability to cross the placenta, with the subsequent risk to the foetus due to its mechanism of action, use of colchicine during pregnancy is contraindicated (see sections 4.3 and 5.3).
Colchicine is excreted in human breast milk.
It is recommended not to administer it during breast-feeding.
4.7 Effects on ability to drive and use machines.
This medicinal product has no influence on the ability to drive and use machines.
4.8. Undesirable effects.
The common adverse reactions that have been reported include nausea, vomiting and abdominal pain. High doses may cause severe diarrhoea, gastrointestinal bleeding, skin rash and renal and hepatic disorders.
Peripheral neuropathy, myopathy, rhabdomyolysis, alopecia, azoospermia and, with prolonged treatment, bone marrow impairment with the presence of agranulocytosis, thrombocytopoenia and aplastic anaemia, have been reported occasionally.
Treatment should be discontinued upon presentation of the first symptom of nausea, vomiting and abdominal pain or diarrhoea, and the patient should attend an emergency room.
According to the AGREE study (see section 5.1), in which 185 patients with acute gout attack were distributed into three different treatment groups, namely treatment with high doses of colchicine [1.2 mg followed by 0.6 mg every hour for 6 hours; (total: 4.8 mg)], treatment with low doses [1.2 mg followed by 0.6 mg in the following hour; (total: 1.8 mg)] and treatment with placebo, the incidence of adverse reactions in the different groups was
76.9%, 36.5 % and 27.1% respectively. The incidence of adverse reactions reported most commonly is given below.
Colchicine: Adverse reactions: Dose High(n=52): 40 (76,9), Dose Low(n=74): 27 (36.5), Placebo(n=59): 16 (27,1); OR (95 % IC): Dose High vs. Placebo: 9,0 (3,8-21,2), Dose Low vs. Placebo: 1,5 (0,7-3,2), Dose High vs. Dose Low: 5,8 (2,6-12,9). Gastrointestinal adverse reactions: Dose High(n=52): 40 (76,9), Dose Low(n=74): 19(25,7), Placebo(n=59): 12(20,3); OR (95 % IC): Dose High vs. Placebo: 13,1(5,3-32,3), Dose Low vs. Placebo: 1,4 (0,6-3,1), Dose High vs. Dose Low: 9,6 (4,2-22,1). Diarrhoea: Dose High(n=52): 40 (76,9), Dose Low(n=74): 17(23,0), Placebo(n=59): 8 (13,6); OR (95 % IC): Dose High vs. Placebo: 21,3 (7,9-56,9), Dose Low vs. Placebo: 1,9 (0,8-4,8), Dose High vs. Dose Low: 11,2 (4,8-25,9). Nausea: Dose High(n=52): 9 (17,3), Dose Low(n=74): 3 (4,1), Placebo(n=59): 3 (5,1); OR (95 % IC): Dose High vs. Placebo: 3,9 (1,0-15,3), Dose Low vs. Placebo: 0,8 (0,2-4,1), Dose High vs. Dose Low: 11,2 (4,8-25,9). Vomitos: Dose High(n=52): 9 (17,3), Dose Low(n=74): 0(0), Placebo(n=59): 0(0). Severe adverse: Dose High(n=52): 10(19,2), Dose Low(n=74): 0(0), Placebo(n=59): 1 (1,7); OR (95 % IC): Dose High vs. Placebo: 13,8 (1,7-112). Diarrhoea: Dose High(n=52): 10(19,2), Dose Low(n=74): 0(0), Placebo(n=59): 0(0). Melena: Dose High(n=52): 1(1,92), Dose Low(n=74): 0(0), Placebo(n=59): 0(0). Nausea: Dose High(n=52): 1(1,92), Dose Low(n=74): 0(0), Placebo(n=59): 0(0). Gout: Dose High(n=52): 0(0), Dose Low(n=74): 0(0), Placebo(n=59): 1(1,7).
* The OR could not be calculated as no adverse reaction was observed in some
Colchicine has a narrow therapeutic window and is extremely toxic in the event of overdose. Patients with hepatic or renal, gastrointestinal or cardiac disorders, and elderly patients show a high risk of overdose.
As colchicine overdose is complex, advice from a specialist experienced in overdose must be rapidly sought.
