4.1. 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.

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 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 than 6 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).

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 during initiation of therapy with allopurinol and uricosuric drugs:

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

The treatment duration should be decided after factors such as flare frequency, gout duration and the

presence and size of tophi have been assessed.

Paediatric population

Colchicine Tiofarma 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

For 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 (see also section 5.2).

For patients with severe renal impairment, see section 4.3 contraindications.

Patients with hepatic impairment

Use with caution in patients with mild/moderate hepatic impairment, the dose is 0.5 mg per day. 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).

In children with amyloid nephropathy, higher daily doses up to 2 mg/day might be needed.

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.

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 4.3 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 4.3 contraindications.

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 skin abnormalities (petechiae)

occur, blood counts should be checked immediately

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

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).

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) 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.

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 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. The use of colchicine in children is

primarily indicated for the indication FMF.

Patients with liver or renal impairment should be carefully monitored for adverse effects of colchicine

(see section 5.2).

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.

4.5. 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 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). 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 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).

Concurrent use of such inhibitors and colchicine should be avoided in patients with renal or hepatic

damage (see section 4.4).

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

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.

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 4.4). If, nevertheless, pregnancy occurs during this time period,

genetic counselling should be tasked.

Pregnancy

Animal studies denote reproductive toxicity (see section 5.3).

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 4.4). 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 Colchicine 500 microgram Tablets therapy

taking into account the benefit of breast feeding for the child and the benefit of therapy for the

woman.

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 and aplastic anaemia and thrombocytopenia.

Metabolism and nutrition disorders

Vitamin B12 deficiency

Nervous system disorders

Not known peripheral neuritis, neuropathy

Respiratory, thoracic en mediastinal disorders

Pharyngolaryngeal pain

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.

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

mg.