Each Colchicine 1 mg tablet contains:

active ingredient: colchicine -1 mg

For a full list of excipients, (see section List of excipients).

Tablet.

Colchicine 1 mg tablets: a pink, round, scored on one side, white and darkish pink mottled tablet with beveled edges.

Therapeutic indications

Adults

• Colchicine is indicated for the treatment of acute gout
• Colchicine is indicated for the prophylaxis of a gout attack during initiation of urate-lowering therapy

Adults and paediatric patients

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

Posology

Gout

Acute gout attack

2 to 3 times daily 0.5 mg, possibly preceded by an initial dose of 1 mg. Treatment should end until the acute attack resolves, or earlier in the event of gastrointestinal symptoms and no improvement after 2 to 3 days. No more than 6 mg should be taken as a course of treatment. After completion of a course, another course should not be started for at least 3 days (72 hours). If diarrhoea or vomiting occurs, Colchicine 1000 microgram Tablets should be discontinued immediately as these may be the first signs of an intoxication.

Prophylaxis of gout attack

0.5 – 1 mg per day (to be taken in the evening).

Paediatric population

Colchicine should not be used in children and adolescents.

Specific groups

Concomitant treatment of colchicine with several drugs, mostly inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein have been shown to increase the risk for colchicine toxicity. If a patient has received concomitant therapy with a moderate or potent CYP3A4 inhibitor or with a P-glycoprotein inhibitor, the maximum recommended dosage of oral colchicine should be reduced and should be carefully monitored for adverse effects of colchicine.

Patients with renal impairment

In patients with mild and moderate renal impairment, the dose is 0.5 mg per day and should be carefully monitored for adverse effects of colchicine. For severe renal impairment, (see section Contraindications).

Patients with hepatic impairment

In patients with mild and moderate hepatic impairment, the dose is 0.5 mg per day and should be carefully monitored for adverse effects of colchicine. For severe hepatic impairment, (see section Contraindications).

Familial Mediterranean Fever

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

Colchicine dosage should be increased in a stepwise fashion up to a maximum of 3 mg/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. 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).

Adults

1 to 3 mg per day.

Paediatric population

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

In children with amyloid nephropathy, higher daily doses up to 2 mg/day might be needed. When 0.25mg doses are required, e.g. to control disease in patients who do not clinically respond to the standard dosage, the 0.5 mg and 1 mg tablet are not appropriate.

Specific groups

Concomitant treatment of colchicine with several drugs, mostly inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein have been shown to increase the risk for colchicine toxicity. If a patient has received concomitant therapy with a moderate or potent CYP3A4 inhibitor or with a P-glycoprotein inhibitor, the maximum recommended dosage of oral colchicine should be reduced and should be carefully monitored for adverse effects of colchicine.

Patients with renal impairment

In patients with mild and moderate renal impairment, the starting dose should be reduced by 50% (e.g. ≤ 1mg/day) and should be carefully monitored for adverse effects of colchicine. For severe renal impairment, (see section Contraindications).

Patients with hepatic impairment

In patients with mild and moderate hepatic impairment the starting dose should be reduced by 50% (e.g. ≤ 1mg/day) and should be carefully monitored for adverse effects of colchicine. For severe hepatic impairment, (see section Contraindications).

Method of Administration

Oral route.

Tablet should be swallowed with a glass of water.

For children younger than 1 year a colchicine oral solution can be considered.

• Hypersensitivity to the active substance or to any of the excipients listed in section 1.
• Patients with blood dyscrasias
• Patients with severe renal impairment
• Patients with severe hepatic impairment
• Pregnancy
• Breastfeeding
• Women of childbearing potential unless using effective contraceptive measures
• 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

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

If patients develop signs or symptoms that could indicate a blood cell dyscrasia, such as fever, stomatitis, sore throat, or prolonged bleeding, treatment with colchicine should be immediately discontinued and a full haematological investigation should be conducted.

Caution is advised in case of:

• Liver or renal impairment
• Cardiovascular disease
• Gastrointestinal disorders
• Elderly and debilitated patients
• Patients with abnormalities in blood counts

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 count are essential. If skin abnormalities (petechiae) occur, blood counts should be checked immediately.

Macrolides, CYP3A4 inhibitors, ciclosporin, HIV protease inhibitors, calcium channel blockers, and statins may cause clinically significant interactions with colchicine which may lead to colchicine-induced toxicity (see section Interaction with other medicinal products and other forms of interaction).

Co-administration with P-gp inhibitors and/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 strong CYP3A4 inhibitor is required in patients with normal renal and or hepatic function, a reduction in colchicine dosage is recommended (see sections Posology and method of administration and Interaction with other medicinal products and other forms of interaction) and patients should be carefully monitored for adverse effects of colchicine.

For patients with an impaired renal or hepatic function, the combined use of colchicine and P-gp inhibitors and/or strong CYP3A4 inhibitors should be avoided whenever possible, as it may be difficult to forecast and control systemic exposure to colchicine. In those exceptional cases where continuation of colchicine when starting P-gp inhibitors and/or strong CYP3A4 inhibitors is considered a benefit, despite the potential risk of overdose, significant dose reductions of colchicine dose and careful clinical monitoring should be applied.

Contains surcose. Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Contains color red E-124. May cause allergic reactions.

Long-term use of colchicine may be associated with vitamin B12 deficiency.

In case colchicine is used for treatment of acute gout or for prophylaxis of a gout attack during initiation of urate-lowering therapy

Patients should be carefully informed about the potential risk of a possible pregnancy and about effective contraception measures to be followed. Female patients should use effective contraception during and for at least three months following termination of colchicine therapy (see section Fertility, pregnancy and lactation). Based on concerns about a potential damage to sperm cells (see section Preclinical safety data), male patients should not father a child during and for at least 6 months following termination of colchicine therapy (see section Fertility, pregnancy and lactation).

Paediatric population

No long-term safety data are available in paediatric patients. The use of colchicine in children is primarily indicated for the indication FMF.

Interaction with other medicinal products and other forms of interaction

Interactions with other drugs are not or scarcely documented. 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 may reduce metabolism of colchicine and thus increase plasma levels of colchicine.

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 may increase. Toxicity, including fatal cases, have been reported during concurrent use of inhibitors such as macrolides (clarithromycin and erythromycin), ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors, calcium channel antagonists such as verapamil and diltiazem. It has been reported that co-administration of azithromycin with colchicine leads to increased serum levels of colchicine. During treatment with azithromycin and after discontinuation, clinical follow-up, and potentially follow up of serum levels of colchicine, is required (see section Special warnings and precautions for use).

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

If treatment with a P-gp inhibitor (e.g. ciclosporin, verapamil or quinidine) or strong CYP3A4 inhibitor (e.g. ritonavir, atazanavir, indinavir, clarithromycin, telithromycin, itraconazole or ketaconazole) is required in patients with normal renal or hepatic function, adjustment of colchicine dosage may be necessary.

Concurrent use of such inhibitors and colchicine should be avoided in patients with renal or hepatic damage (see section Special warnings and precautions for use).

Reversible malabsorption of cyanocobalamine (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.

Fertility

Animal research has shown that administration of colchicine may negatively influence spermatogenesis (see section Preclinical safety data). Rare cases of reversible oligospermia and azoospermia in men are known from literature.

In case Colchicine is used for treatment of FMF

Since the course of FMF without treatment may also lead to infertility, the use of colchicine should be weighed against the potential risks and may be considered, if clinically needed.

In case colchicine is used for treatment of acute gout or for prophylaxis of a gout attack during initiation of urate-lowering therapy

Male patients should not father a child during and for at least 6 months following termination of colchicine therapy (see section Special warnings and precautions for use). If, nevertheless, pregnancy occurs during this time period, genetic counselling should be tasked.

Pregnancy

Animal studies denote reproductive toxicity (see section Preclinical safety data).

In case colchicine is used for treatment of FMF

A moderate amount of data on pregnant women with FMF indicate no malformative or feto/ neonatal toxicity of colchicine. Since the course of FMF without treatment may also negatively influence pregnancy, the use of colchicine during pregnancy should be weighed against the potential risks and may be considered, if clinically needed.

In case colchicine is used for treatment of acute gout or for prophylaxis of a gout attack during initiation of urate-lowering therapy

There is a limited amount of data from the use of colchicine in pregnant women with gout. As a precautionary measure, use of colchicine in this patient population and in women of childbearing potential not using effective contraception, should be avoided and may only be considered if other treatment options, including NSAIDs and glucocorticoids, are not applicable.

Female patients have to use effective contraception during and for at least three months following termination of colchicine therapy (see section Special warnings and precautions for use). If, nevertheless, pregnancy occurs during this time period, genetic counselling should be tasked.

Breast-feeding

Colchicine/metabolites is /are found in breastfed newborns/infants of treated women. There is insufficient information on the effects of colchicine in newborns/infants. Colchicine should not be used in breast-feeding women with gout. In lactating mothers with FMF, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from {Invented name} therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

No data 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.

The following adverse reactions have been observed.

The frequencies are unknown, unless listed under one of the following classifications: Very common (≥ 1/10)

Common (≥ 1/100, < 1/10) Uncommon (≥ 1/1,000, < 1/100) Rare (≥ 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

Blood and lymphatic system disorders

Bone marrow depression with agranulocytosis and aplastic anemia.

Nervous system disorders Peripheral neuritis, neuropathy

Gastrointestinal disorders

Common: abdominal pain, nausea, vomiting and diarrhea

Hepatobiliary disorders

Hepatotoxicity

Skin and subcutaneous tissue disorders

Alopecia, rash

Musculoskeletal and connective tissue disorders

Myopathy and rhabdomyolysis

Reproductive system and breast disorders

Amenorrhoea, dysmenorrhoea, oligospermia, azoospermia

Respiratory, thoracic en mediastinal disorders

Pharyngolaryngeal pain

Metabolism and nutrition disorders

Vitamin B12 deficiency

Paediatric population

No long-term safety data are available in paediatric patients.

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 Arpimed “LLC” by going to www.arpimed.com and fill out the appropriate form ″Report an adverse reaction or inefficiency of drug″. Hotline number: (+374 55) 05 79 86. And by using Scientific Centre of Drug and Medical Technology Expertise after academician E. Gabrielyan ″CJSC″, going to the site: www.pharm.am in ″Report about adverse effect of medicine″ section and fill out the ″Report of adverse reaction or manufacturing problem of medicinal product″. Hotline numbers: +37410200505; +37496220505.

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, 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 activate charcoals in adults who have ingested more than 0.1 mg/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 strongly (7 – 65 mg in one dose), but for adults it is generally about 20 mg.

ATC code: M04AC01.

Drugs for gout, with no effect on uric acid metabolism.

Mechanism of action

The mechanism of action of colchicine in the treatment of gout is not completely known. Urate crystals are phagocytosed by leukocytes. Hereby inflammatory factors are released. Colchicine inhibits these processes. Other properties of colchicine, such as interaction with microtubules, could also contribute to its action.

Onset of actions is approximately 12 hours after oral administration and is maximal after 1 to 2 days.

Absorption

Colchicine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations are met usually after 30 to 120 minutes.

Distribution

Plasma protein binding of colchicine is approximately 30%. It accumulates in leucocytes.

Elimination

Colchicine is partially metabolized in the liver and then then in part via the bile. It is largely excreted (80%) in unchanged form and as metabolites in the faeces. 10-20% is excreted in urine. The plasma half-life is 30-60 minutes and approximately 60 hours in leukocytes.

Paediatric population

No pharmacokinetics data are available in children.

Colchicine causes DNA damage in vitro and chromosomal aberrations were observed in vivo. No toxicity data are available from own preclinical research.

Studies in animals have shown that colchicine-induced disruption op microtubule formation has an effect on meiosis and mitosis. After colchicine exposure a reduced sperm count and sperm cells with abnormal morphology have been demonstrated in male animals. The doses used in these studies were substantially higher than the dose prescribed for use in patients. High doses of colchicine can cause teratogenicity and embryo toxicity in mice, rats and rabbits.

List of excipients

Each Colchine 1 mg tablet contains:

Sucrose

Povidone

Sodium starch glycolate

Magnesium stearate

Color red E-124

Microcrystalline cellulose

Not applicable.

3 years

Store at temperature not higher than 25⁰C, in a dry place, and protect from light. Keep out of the reach of children.

Colchicine, 1  mg tablets:

24 tablets are packed into PVC-Alu blister packet (inside package)

4 blisters are packed with 24 tablets in each are inserted together with the leaflet into cardboard boxes (outer package).

No special requirements.