The Superiority of Compressed Colchicine Tablets over Coated Colchicine Tablets for Familial Mediterranean Fever

Abstract

Background and Objectives: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent febrile attacks and serosal inflammation. The goals of FMF treatment are to prevent acute attacks and the development of amyloidosis. This study aimed to investigate the benefit of switching to compressed colchicine tablets in patients with FMF who are resistant or intolerant to the pharmaceutical preparation of coated colchicine tablets in terms of attack frequency and side effects. Materials and Methods: Patients who developed resistance and intolerance under coated colchicine tablet treatment and, therefore, switched to compressed colchicine tablets were identified. The attack frequencies and drug-related side effects in patients using the two different pharmaceutical colchicine preparations were compared. Results: The mean age of the 172 patients treated with compressed tablets alone following coated tablets was 36.3 ± 11.4 years, and 75 (43.6%) were male. The most common genetic mutation was detected as M694V in 111 (64.5%) patients, and 36 (20.9%) of them were homozygous. A decrease in the daily colchicine dose was found after switching to compressed colchicine tablets in patients followed for 7 years (2.1 ± 0.7 mg vs. 1.7 ± 0.5 mg; p < 0.001). Episodes lasted for one to three days and then resolved spontaneously. After treatment with the compressed tablet form of colchicine, 129 (75%), 33 (19%), and 10 (6%) patients had 0–3, 4–6, and more than 7 attacks, respectively (p < 0.001). Diarrhea and aminotransferase elevation, the most common side effects in patients using coated colchicine tablets, decreased after using compressed colchicine tablets (p < 0.001). Conclusions: Compressed colchicine tablets were shown to be effective in patients who did not respond to coated colchicine therapy and those with pre-treatment intolerance to biological agents.

1. Introduction

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is most common in individuals of North African, Jewish, Armenian, Turkish, and Arab origin [1]. Affected individuals have pathogenic mutations in the Mediterranean fever (MEFV) gene. FMF is characterized by recurrent attacks of fever, serositis, and erysipelas-like erythema. The first attack usually occurs in childhood. During these attacks, serum markers of systemic inflammation, including the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) protein, and fibrinogen, are elevated [2]. FMF treatment aims to prevent attacks, minimize subclinical inflammation, and prevent the development and progression of amyloidosis [3]. Colchicine is safe at doses of 1 to 2 mg/day, even when given continuously over decades, provided that kidney and liver functions are intact. Side effects, most commonly gastrointestinal, are uncommon at low doses (0.5 to 1.2 mg per day), even when given continuously over years. Less common (<1%) side effects include bone marrow suppression, hepatotoxicity, and myotoxicity. The mainstay of treatment is colchicine; however, approximately 5% of FMF patients are resistant, and 2 to 5% cannot tolerate the drug due to gastrointestinal side effects [4]. Interleukin 1 (IL-1) inhibition is a second-line treatment in patients who cannot use colchicine treatment due to resistance or side effects [5]. Although several recent studies have shown that different pharmaceutical colchicine preparations may be effective in treating FMF, they have not been evaluated with sufficient numbers of patients, side effect profiles, or disease activity scores [6,7]. Two colchicine preparations are currently produced and approved in Turkey. The film-coated (Colchicum-Dispert^®, Recordati, İstanbul, Turkey) and sugar-coated (Kolsin^®, İbrahim Etem Ulagay, Turkey) tablet forms are covered free of charge by the social insurance system [8]. When resistance or intolerance to these colchicine preparations is observed in FMF patients, it is common practice for Turkish rheumatologists to replace them with an imported compressed tablet form that is not available on the Turkish market. If the rheumatologist reports the ineffectiveness of coated colchicine preparations, the social insurance system also pays for the imported preparations. Colchicine opocalcium^® (Mayoly Spindler, Chatou, France) and colchicina lirca^® (Acarpia, Milano, Italy) are imported preparations that are not available on the Turkish market [8].

This study primarily aimed to evaluate the benefit of compressed colchicine tablets according to attack frequency and disease activity scores in adult patients with FMF that was resistant to coated colchicine tablets and secondarily aimed to evaluate the use of imported pharmaceutical preparations in case of adverse reactions to domestic pharmaceutical preparations.

2. Materials and Methods

2.1. Study Design

This study consisted of 172 patients with a clinical diagnosis of FMF who met the Tel Hashomer requirements, followed in the rheumatology outpatient clinic of a tertiary referral center, between January 2017 and September 2024.

