Colchicine 500 microgram tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Colchicine 500 microgram tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 microgram of Colchicine

Excipients with known effect:

Colchicine 500 microgram tablets contain 50.50 mg lactose monohydrate, equivalent to 47.82 mg of lactose anhydrous as a diluent.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White to off white, biconvex round uncoated tablets with ‘L’ debossed on one side and plain on other side. (ca. 5mm diameter, ca. 2.6 mm thickness)

4 CLINICAL PARTICULARS

Important warning!

Because of the narrow therapeutic range of colchicine, the recommended maximum dose must not be exceeded. Overdosing, including by ignoring interactions, can lead to a fatal, very painful and irreversible poisoning with a fatal outcome. Please refer to sections 4.4, 4.5., 4.8 and 4.9 of this SmPC. The medicinal product must be kept out of reach of others before and after use.

4.1 Therapeutic indications

Adult

• Colchicine is indicated for the treatment of acute gout when NSAIDs are contraindicated or are not tolerated by the patient.
• Colchicine is indicated for the prophylaxis of a gout attack during initiation of urate-lowering therapy when NSAIDs are contraindicated or are not tolerated by the patient.

4.2 Posology and method of administration

Posology

Adults

Treatment of Acute gout attack:

One 500 microgram tablet two to four (2-4) times daily until symptoms are relieved.

The course of treatment should end when symptoms are relieved or when a total of 6 mg (twelve 500 microgram tablets) have been taken. No more than 6 mg of colchicine 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).

If diarrhoea or vomiting occurs, Colchicine 500 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 500 microgram Tablets 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 4.3 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 4.3 contraindications.

Method of

Administration Oral

route.

The tablet should be swallowed with a glass of water.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• 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 (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 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, diarrhoea occur.

If patients develop signs or symptoms that could indicate a blood cell dyscrasia, such as fever, stomatitis, sore throat, or prolonged bleeding, bruising or skin disorders, 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 disease
• 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 4.5).

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 or hepatic function, a reduction in colchicine dosage is recommended (see sections 4.2 and 4.5) and patients should be carefully monitored for adverse effects of colchicine.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Where 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 7 months following termination of colchicine therapy (see section 4.6). Based on concerns about a potential damage to sperm cells (see section 5.3), male patients should not father a child during and for at least 6 months following termination of colchicine therapy (see section 4.6).

Paediatric population

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

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 may 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 antagonists such as verapamil and diltiazem and disulfiram (see section 4.4).

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.

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 ketaconazole) (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 moderate 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 summarized in the table below:

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.

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

Animal research has shown that administration of colchicine may negatively influence spermatogenesis (see section 5.3). Rare cases of reversible oligospermia and azoospermia in men are known from literature.

Male patients should not father a child during and for at least 6 months following termination of colchicine therapy (see section 4.4). If, nevertheless, pregnancy occurs during this time period, genetic counselling should be offered.

Pregnancy

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

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 (see section 4.1) and glucocorticoids, are not applicable. Women should be advised not to become pregnant whilst taking Colchicine and female patients must use effective contraception during and for at least 7 months following termination of colchicine therapy (see section 4.4). If, nevertheless, pregnancy occurs during this time period, genetic counselling should be offered. 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 7 months of cessation of therapy.

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 (see section 4.3).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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)

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 disorders

Common: abdominal pain, nausea, vomiting and diarrhoea Not known: gastrointestinal haemorrhage

Hepatobiliary disorders

Not known:

hepatotoxicity

Renal and urinary

disorders Not known:

renal damage.

Skin and subcutaneous tissue disorders

Not known: Alopecia, rash

Musculoskeletal and connective tissue disorders Not known: Myopathy and rhabdomyolysis

Reproductive system and breast disorders

Not known: Amenorrhoea, dysmenorrhoea, oligospermia, azoospermia

Respiratory, thoracic en mediastinal disorders

Pharyngolaryngeal pain

Metabolism and nutrition disorders

Vitamin B12 deficiency

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

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, leucocytosis, 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 leucocytosis 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs for gout, with no effect on uric acid metabolism. ATC code: M04AC01

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.

In the AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study low- and high-dose colchicine were compared using a randomized, placebo-controlled design. The high-dose prolonged colchicine regimen (4.8 mg total over 6 hours) was compared with a placebo and a low-dose abbreviated regimen (1.8 mg total over 1 hour, i.e. 1.2 mg followed by 0.6 mg in 1 hour). Both colchicine regimens were significantly more effective than placebo, with 32.7% responders in the high-dose group, 37.8% responders in the low-dose group, and 15.5% responders in the placebo group (P = 0.034 and P = 0.005, respectively, versus placebo). The results at the primary 24-hour end point demonstrate superior safety of low-dose colchicine, without loss of efficacy, relative to high-dose colchicine for early acute gout flare (self-administered within 12 hours of flare onset). The pharmacokinetic analysis performed in this study showed that the colchicine plasma concentration was decreased substantially from about 12 hours after administration in healthy volunteers.

Colchicine prophylaxis (0.6 mg twice daily) during initiation of allopurinol for chronic gouty arthritis reduced the frequency and severity of acute flares and reduced the likelihood of recurrent flares. Treatment may be discontinued for up to 6 months, based on clinical data. Prospective randomized controlled trials are needed to further evaluate flare prophylaxis for up to 6 months, after 6 months, and over time.

5.2 Pharmacokinetic properties

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. The terminal half-life is 3 to 10 hours.

Renal impairment

Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

Paediatric population

No pharmacokinetics data are available in children.

5.3 Preclinical safety data

Genotoxicity

In one study, a bacterial test is indicated that colchicine has a slight mutagenic effect. However, two other bacterial tests and a test in Drosophila melanogaster found that colchicine was not mutagenic.

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

Teratogenicity

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Pregelatinised starch (maize)

Sodium starch glycolate

Colloidal anhydrous silica

Stearic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister Pack - 48 months

Bottle Pack- 36 months

Shelf life after opening the bottle is 100 days

6.4 Special precautions for storage

Store in the original container protected from light.

6.5 Nature and contents of container

Blister of PVC/PVDC with Aluminium lidding foil. Each pack contains 10, 14, 20, 28, 30, 40, 56, 60, 84, 90, 98 and 100 tablets.

HDPE bottle with child-resistant white polypropylene closure. Each bottle contains 30 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Key House, Sarum Hill,

Basingstoke,

RG21 8SR,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0790

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

07/09/2026

10 DATE OF REVISION OF THE TEXT

07/09/2026