Colchicine lirka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLCHICINE LIRCA (COLCHICINE LIRCA)

Composition:

Active substance: colchicine;

1 tablet contains colchicine 1 mg;

Excipients: lactose monohydrate; sucrose; gum arabic; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: whitish (from white to yellowish) round tablets with a score mark on one side.

Pharmacotherapeutic group.

Medicinal products affecting the musculoskeletal system. Medicinal products used in gout. Preparations which do not affect uric acid metabolism. Colchicine.

ATC Code M04A C01.

Pharmacological properties.

Pharmacodynamics.

The active substance of the medicinal product Colchicine Lirka is colchicine – an alkaloid extracted from the seeds of autumn crocus (Colchicum autumnale), a herbaceous plant belonging to the Liliaceae family.

The extract of this plant has diuretic, analgesic and anti-inflammatory properties, therefore it is used in the treatment of rheumatism, arthritis, and particularly as an anti-gout agent.

Although the mechanism of the anti-gout action of colchicine is not fully understood, it is believed that the drug reduces the inflammatory response to the deposition of monosodium urate crystals in tissues due to its ability to inhibit metabolism, mobility and chemotaxis of polymorphonuclear cells and/or other leukocyte functions. Colchicine also directly affects the deposition of monosodium urate by reducing lactic acid production by polymorphonuclear leukocytes, and indirectly by inhibiting phagocytosis.

In addition, colchicine inhibits cell division by interfering with the formation of the mitotic spindle at the metaphase stage, which has been observed in granulocytes.

These effects have been observed both in cell cultures and in cells of patients receiving colchicine treatment. Colchicine has potential dose-dependent toxicity; therefore, colchicine therapy should be adjusted according to individual tolerance, which varies significantly, considering early signs of toxicity such as gastrointestinal disturbances, particularly diarrhea, as an indicator.

Pharmacokinetics.

After oral administration, colchicine is rapidly absorbed. Maximum plasma concentration is reached within 30 minutes to 2 hours.

After absorption, colchicine is partially transformed into oxycollchicine, which selectively accumulates in the kidneys and is excreted relatively slowly. Thus, accumulation of colchicine and its metabolites may occur in patients with impaired renal function. The elimination half-life (t_1/2) in healthy subjects is 65 ± 15 minutes, total clearance is 601 ± 155 mL/min, and volume of distribution is 49 ± 9 L.

Enterohepatic recirculation occurs to a significant extent, which may lead to gastrointestinal adverse effects when higher doses are administered. Colchicine distributes into kidney, liver, spleen and intestinal tissues and concentrates predominantly in leukocytes. Colchicine can be detected in leukocytes up to 10 days after administration. Colchicine is metabolized in the liver and other tissues. The distribution half-life in plasma is 3–5 minutes. The elimination half-life ranges from 1.7 to 20.9 hours in patients with normal renal function and increases in patients with impaired renal function; therefore, dose reduction is recommended. Colchicine and its metabolites are primarily excreted in feces, while 10–20% are excreted unchanged in urine.

Renal excretion may increase in patients with liver disease.

Clinical characteristics.

Indications.

Acute attack of gouty arthritis.

For prophylactic treatment of recurrent gouty arthritis.

For treatment of acute and recurrent pericarditis.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Severe cardiac, renal, and/or gastrointestinal insufficiency.

Patients with renal or hepatic impairment who are taking P-glycoprotein inhibitors or CYP3A4 enzyme inhibitors (see section "Interaction with other medicinal products and other types of interactions"). Life-threatening and fatal colchicine toxicity has been reported in these patients when treated with therapeutic doses.

Pregnancy and breastfeeding period.

Patients undergoing dialysis.

Interaction with other medicinal products and other types of interactions.

There are no data on incompatibility when using this medicinal product with typical drugs for the treatment of gout or interactions with laboratory tests.

Colchicine is a substrate of CYP3A4 and the P-glycoprotein transport protein. In the presence of CYP3A4 or P-glycoprotein inhibitors, colchicine blood concentration may increase.

Concomitant use of colchicine with cytochrome P450 3A4 (CYP3A4) inhibitors or P-glycoprotein (P-gp) inhibitors increases the risk of potentially toxic colchicine effects.

Concomitant administration of colchicine with cyclosporine, HMG-CoA reductase inhibitors (statins), fibrates, ketoconazole, certain anti-HIV drugs, macrolide antibiotics, cimetidine, verapamil, diltiazem, ranolazine, digoxin, large quantities of grapefruit juice (1000 mL/day), and other CYP3A4 or P-glycoprotein inhibitors, especially in patients with renal impairment, may lead to bone marrow suppression, agranulocytosis, neuromyopathy, myopathy or rhabdomyolysis, and other adverse effects, as well as high, potentially life-threatening levels of colchicine in blood serum.

Life-threatening and fatal drug interactions have been reported in patients receiving colchicine in combination with strong P-glycoprotein and CYP3A4 inhibitors.

If treatment with a P-glycoprotein inhibitor or a strong CYP3A4 inhibitor is required, dose adjustment of colchicine may be necessary for patients with normal renal or hepatic function.

Main drugs or drug classes metabolized by the same CYP3A isoenzyme include alprazolam, oral anticoagulants (e.g., warfarin), astemizole, carbamazepine, cilostazol, cisapride, clarithromycin, telithromycin, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, pimozide, quinidine, rifabutin, rifapentine, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, vinblastine, ritonavir, atazanavir, indinavir, saquinavir, efavirenz, nevirapine, or zidovudine. Other drugs that interact via a similar mechanism through other cytochrome P450 isoenzymes include phenytoin, theophylline, valproate, and phenobarbital.

Concomitant use with P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin, and ticagrelor) leads to increased plasma concentrations of colchicine. Elevated plasma levels of colchicine have been reported after single doses of ketoconazole, ritonavir, verapamil, and diltiazem.

P-glycoprotein inhibitors or potent CYP3A4 inhibitors. Colchicine is contraindicated in patients with impaired renal or hepatic function who are receiving P-glycoprotein inhibitors or potent CYP3A4 inhibitors.

Macrolides (e.g., clarithromycin and erythromycin), as CYP3A4 inhibitors, should not be used to treat patients with impaired renal or hepatic function who are receiving colchicine. Concomitant use of colchicine with erythromycin/clarithromycin in such patients is contraindicated.

In patients with normal renal and hepatic function, a reduction in colchicine dose or temporary discontinuation of colchicine is recommended if treatment with a P-glycoprotein inhibitor or a potent CYP3A4 inhibitor becomes necessary (see section "Special precautions for use").

Statins. Cases of rhabdomyolysis have been reported in patients receiving statins concomitantly. Patients should be advised to report muscle pain and weakness.

Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, or fibrates (associated with myotoxicity) and cyclosporine with colchicine may result in myopathy. Symptoms usually resolve after discontinuation within a period ranging from 1 week to several months.

Colchicine may impair vitamin B12 absorption.

Special precautions for use

Colchicine is potentially toxic, therefore it is essential not to exceed the dose prescribed by a healthcare professional with appropriate knowledge and experience.

Patients with renal impairment and cardiovascular diseases

In patients with renal impairment, disorders such as bone marrow suppression, agranulocytosis, neuromyopathy, myopathy, and rhabdomyolysis may occur.

Extreme caution is required in patients with more severe circulatory and renal disorders (dehydration, blood pressure changes, impaired renal function).

Patients with gastrointestinal disorders

In patients with gastrointestinal disorders, symptoms may be exacerbated due to the antimicrotubular activity of colchicine, leading to diarrhea, nausea, vomiting, and abdominal pain.

Treatment of acute gout attacks in patients with renal impairment

For the treatment of gout attacks in patients with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–50 mL/min) renal impairment, colchicine should be used with caution. In patients with moderate renal impairment, the dose should be reduced or the dosing interval extended. Treatment in these patients should be closely monitored to avoid adverse effects.

In patients with severe renal impairment (creatinine clearance <30 mL/min), treatment should initially start with ½ tablet (0.5 mg) daily. The dose should be increased only under close monitoring to avoid adverse effects. Although dose adjustment is not required for the treatment of gout attacks, repeated treatment courses in patients with severe renal impairment should not occur more frequently than once every 2 weeks. For patients with gout attacks requiring repeated treatment courses, alternative therapies should be considered.

Colchicine treatment is contraindicated in patients undergoing dialysis (see section "Contraindications").

Treatment of acute gout attacks in patients with hepatic impairment

For the treatment of gout attacks in patients with mild to moderate hepatic impairment, dose adjustment is not usually required; however, careful monitoring for adverse effects is necessary. In patients with severe hepatic impairment, dose reduction should be considered.

Treatment of elderly patients

Colchicine should be used with extreme caution in elderly and debilitated patients, particularly in the presence of renal, gastrointestinal, or cardiac disorders.

If weakness, anorexia, nausea, vomiting, or diarrhea occur, the dose should be reduced.

Clarithromycin

Post-marketing reports have described cases of toxicity associated with concomitant use of colchicine and clarithromycin, particularly in elderly patients and sometimes in patients with renal impairment. Fatal outcomes have been reported in some of these cases. If concomitant use of colchicine and clarithromycin is necessary, patients should be closely monitored for signs of colchicine toxicity.

Excipients

Colchicine Lirka contains lactose; therefore, this medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Colchicine Lirka contains sucrose; therefore, this medicinal product should not be administered to patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Allergic reactions are more commonly observed in patients with hypersensitivity to acetylsalicylic acid.

The medicinal product must be stored out of reach of others, both before and after use. This is a toxic medicinal product!

Use during pregnancy or breastfeeding

Pregnancy

Published animal studies on reproductive and developmental effects indicate that colchicine exhibits embryofetal toxicity, teratogenicity, and altered postnatal development at exposures achieved following administration of the drug at recommended therapeutic or higher doses.

Use during pregnancy is contraindicated.

Breastfeeding

Colchicine is excreted in breast milk.

Available physicochemical, pharmacodynamic, and toxicological data on colchicine indicate excretion into breast milk and potential risk to the infant; therefore, risk to the nursing infant cannot be excluded.

Use during breastfeeding is contraindicated.

Fertility

Published non-clinical studies have shown that colchicine-induced disruption of microtubule formation affects meiosis and mitosis.

Colchicine use causes morphological abnormalities of spermatozoa and reduced sperm count in men, as well as disturbances in sperm penetration, the second meiotic division, and oocyte cell division in women taking colchicine.

Although male infertility due to colchicine use is rare, cases of azoospermia have been reported after discontinuation of the drug.

Case reports and epidemiological studies in women have not established a clear association between colchicine use and female infertility.

Ability to influence reaction speed when driving or operating machinery

Colchicine Lirka does not affect the ability to drive vehicles or operate machinery.

Dosage and Administration

Dosage

Gouty Arthritis

Treatment of acute gout attacks should be initiated as early as possible (within the first 12 hours of an acute gout attack). Clinical improvement is expected within 12 hours.

Initially, take 1 tablet (1 mg of the drug), then 1 hour later take ½ tablet (0.5 mg of the drug). After this, do not take any more tablets for the next 12 hours.

If necessary, the dose may be repeated after 12 hours. The maximum daily dose is ½ tablet (0.5 mg of the drug) every 8 hours until symptoms improve.

The treatment course should be completed after symptom relief or after taking 6 tablets (6 mg). During the treatment course, no more than 6 tablets (6 mg) should be taken.

Repeat treatment courses should not be initiated earlier than 3 days (72 hours) after completion of the previous course.

Prophylaxis of gout attacks: Adults should take ½–1 tablet (0.5–1 mg of the drug) daily for no longer than 6 months. Individual treatment duration should be determined based on factors such as frequency of flare-ups, duration of disease, and presence and size of tophi.

Acute and Recurrent Pericarditis

The recommended daily dose of colchicine for acute and recurrent pericarditis is ½–1 tablet (0.5 mg–1 mg) per day: 0.5 mg twice daily for adult patients weighing > 70 kg or 0.5 mg once daily for adult patients weighing ≤ 70 kg, or for patients intolerant to higher doses, administered for at least six months in recurrent pericarditis and at least three months in acute pericarditis.

In most clinical studies, the dose of colchicine used was 1 tablet (1 mg).

Administration

For oral use. The tablet may be swallowed whole or divided into two halves along the break line to obtain a single dose of 0.5 mg.

The recommended dose may need adjustment depending on the patient's renal and hepatic function.

Renal Impairment

Use with caution in patients with mild renal impairment. For patients with moderate renal impairment, the dose should be reduced or the dosing interval extended. Such patients should be closely monitored for adverse effects of colchicine. For information on treatment in patients with severe renal impairment, see section "Contraindications".

Hepatic Impairment

Use with caution in patients with mild to moderate hepatic impairment. Such patients should be closely monitored for adverse effects of colchicine. For use in patients with severe hepatic impairment, see section "Contraindications".

Special Patient Groups

Concomitant use of colchicine with certain drugs, particularly inhibitors of cytochrome P450 3A4 (CYP3A4) and/or P-glycoprotein, increases the risk of colchicine toxicity. If a patient is receiving concomitant therapy with a moderate or strong CYP3A4 inhibitor or a P-glycoprotein inhibitor, the maximum recommended dose of colchicine for oral administration should be reduced, and patients should be closely monitored for adverse effects.

Children

The drug is not indicated for use in children.

Overdose

Overdose and failure to follow recommendations regarding drug interactions may lead to poisoning, which can cause severe pain and may result in fatal outcomes.

Colchicine has a narrow therapeutic index and is highly toxic in overdose. Patients with renal or hepatic impairment, gastrointestinal or cardiovascular disorders, and elderly patients are at increased risk of toxicity. Patients who have overdosed on colchicine, even in the absence of early symptoms, should seek immediate medical evaluation.

Acute intoxication may occur after ingestion of approximately 20 mg (20 tablets) of colchicine in adults and 5 mg (5 tablets) in children. Chronic intoxication may develop after repeated dosing in patients with gout following ingestion of 10 mg or more over several days.

Since colchicine inhibits mitosis, organs with higher rates of cell proliferation are most affected.

Symptoms

The exact dose of colchicine causing significant toxicity is unknown. Fatal cases have been reported after administration of 7 mg over 4 days, while other patients have survived after ingesting more than 60 mg. A review of 150 patients after colchicine overdose showed that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicity, manifesting as gastrointestinal disturbances, whereas those who ingested between 0.5 mg/kg and 0.8 mg/kg experienced more severe reactions such as myelosuppression. A 100% mortality rate was observed in patients who ingested more than 0.8 mg/kg.

The first stage of acute colchicine poisoning begins within 24 hours of ingestion and includes gastrointestinal disturbances such as dehydration, abdominal pain, hemorrhagic gastroenteritis, hypovolemia, diarrhea, nausea, and vomiting, accompanied by electrolyte imbalances, leukocytosis, and hypotension in severe cases.

The second stage, occurring between 24 and 72 hours after ingestion, may involve life-threatening complications such as multiorgan failure, acute renal failure, confusion, coma, peripheral motor and sensory neuropathy, myocardial depression, pancytopenia, arrhythmias, respiratory failure, and coagulopathy.

Death may result from respiratory and cardiovascular failure.

If the patient survives, recovery of affected organs may be accompanied by rebound leukocytosis and alopecia, beginning approximately 1 week after the initial overdose.

Treatment

No antidote is available.

In case of colchicine overdose, gastric lavage should be performed, preferably within 60 minutes of ingestion, along with administration of activated charcoal. Diarrhea should not be treated, as gastrointestinal elimination is a major route of colchicine excretion.

In adults, vomiting may be induced, for example, using warm hypertonic sodium chloride solution (2–3 teaspoons per glass) or apomorphine (0.1–0.15 mg/kg body weight).

In children under 6 years of age, 1 tablespoon of syrup of ipecac in 100–200 mL of juice may be used to induce vomiting, followed by gastric lavage and repeated or continuous administration of activated charcoal.

Hemodialysis is ineffective (due to large volume of distribution).

Treatment is primarily symptomatic and supportive (respiratory monitoring, maintenance of blood pressure and circulation, correction of fluid and electrolyte imbalances). Pain relief may require cautious use of analgesics and administration of atropine (if needed), as well as benzodiazepines, papaverine, or tanalbine if seizures occur. Digoxin may be prescribed to support cardiac function.

Prophylactic antibiotic therapy is recommended. Dexamethasone is indicated in cases of elevated cerebrospinal fluid pressure. Lumbar puncture may also be necessary. Oxygen therapy or mechanical ventilation may be required.

Opioids should not be used!

Hemodynamic, cardiac, and respiratory parameters, as well as blood electrolyte levels, should be carefully monitored and controlled.

Adverse reactions.

In high doses, this medicinal product may cause profuse diarrhea, gastrointestinal bleeding, rash, and kidney and liver damage. However, to achieve the appropriate therapeutic effect, this medicinal product must be administered at the full dose.

Colchicine may cause reversible impairment of vitamin B12 absorption due to dysfunction of the ileal mucosa. The table below summarizes the main adverse effects of colchicine by frequency of occurrence (coded according to the MedDRA dictionary, version 16.1): 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), frequency not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life.

5 years.

Storage conditions.

Keep out of the reach of children. No special storage conditions required.

Packaging.

30 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Haupt Pharma Amareg GmbH.

Manufacturer's address and location of operations.

Donaustraße 378, 93055 Regensburg, Germany.