2.2. Patients and Data Collection

Patients resistant to coated colchicine preparation forms (Colchicum dispert and Kolsin) and those under treatment with compressed colchicine opocalcium were included in this study. After the treatment change, the changes in the number of attacks in the patients were recorded in the patient files. The inclusion criteria for this study were defined as patients who were older than 18 years of age, primarily used colchicine-coated tablets with a diagnosis of FMF, and regularly attended outpatient clinic follow-ups. Patients taking anti-interleukin-1 drugs, other biological agents, and with poor treatment compliance who did not attend routine outpatient clinic follow-ups were excluded from this study, alongside those with ongoing subclinical inflammation, because there was a risk of developing amyloidosis. Patients who developed drug-related intolerance despite receiving effective treatment doses were considered as those experiencing side effects. The frequency of side effects before and after treatment with the compressed form of colchicine was compared. The International Severity Scoring System (ISSF) [9] and Autoinflammatory Disease Activity Index (AIDAI) [10] scores were used for disease activity. Colchicine resistance was defined as one or more episodes per month despite using the maximally tolerated colchicine doses for at least 6 months, as described in the European League Against Rheumatism (EULAR) guidelines [11]. The mean drug doses and frequency of attacks were evaluated according to the colchicine preparations. This study was carried out with the permission of the Local Ethics Committee (date: 19 March 2024; decision no: 2024/138).

2.3. Variables

Demographic characteristics, clinical findings, laboratory parameters, MEFV gene mutations, number of attacks, drug-related side effects, and treatment compliance were evaluated in outpatient clinic controls every three months and recorded in the patient files. Patients whose treatment was changed due to side effects were asked about symptoms associated with the previous treatment (e.g., diarrhea and vomiting/nausea). Changes in these symptoms after the change in treatment were recorded in the patient files. Laboratory abnormalities associated with the drug (e.g., aminotransferase elevation, leukopenia, creatine kinase elevation, and lactate dehydrogenase elevation) were obtained from the patient files before and after the treatment change. In patients who were switched to compressed tablet colchicine treatment due to an increase in the per yearly number of attacks, the number of attacks was questioned at the controls depending on the previous treatment. Episodes lasted for one to three days and then resolved spontaneously. Side effects related to the drug were as follows: diarrhea, elevated aminotransferase levels, nausea–vomiting, leukopenia, and myopathy.

2.4. Statistical Analysis

The statistical analyses were conducted using version 28 of the Statistical Package for Social Sciences (Armonk, NY, USA: IBM Corp.) program for Windows. Visual (histograms and probability plots) and analytical (Kolmogorov–Smirnov’s and Shapiro–Wilk’s tests) methods were utilized to assess whether the variables were normally distributed. Normally distributed variables were expressed as means ± standard deviation (SD), skewed variables as medians (interquartile range (IQR)), and categorical variables as numbers and percentages (%). The chi-square test or Fisher’s exact test was used to evaluate categorical variables (when the chi-square test assumptions did not hold). The Mann–Whitney U or Kruskal–Wallis test was used for non-normally distributed continuous data and an independent t-test for normally distributed continuous data. The Wilcoxon signed-rank test was used for dependent variables in repeated measurements. The sample size was determined to be at least 170 patients in the power analysis, with an effect size of 0.5. Statistical significance was determined by accepting p-values of less than 0.05.

3. Results

This study included 201 FMF patients receiving compressed tablet colchicine treatment due to resistance or intolerance to at least one coated colchicine tablet. However, 29 patients were excluded from this study due to using anti-IL-1 therapy. The final analysis was conducted in 172 patients treated with only compressed tablets after coated tablets in total. The patients’ mean age was 36.3 ± 11.4, and 75 (43.6%) were male. There was no family history in 91 (52.9%) of the patients, and an affected first-degree relative was found in 40 (23.3%). Demographic characteristics, clinical findings, laboratory parameters, and other information about the patients are given in

Table 1. Demographic characteristics, clinical findings, and laboratory parameters of the patients.