The exact dose of colchicine that causes significant toxicity is unknown. Deaths have been reported with doses as low as 7 mg over a period of four days, whereas there are cases where patients have survived doses of more than 60 mg.
A review of 150 patients with overdose showed that those receiving a dose of less than 0.5 mg/kg survived with a milder toxicity profile, whereas those receiving a dose of between 0.5 and 0.8 mg/kg experienced more severe reactions, including myelosuppression. The mortality in patients taking more than 0.8 mg/kg was 100%.
There may be a delay of up to 6 hours in the onset of toxicity, and some of the signs may even be delayed for more than one week. Therefore, any patient with suspected overdose must seek immediate specialised medical care, even in the absence of apparent signs.
The first signs of acute colchicine toxicity normally appear at around 24 hours postadministration.
The most common symptoms include burning and discomfort in the mouth and throat, swallowing difficulties, digestive disorders such as nausea, vomiting, diffuse abdominal pain, tenesmus, severe diarrhoea, which may occasionally be bloody and lead to dehydration (metabolic acidosis) and circulatory disorders (hypotension), which together may lead to hypovolaemic shock. Peripheral leukocytosis has been observed on occasions.
The signs of toxicity after the first 24 hours and up to 7 days later include confusion, alopecia, cardiac disorders (including arrhythmia and decreased cardiac output), renal and hepatic impairment, respiratory distress, hyperpyrexia and bone marrow depression. These signs may progress to multiple organ failure associated with bone marrow aplasia, CNS toxicity, seizures, coma, hepatocellular damage, rhabdomyolysis, respiratory distress, renal and cardiac damage and disseminated intravascular coagulation. Death generally results from cardiorespiratory depression.
Patients who survive for 7 days post-overdose may present alopecia, rebound leukocytosis and stomatitis (around 10 days post-overdose).
Treatment of colchicine overdose must include the use of oral activated charcoal for up to one hour in adults who have taken more than 0.1 mg/kg body weight of colchicine and in children who have taken any amount. A higher dose of activated charcoal may enhance systemic elimination and should be considered in patients who have taken more than 0.3 mg/kg body weight.
There is no specific antidote for colchicine. Gastric lavage may be considered.
Haemodialysis and haemoperfusion do not enhance colchicine clearance. Management should include general symptomatic and supportive measures as indicated by the patient's clinical condition, including monitoring of vital signs, ECG, haematological and biochemical indices. Breathing may need assistance. Circulation should be maintained and fluid and electrolyte imbalance corrected.
Morphine sulphate 10 mg may be given intramuscularly to relieve severe abdominal pain.
To allow for managing the delayed onset of symptoms, patients should be carefully monitored for at least 6 hours post-administration, or for 12 hours if they have taken more than 0.3 mg/kg. After this time, asymptomatic patients may be discharged with advice to return if gastrointestinal symptoms appear.
5. PHARMACOLOGICAL PROPERTIES.
5.1 Pharmacodynamic properties.
Pharmacotherapeutic group: M04AX Other antigout preparations.
Colchicine is used to relive acute gout attacks and for the prophylaxis of acute attacks.
Colchicine is also indicated for the treatment of chronic gout and familial Mediterranean fever.
The mechanism of action of colchicine is not fully understood. Colchicine probably produces an immediate response in gout attacks due to a reduction in the inflammatory reaction caused by urate crystals. This effect occurs due to different actions, including a reduction in leukocyte mobility.
Colchicine inhibits the phagocytosis of urate microcrystals, thereby reducing the production of lactic acid and maintaining a normal local pH. Acidity enhances the precipitation of urate crystals, which is the cause of gout attacks.
Colchicine has no analgesic activity and has no effect on the plasma concentrations or clearance of uric acid. It also shows antimitotic activity (inhibition or prevention of cell division in the meta- and anaphases).
Colchicine presents other pharmacological activities in animals, where it impairs neuromuscular function, enhances gastrointestinal activity by neurogenic stimulation, increases the sensitivity to central depressants, enhances the response to sympathomimetics, depresses the respiratory centre, causes vasoconstriction, causes hypertension by vasomotor centre stimulation and decreases body temperature.
