Introduction
The drug colchicine (ATC code: M04AC01) is registered in the Russian Federation (P N014955/01) for the treatment of acute gouty attacks, for the prevention of relapse of acute gouty attacks, with similar indications the drug is registered in a number of European countries and the USA.
The antigout effect of colchicine is associated with a decrease in the migration of leukocytes to the site of inflammation and inhibition of phagocytosis of microcrystals of uric acid salts. It also has an antimitotic effect, completely or partially suppresses cell division at the stage of anaphase and metaphase, and prevents degranulation of neutrophils [1]. According to the approved instructions for medical use, in case of an acute attack of gout, the patient can take up to 8 mg on the first day, and again no earlier than 3 days later. To prevent acute attacks of gout, it is allowed to take 0.5-1.5 mg daily or every other day for 3 months [1]. In the UK, a slightly different regimen is used with more stringent dose restrictions for an acute attack of gout: no more than 1.5 mg in the first 12 hours, then a 12-hour break, then 0.5 mg 3 times a day until improvement or the maximum course dose is reached 6 mg [2].
Colchicine is rapidly and intensively absorbed from the gastrointestinal tract, the half-life is 9.3 hours, the volume of distribution is 473 liters. Colchicine is metabolized in the liver and excreted mainly in the bile, about 23% by the kidneys [1].
In recent years, colchicine, which has demonstrated an anti-inflammatory effect [3, 6], has been actively studied in relation to the secondary prevention and treatment of cardiovascular diseases, since inflammation is considered as one of the important elements of their pathogenesis. A 2021 Cochrane review concluded that colchicine may reduce the incidence of myocardial infarction in high-risk patients, but noted that further research is needed [4]. In 2021, a clinical study was published on the long-term use of colchicine at a dose of 0.5 mg per day in 4,757 patients who suffered a myocardial infarction within 30 days prior to inclusion. During follow-up (22 months), a reduction in the risk of death, reinfarction, acute cerebrovascular accident, and hospitalization for acute coronary syndrome was found. An increased risk of pneumonia was found in the colchicine group (0.9%) compared with placebo (0.4%) [5].
In 2021, the role of microtubules, the polymerization of which is disrupted by colchicine, in the penetration of coronavirus NL63 into host cells was demonstrated [7]. In 2014, a single report was published on the possible therapeutic effect of colchicine in severe viral myocarditis [8]. At the same time, Cumhur Cure M et al. note that colchicine is not able to achieve a sufficient increase in intracellular pH for a significant antiviral effect [18].
In connection with the data mentioned above, proposals have arisen to use colchicine in the treatment of patients with COVID-19 [9][10].
Possibility of use for COVID-19
As of June 6, 2021, colchicine is not included in Russian [13], American [12], Canadian [14], Australian [11], Italian [15] recommendations for the treatment of COVID-19.
The ClinicalTrials.gov database found 13 clinical studies (CTs) on the use of colchicine in the treatment or prevention of COVID-19; there are no completed studies. Trial NCT04350320 examines the effect of colchicine in addition to standard therapy in hospitalized patients, with a dosing regimen of 1.5 mg on the first day, then 1 mg daily for a week and 0.5 mg daily until the end of the 28-day treatment period [21]. In hospitalized patients with hypoxemia, trial NCT04375202 is studying the effect of 0.5 mg of the drug 3 times a day for 30 days or until discharge [21]. In study NCT04363437, colchicine is used to prevent acute respiratory distress syndrome (ARDS) in hospitalized patients with severe COVID-19 at a dose of 1.2 mg on the first day (with an additional bolus of 0.6 mg after 2 hours in the absence of gastrointestinal symptoms ), and then 0.6 mg 2 times a day for 14 days or until discharge [21]. The NCT04355143 study evaluates the effect of colchicine in addition to standard therapy in hospitalized patients with COVID-19 and signs of myocardial damage, the dosing regimen is 0.6 mg twice a day for 30 days [21].
Noteworthy is the large Canadian randomized multicenter trial NCT04322682, which is expected to include 6,000 patients aged 40 years or older with a diagnosis of COVID-19 established within 24 hours before enrollment, undergoing outpatient treatment and having at least one of the following factors risk: age 70 years and older, diabetes mellitus, uncontrolled hypertension, obstructive pulmonary disease, heart failure, coronary artery disease, fever above 38.3 °C, shortness of breath on examination, pancytopenia or lymphopenia with neutrophilic leukocytosis. Dosage regimen: 0.5 mg 2 times a day in the first three days, and 0.5 mg once over the next 27 days. The primary endpoint was death or hospitalization [21].
In the register of clinical trials of the Ministry of Health of the Russian Federation, no information on clinical trials using colchicine was found. In off-label mode, the drug is used at the Medical Center of Moscow State University as part of complex basic therapy for patients with moderate and severe COVID-19: 1 mg on the first day, then 0.5 mg once a day, or 1 mg once a day for 3 days, then 0.5 mg once a day [16]. At the time of preparation of this review, no scientific publications on the results of using this scheme were found.
In the publication of Della-Torre E et al. describes 9 clinical cases of patients with COVID-19 who received colchicine at a dose of 1 g at an interval of 12 hours, then 1 g per day until the 3rd day of stable normothermia. In all patients, the temperature returned to normal within 72 hours [17].
A retrospective analysis of a cohort of 14,520 people tested for SARS-CoV-2 in Israel found no difference in the frequency of colchicine use between infected and uninfected individuals, calling into question the preventive effectiveness of this drug [19].
Colchicine in the treatment of patients with COVID-19. Data from ColCorona and RECOVERY studies
During the weekly conference “Scientific Tuesday”, a cardiologist from the Federal State Budgetary Institution “National Medical Research Center for TPM” of the Ministry of Health of Russia, senior researcher, Ph.D. Yuri Vyacheslavovich Mareev presented data from the ColCorona and RECOVERY studies on the use of colchicine in the treatment of COVID-19.
The search for drugs to treat patients with COVID-19 continues. Of particular interest is the study of drugs that reduce the severity of inflammation, in particular colchicine. A number of observational and small-scale randomized studies have shown the effect of using the drug in patients with COVID-19 (,), but the data from these studies are not enough to introduce the drug into patient treatment protocols. Let us consider the recently published large RCTs on the use of colchicine in patients with COVID-19.
The first study is the work of ColCorona (). This study was a randomized, double-blind trial that included outpatients with COVID-19 over 40 years of age who had additional risk factors for hospitalization due to COVID-19. Patients were enrolled within 24 hours of diagnosis without a face-to-face clinic visit, and the designated center was required to provide medication (colchicine or placebo) within 4 hours. The study was completed ahead of schedule after recruiting 75% of the planned 6,000 patients (4,488 people). The early completion of the study was associated with problems in the logistics of the work ().
Patients were divided into colchicine and placebo groups. When analyzing all 4488 patients included, there was a trend that did not reach statistical significance in reducing the risk of the composite endpoint of death or hospitalization due to COVID-19. In an analysis of 4,159 patients (92.7% of total patients) with a positive PCR test, there was a statistically significant reduction in the composite endpoint of “death or hospitalization due to COVID-19” by 25%.
ColCorona provides hope for the use of colchicine in the treatment of outpatients with COVID-19. But the early completion of the work does not allow us to draw final conclusions about the effectiveness of the drug against COVID-19. Many researchers noted that, despite the interesting results, the early completion of the work does not allow us to accurately say about the advisability of using colchicine in patients with COVID-19 ().
It is also worth noting the side effects. In the colchicine group, there was a large number of diarrhea (number of people per side effect, number need to harm, 16) and pulmonary embolisms (number of people per side effect, 250). At the same time, diarrhea is a known side effect of the drug, but there was no indication of an increased risk of thromboembolic complications in the COLCOT and LoDoCO2 studies (Nidorf SM et al NEJM), which studied the possibility of preventing cardiovascular complications during the use of colchicine. Whether colchicine increases the risk of thromboembolic complications in patients with COVID-19 requires further clarification.
The second study is the work of RECOVERY. The RECOVERY trial was a large randomized trial in England that compared a range of medications, including colchicine, with standard care in hospitalized patients with COVID-19.
The colchicine arm of the RECOVERY trial included 11,340 () patients. According to the study, there was no difference in the risk of the primary endpoint (death within 28 days) and no other benefits were noted with the use of colchicine compared with usual management of hospitalized patients with COVID-19.
Thus, the RECOVERY study did not reveal the effectiveness of colchicine in inpatients with COVID-19, and the ColCorona study suggests a possible positive effect of colchicine in outpatients with COVID-19, but the latter requires confirmation in ongoing randomized trials. This includes an international study with Russian participation, ACTCOVID19 (), which is studying both outpatient and hospitalized patients with COVID-19.
In conclusion, it should be noted that colchicine is not a drug for self-administration without a doctor’s prescription, it is contraindicated for pregnant and lactating women, it has a number of side effects and interactions with other medications, and it is not included in the 11th version of the temporary recommendations of the Russian Ministry of Health for treatment COVID-19 ().
Safety of Colchicine
Undesirable effects of colchicine include diarrhea, nausea, vomiting and stomach pain, and less commonly, leukopenia and agranulocytosis. The frequency of other undesirable effects (kidney damage, liver damage, neuropathy, myopathy, etc.) has not been precisely established [1][2]. Colchicine is contraindicated for use during pregnancy and lactation, with liver or kidney failure (especially in patients on dialysis), as well as with severe inhibition of hematopoiesis. Caution should be used in elderly patients; with cachexia; having severe gastrointestinal dysfunction; with severe dysfunction of the cardiovascular system [1]. Women of childbearing age can receive colchicine only if they are using an effective method of contraception [2].
Treatment must be carried out under close hematological and clinical supervision. If severe side effects from the gastrointestinal tract occur, the dose should be reduced or the drug discontinued. When the number of leukocytes decreases below 3000/μl (3×109/l) and platelets below 100,000/μl (100×109/l), the intake is stopped until the blood picture normalizes [1].
Drug interactions: colchicine enhances the effect of depressants and sympathomimetic drugs, interferes with the absorption of cyanocobalamin, NSAIDs and other drugs that cause myelodepression, increases the risk of developing leukopenia and thrombocytopenia [1].
The US Food and Drug Administration (FDA) issued a warning in 2015 with new data on the risks of colchicine. Cases of fatal toxicity of colchicine have been identified when used in therapeutic doses in combination with other drugs, in particular clarithromycin. This highlights the major role of drugs that affect the intestinal absorption and/or hepatic metabolism of colchicine in the development of toxicity. In addition, it was noted that doses lower than those traditionally used had a sufficient effect on gout, while being accompanied by less pronounced undesirable effects. The agency recommends against the use of P-gp inhibitors or strong CYP3A4 inhibitors in patients with hepatic or renal impairment receiving colchicine. If such drugs are vitally needed, then the dose of colchicine should be reduced or its use discontinued [20]. The British Medicines Agency recommends, in particular, the following dose adjustments: reduce the dose of colchicine by 4 times when used together with ritonavir, ketoconazole, clarithromycin, cyclosporine; 2 times - when used with diltiazem and verapamil [2]. These recommendations appear to be particularly relevant for patients with COVID-19.
Colchicine instructions for use
Indications for use
The tablets are designed specifically for people suffering from gout - this is the main area of application. In addition, they are recommended to be taken for such health problems as:
- SSL;
- amyloidosis;
- gouty arthritis;
- scleroderma (in some cases);
- phlebitis (in certain cases);
- chondrocalcinosis;
- inflammatory processes in the oral cavity, larynx, nasal cavity and ear canal.
Regardless of the type of problem, a preliminary consultation with your doctor is necessary!
pharmachologic effect
When it enters the stomach and then the intestines, Colchicine is absorbed into its walls and enters the liver, kidneys, spleen and other organs through the bloodstream. The alkaloid is partially absorbed in the liver. The active substance does not penetrate into the lungs, heart and skeletal muscles. It is gradually excreted from the body in urine, sweat and feces.
How to take, course of administration and dosage
The daily dosage, as well as the duration of treatment, varies depending on the disease and the age of the person. Therefore, a specialist should give precise instructions. Here are approximate recommendations from manufacturers:
Gout (treatment regimen by day)
- 1 day. 1 mg each. 3 times a day.
- 2 days. 1 mg each. 2 times a day.
- 3 days. 1 mg each. 2 times a day.
- 4 days. Once a day 1 mg.
In order to prevent gout attacks, tablets are taken in an individual course 2 times a year.
Familial Mediterranean fever
- 1 day. 1 mg each. 3 times a day.
- 2 days. 1 mg each. 2 times a day.
- 3 days. Once a day 1 mg.
To prevent attacks, take 1 mg. once a day for 2-3 months, after which they take a month-long break. During the hot season, tablets can be taken without interruption - this is done in winter.
Amyloidosis
The dosage is determined only by the attending physician - self-medication is unacceptable! The course is long - up to 4-5 years.
Contraindications
Tablets are strictly prohibited in case of individual intolerance to one or more components included in their composition. The medicine should not be taken if:
- neutropenia;
- bone marrow pathologies;
- alcohol dependence (alcohol should be completely avoided during treatment);
- liver diseases;
- kidney diseases;
- purulent infections.
Contraindications also include pregnancy, lactation and old age.
Side effects
In case of an overdose, nausea, vomiting, severe intestinal upset may occur, the stomach becomes painful, and the oral cavity may also hurt. Sometimes a person feels a burning sensation on the skin. In severe cases, hemorrhagic gastroenteritis and severe dehydration develop, which can lead to serious problems.
If there was no overdose, then the side effects are as follows:
- allergic reaction (redness, rash);
- nausea;
- stomach pain;
- diarrhea.
Very rarely, long-term treatment can cause the development of agranulocytosis, malabsorption syndrome, thrombocytopenia, myopathy, leukopenia or neutropenia.
Special instructions
In case of an overdose of the drug, nausea, vomiting, severe diarrhea, abdominal and oral pain, hemorrhagic gastroenteritis, burning of the skin, severe dehydration with hypotension and hypovolemic shock occur.
Storage conditions
Tablets are stored out of the reach of children. The optimal temperature is up to +25 degrees. Protect from sunlight.