Colchicine 500 microgram Tablets

Each tablet contains 500micrograms of colchicine.

Excipients with known effect

Each tablet contains lactose monohydrate equivalent to 45.45 mg of lactose anhydrous.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially 'sodium-free'.

For the full list of excipients, see section 6.1.

Tablet.

Colchicine 500 microgram tablets are white, round tablets debossed with C5 on one side and plain on other side.

Tablet dimensions : 7.4 mm ± 0.2mm

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

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 of 500 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.

Familial Mediterranean Fever

Adults

1 to 3 mg (2 to 6 tablets) per day.

The dose may be given as a single dose or doses higher than 1 mg (2 tablets) per day may be divided and given twice daily.

Colchicine dosage should be increased in a stepwise fashion up to a maximum of 3 mg (6 tablets) per 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 (2 tablets) per day).

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

• 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)

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, or 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 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 4.2 and 4.5).

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

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) .

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 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:

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.

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.

Breast-feeding

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

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) Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Not known: Bone marrow depression with agranulocytosis and 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

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

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 widely (7 – 65 mg in one dose), but for adults but it is generally about 20 mg.

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

ATC code: M04AC01

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 continued 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.

The mechanism of action of colchicine in the treatment of gout is not clearly understood. Colchicine is considered to act against the inflammatory response to urate crystals, by possibly inhibiting the migration of granulocytes into the inflamed area. Other properties of colchicine, such as interaction with the microtubules, could also contribute to the operation. Onset of action is approximately 12 hours after oral administration and is maximal after 1 to 2 days.

Colchicine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations are met usually after 30 to 120 minutes. The terminal half-life is 3 to 10 hours. Plasma protein binding is approximately 30%.

Colchicine is partially metabolised in the liver and then in part via the bile. It accumulates in leucocytes. Colchicine is largely excreted (80%) in unchanged form and as metabolites in the faeces. 10-20% is excreted in the urine.

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.

The influence of renal impairment on the pharmacokinetics of colchicine was assessed in a study in patients with familial Mediterranean fever (FMF), 5 women and 4 men, with (n=4) and without (n=5) renal impairment. The mean age was 30 years (range 19-42 years). All 5 patients with renal impairment had biopsy-proven amyloidosis; 4 were on routine haemodialysis and 1 had a serum creatinine CL of 15 ml/min. They could therefore be classified as having severe renal impairment.

Subjects received 1 mg colchicine except for 1 subject with cirrhosis who received 500 micrograms. A 4-fold decrease in colchicine CL was observed in subjects with renal impairment compared to those with normal renal function (0.168 ± 0.063 l/h/kg vs. 0.727 ± 0.110 l/h/kg). The terminal half-life was 18.8 ± 1.2 h for subjects with severe renal impairment and 4.4 ± 1.0 h for those with normal renal function. The volume of distribution was similar between groups. The patient with cirrhosis had a 10-fold lower CL compared to the subjects with normal renal function.

Paediatric population

No pharmacokinetics data are available in children

Genotoxicity

In one study, a bacterial test 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.

Tests have shown that colchicine induces chromosomal aberrations and micronuclei, and causes some DNA damage.

Teratogenicity

Tests in animals have shown that colchicine is teratogenic

Microcrystalline cellulose

Lactose monohydrate

Sodium starch glycolate

Magnesium stearate E572

Povidone K-30

Not applicable.

2 years.

Keep the blister in the outer carton, in order to protect from light.

Packed in blisters of Alu/PVC in 10, 14, 20, 28, 30, 40, 50, 56, 60, 70, 80, 84, 90, 100, 112's pack sizes.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

For patients where oral administration of a tablet is not possible, administration can be achieved by tablet solubilisation, and subsequent administration as an oral dispersion, or via a nasogastric tube or a percutaneous endoscopic gastrostomy (PEG) tube. Such dispersions should be administered as suggested in the following recommendations. For dosage see section 4.2.

Administration as an oral dispersion:

The dose may be dispersed in a medicines cup containing between 10 ml – 30 ml of water. Add a single tablet to the volume of water and stir for five seconds using a suitable stirring device e.g. spoon. Allow to stand for about 2 minutes and stir for five seconds, and 5 minutes after tablet addition, stir for a further five seconds and administer the entire volume orally immediately. To ensure complete administration of the dose, the cup should be rinsed with a further quantity of water, 10 ml – 30 ml, and administered orally.

Alternatively, the dose may be administered via a 5 ml oral dosing syringe (enteral medicines dispenser). Remove the plunger and insert one tablet into the device. Replace the plunger and depress until in contact with the tablet. Draw up 5 ml of water into the device and expel any residual air. Disperse the tablet by rotation of the dispenser in a vertical axis, five times, allow to stand for 5 minutes, repeat the five rotations, allow again to stand for five minutes, repeat the five rotations. Administer the required dose immediately. To ensure complete dosage administration, a further 5 ml quantity of water should be drawn up into the dosing syringe and administered immediately.

Administration via a nasogastric or percutaneous endoscopic gastrostomy (PEG) Tube:

Tubes made of polyurethane, polyvinylchloride, or silicone are suitable for use. There is no data available on tubes made of latex. Therefore, latex tubes should not be used. Use a 60 ml syringe and remove the plunger, insert one tablet in the syringe barrel, and replace the plunger, depressing until just clear of tablet.

Draw 30 ml of water into the syringe, and manually shake for 30 seconds. Shake for another 30 seconds after 5 minutes, 10 minutes, and 15 minutes post water draw up. Administer the dispersed dose, via nasogastric or PEG tube immediately after preparation. Following administration, the dosing syringe should be disconnected and flushed with a further quantity, 10 ml – 30 ml of water, which should also be administered via tube to ensure complete dosage administration. In cases of fluid restriction, the initial volume for dispersion may be reduced to a minimum of 10 ml.

Strides Pharma UK Ltd.

Unit 4, Metro Centre, Tolpits Lane,

Watford, Hertfordshire,

WD18 9SS United Kingdom

PL 13606/0271

28/07/2022

28/07/2022