The multicentre, double-blind, placebo-controlled AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study, evaluated the percentage of patients who responded to the following colchicine treatment regimes:
· Group 1: High dose of colchicine (1.2 mg followed by 0.6 mg/hour for 6 hours [total
dose: 4.8 mg])
· Group 2: Low dose of colchicine (1.2 mg followed by 0.6 mg/hour for 1 hour [1.8
· Group 3: Placebo
A total of 184 patients were included in the intention to treat analysis. The primary endpoint of this study was the percentage of treatment responders, defined as any patient who presented a ≥50% reduction in perceived pain within 24 hours of the first dose of drug with no rescue drugs. A total of 28 of 74 patients in the low-dose group (37.8%), 17 of 52 patients in the high-dose group (32.7 %) and 9 of 58 patients in the placebo group (15.5%) responded to treatment (p=0.005 and p=0.034, respectively, versus placebo). During the first few hours
of treatment, 23 (31.1%) patients in the low-dose group (p=0.027 versus placebo), 18 (34.6%) patients in the high-dose group (p=0.103 versus placebo) and 29 (50%) patients in the placebo group required rescue drugs. The low-dose group showed a similar adverse effects profile to the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). A high dose of colchicine was significantly associated with diarrhoea, vomiting and other adverse events in comparison with the use of a low dose of colchicine or
Forty patients in the high-dose group (76.9%) experienced diarrhoea (OR: 21.3; 95% CI 7.9- 56.9), 10 (19.2%) experienced severe diarrhoea and a further nine (17.3%) vomiting. In the low-dose group, 23% of patients experienced diarrhoea (OR: 1.9; 95% CI 0.8-4.8) and none experienced either severe diarrhoea or vomiting.
Low doses of colchicine gave similar peak plasma concentration and efficacy values to high doses for the treatment of acute gout attacks, with a similar safety profile to placebo.
5.2 Pharmacokinetic properties.
Colchicine is absorbed orally with an approximate bioavailability of 45%.
Approximately 39% is bound to albumin, with no direct relationship with concentration.
It binds to all tissues, mainly the intestinal mucosa, the liver, kidney and spleen, but not to the myocardium, skeletal muscle or lungs.
It has been reported that colchicine crosses the placenta, with foetal plasma levels of approximately 15% of those found in the mother. The concentration in human breast milk is similar to that observed in plasma from the mother.
The mean volume of distribution ranges from 2 to 8 l/kg.
Colchicine is partially metabolised in the liver by demethylation to two main metabolites, namely 2-O-demethylcolchicine and 3-O-demethylcolchicine, and a minor metabolite, namely 10-O-demethylcolchicine. CYP3A4 is involved in colchicine metabolism. The plasma levels of the two main metabolites are less than 5% of that for colchicine. The pharmacological activity of these metabolites is unknown.
Colchicine and its metabolites undergo enterohepatic circulation.
Clearance is significantly decreased and the half-life extended in patients with severe hepatic impairment. The findings in patients with mild to moderate hepatic impairment show high interpatient variability.
Renal clearance of colchicine has been estimated at 0.727 l/h/kg in patients with good renal function. Renal clearance was reduced by 75% in patients with severe renal impairment. There are no data in patients with mild to moderate renal impairment.
Colchicine is not cleared by haemodialysis.
The elimination half-life in healthy volunteers (aged between 25 and 28 years) reported in the literature ranges from 26.6 to 31.2 hours.
Colchicine is a substrate of P glycoprotein.
No gender-based pharmacokinetic differences have been reported.
The pharmacokinetics in paediatric patients have not been described.
According to a study published in elderly patients, the mean peak plasma concentration and AUC were twice as high as those in young subjects. This difference could be explained by reduced renal function in the former.
5.3 Preclinical safety data.
Preclinical safety data showed no risks in humans other than those expected due to the established administration conditions. However, colchicine was teratogenic in animals.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients.
Magnesium stearate, calcium hydrogenophosphas dihydricus, silicified microcrystalline cellulose.
6.3 Shelf life
6.4 Special precautions for storage.
This medicine does not require any special storage conditions.
6.5 Nature and contents of container.
A cardboard box containing 1 blister of 20 tablets.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
SEID, S.A. Carretera de Sabadell a Granollers Km. 15
08185 LLIÇA DE VALL - Barcelona- SPAIN
8. MARKETING AUTHORISATION NUMBER
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT