4.1. Therapeutic indications

Adults

• Treatment of acute gout.

• Prophylaxis of gout attack during initiation of therapy with allopurinol and 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 of acute gout attack:

1 mg (2 tablets) to start followed by 500 micrograms (1 tablet) after1 hour.

No further tablets should be taken for 12 hours.

After 12 hours, treatment can resume if necessary with a maximum dose of500 micrograms (1 tablet) every 8 hours until symptoms are relieved.. The course of treatment should end when symptoms are relieved or when a total of 6 mg (12 tablets) has been taken.

No more than6 mg (12 tablets) should be taken as a course of treatment.

After completion of a course, another course should not be started for at least three days (72 hours).

Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs:

500 micrograms twice daily.

The treatment duration should be decided after factors such as flare frequency, gout duration and the presence and size of tophi have been assessed.

Patients with renal impairment

Use with caution in patients with mild renal impairment. For patients with moderate renal impairment, reduce dose or increase interval between doses. Such patients should be carefully monitored for adverse effects of colchicine (see also section 5.2).

For patients with severe renal impairment, see section 4.3.

Patients with hepatic impairment

Use with caution in patients with mild/moderate hepatic impairment. Such patients should be carefully monitored for adverse effects of colchicine.

For patients with severe hepatic impairment, see section 4.3.

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:

0.5 mg / day in children less than 5 years of age (1 tablet);

1 mg / day in children from 5 to 10 years of age (2 tablets);

1.5 mg / day in children over 10 years (3 tablets).

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

Colchicine dosage should be increased in a stepwise fashion (e.g., 0.25mg/step) up to a maximum of 2mg/day (four tablets a 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).

Elderly

Use with caution.

Method of Administration

For Oral administration

Tablets should be swallowed whole with a glass of water.

In certain circumstances, it may not be possible to administer the tablets orally, please refer to recommendations in section 6.6 for administration as an oral dispersion. These recommendations are also suitable for administration via nasogastric tube or percutaneous endoscopic gastrostomy (PEG) tube.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Patients with blood dyscrasias

• Pregnancy

• Breastfeeding

• Women of childbearing potential unless using effective contraceptive measures

• Patients with severe renal impairment

• Patients with severe hepatic impairment

• Colchicine should not be used in patients undergoing haemodialysis since it cannot be removed by dialysis or exchange transfusion.

• Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a P-glycoprotein (P-gp) inhibitor or a strong CYP3A4 inhibitor (see section 4.5)

4.4. Special warnings and precautions for use

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

Colchicine has a narrow therapeutic window. The administration should be discontinued if toxic symptoms such as nausea, vomiting, abdominal pain, diarrhoea occur.

Colchicine 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 colchicine should be immediately discontinued and a full haematological investigation should be conducted straight away.

Caution is advised in case of: • liver or renal impairment• cardiovascular disease• gastrointestinal disorders• elderly and debilitated patients• patients with abnormalities in blood counts

Patients with liver or renal impairment should be carefully monitored for adverse effects of colchicine (see section 5.2).

Co-administration with P-gp inhibitors and/or moderate or strong CYP3A4 inhibitors will increase the exposure to colchicine, which may lead to colchicine-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 colchicine dosage or interruption of colchicine treatment is recommended (see section 4.5).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Colchicine is a substrate for both CYP3A4 and the transport protein P-gp. 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 and erythromycin), ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors, calcium channel blockers (verapamil and diltiazem) and disulfiram (see section 4.4).

Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a P-gp 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).

A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with a P-gp inhibitor or strong CYP3A4 inhibitor is required (see section 4.4).

A 4-fold reduction in colchicine dosage is recommended when co-administered with a P-gp inhibitor and/or a strong CYP3A4 inhibitor. A 2-fold reduction in colchicine dosage is recommended when co-administered with a moderate CYP3A4 inhibitor.

The magnitude of interactions with strong and moderate CYP3A4 inhibitors as well as with P-gp inhibitors from performed in vivo studies is summarised in the table below:

Single dose of 0.6 mg colchicine without or with:

Number of subjects

% change in colchicine pharmacokinetic parameters

Guidance for dose reduction:

Cmax

AUCo-t

Strong CYP3A4 inhibitors

Clarithromycin 250 mg twice daily for 7 days

Ketoconazole 200 mg twice daily for 5 days

Ritonavir 100 mg twice daily for 5 days

N=23

N=24

N=18

297

190

267

339

287

345

4-fold

Acute gout regimen to be repeated no earlier than 3 days.

Moderate CYP3A4 inhibitors

Verapamil ER 240 mg once daily for 5 days

Diltiazem ER 240 mg once daily for 7 days

Grapefruit juice 240 ml twice daily for 4 days

N=24

N=20

N=21

130

129

93

188

177

95

2-fold

Acute gout regimen to be repeated no earlier than 3 days.

Potent P-gp inhibitors

Cyclosporin 100 mg single dose

N=23

324

317

4-fold

Acute gout regimen to be repeated no earlier than 3 days.

Given the nature of the side effects, caution is advised with concomitant administration of drugs that can affect the blood count or have a negative effect on hepatic and/or renal function.

In addition, substances such as cimetidine and tolbutamide reduce metabolism of colchicine and thus plasma levels of colchicine increase.

Grapefruit juice may increase plasma levels of colchicine. Grapefruit juice should therefore not be taken together with colchicine.

Reversible malabsorption of cyanocobalamin (vitamin B12) may be induced by an altered function of the intestinal mucosa.

The risk of myopathy and rhabdomyolysis is increased by a combination of colchicine with statins, fibrates, ciclosporin or digoxin.

4.6. Fertility, pregnancy and lactation

Fertility

Colchicine administration in animals induces significant reductions in fertility.

Pregnancy

Colchicine is genotoxic in vitro and in vivo, and is teratogenic in animal studies (see section 5.3). Colchicine is therefore contraindicated in pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during treatment.

Women should be advised not to become pregnant whilst taking Colchicine and for nine months following the cessation of therapy and should use barrier or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be appraised of the potential risks to the foetus, should they become pregnant whilst taking medicine or within nine months of cessation of therapy.

Breastfeeding

Colchicine is excreted in breast milk. Therefore, use of colchicine is contraindicated in women who are breastfeeding (see section 4.3).

4.7. Effects on ability to drive and use machines

No details are available regarding the influence of colchicine on the ability to drive and use machines. However, the possibility of drowsiness and dizziness should be taken into account.

4.8. Undesirable effects

The following adverse reactions have been observed.The frequencies are listed under one of the following classifications:

Very common > 1/10Common > 1/100 and < 1/10Uncommon > 1/1,000 and < 1/100Rare>1/10,000 and < 1/1,000Very rare < 1/10,000

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Not known: bone marrow depression with agranulocytosis, aplastic anaemia and thrombocytopenia.

Nervous system disorders

Not known: peripheral neuritis, neuropathy.

Gastrointestinal system disorders

Common: abdominal pain, nausea, vomiting and diarrhoea.

Not known: gastrointestinal haemorrhage.

Hepatobiliary disorders

Not known: Hepatotoxicity

Skin and subcutaneous tissue disorders

Not known: alopecia, rash.

Musculoskeletal and connective tissue disorders

Not known: myopathy and rhabdomyolysis.

Renal and urinary disorders

Not known: renal damage.

Reproductive system and breast disorders

Not known: amenorrhoea, dysmenorrhoea, oligospermia, azoospermia.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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, gastro-intestinal or cardiac disease and patients at extremes of age.

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, haemorrhagic gastroenteritis, volume depletion, electrolyte abnormalities, leukocytosis, and 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.

The lethal dose varies widely (7 - 65 mg single dose) for adults but is generally about 20 mg.