Characteristic	Value
Male, n (%)	75 (43.6)
Age, years, mean (SD)	36.3 ± 11.4
Disease duration, years, median (IQR)	18.0 (7.0)
Age during the first attack, years, median (IQR)	14.7 (2.4)
Family history, n (%)
Absent	91 (52.9)
Present (first degree)	40 (23.3)
Present (other)	41 (23.8)
MEFV mutations, n (%)
M694V heterozygous	43 (25.0)
M694V/M694V	36 (20.9)
M694V/M680I	32 (18.6)
Others	32 (18.6)
Unknown	25 (14.5)
No mutation	4 (2.3)
Clinical findings during the attacks, n (%)
Fever	152 (88.4)
Peritonitis	158 (91.9)
Arthritis	79 (45.9)
Myalgia	65 (37.8)
Erysipelas-like erythema	34 (19.8)
Pleuritis	31 (18.0)
Pericarditis	8 (4.7)

SD—standard deviation; IQR—interquartile range.

.

Diarrhea occurring in patients using coated tablets was statistically less frequent after using compressed tablets (p < 0.001). The increase in aminotransferase values in patients using coated tablets was not detected after using compressed tablets (p < 0.001). The frequency of the decrease in side effects after using compressed colchicine tablets is shown in

Table 2. Changes in side effects after compressed colchicine tablet treatment.

Side Effect	Coated Colchicine Tablet	Compressed Colchicine Tablet	p
Diarrhea, n (%)	43 (25)	5 (2.9)	<0.001
Aminotransferase elevation, n (%)	22 (12.8)	4 (2.3)	<0.001
Vomiting–nausea, n (%)	10 (5.8)	1 (0.6)	0.004
Leukopenia, n (%)	8 (4.7)	1 (0.6)	0.016

. A statistically significant improvement was found in the disease activity scores after using compressed colchicine tablets (Figure 1 and Figure 2). After treatment with compressed colchicine tablets, 129 (75%), 33 (19%), and 10 (6%) patients had 0–3, 4–6, and more than 7 attacks, respectively (p < 0.001) (Figure 3).

A statistically significant decrease in the number of attacks per year was detected after the change in pharmaceutical preparation (p < 0.001). However, the mean daily doses of colchicine were 2.1 ± 0.7 mg and 1.7 ± 0.5 mg for the coated and compressed tablets, respectively. A statistically significant decrease in the colchicine dose was found after the pharmaceutical change (p < 0.001).

4. Discussion

In this study, the mean number of attacks per year in patients using coated colchicine tablets was 7.7 ± 2.8, while the mean per year attack frequency after using compressed colchicine tablets was 2.5 ± 1.9. In addition, side effects including diarrhea, aminotransferase elevation, nausea–vomiting, and leucopenia that occurred after using coated colchicine tablets were significantly decreased after switching to compressed colchicine tablets. FMF treatment aims to prevent attacks, suppress subclinical inflammation, and, most importantly, prevent the development of amyloidosis [12].

The results from the Eurofever Registry and a literature review showed that up to 40% of patients treated with colchicine went into partial remission, approximately 5% did not respond, and 2 to 5% could not tolerate the drug, mainly due to gastrointestinal side effects [4]. IL-1 inhibition is a second-line treatment in cases of resistance or intolerance to colchicine. Brief reports indicate that IL-1 inhibition beneficially affects amyloidosis, but more studies are needed. Therefore, it is given to patients resistant to colchicine and using IL-1 inhibitors with colchicine at a tolerable dose to prevent amyloidosis [5,13]. Emmungil et al.’s study [7] found a significant decrease in the number of per-year attacks and disease activity scores of patients when they were switched from coated to compressed colchicine tablets. In another study, decreases were found in the per-year number of attacks in patients after using compressed colchicine tablets and in the number of patients who developed drug-related side effects [6]. In our clinical experience, a decrease in the number of per-year attacks, a significant decrease in the number of patients with drug-related side effects, and a decrease in disease activity scores were found after using compressed colchicine tablets in numerous patients.

The frequency of attacks and side effects decreased with similar daily doses of different pharmaceutical colchicine preparations, which may be related to their pharmacokinetic properties. The pharmaceutical properties of coated and compressed tablet forms of colchicine preparations are shown in

Table 3. Pharmaceutical properties of coated and compressed tablet forms based on product information.

Brand	Colchicum-Dispert®	Kolsin®	Colchicine Opocalcium®
Company, country	Recordati, İstanbul, Turkey	İ.E. Ulagay, İstanbul, Turkey	Mayoly Spindler, Chatou, France
Pharmaceutical form	Film-coated tablet	Sugar-coated tablet	Compressed tablet
Active ingredient	Colchicine	Colchicine	Colchicine
Dose per tablet (mg)	0.5	0.5	1
Excipient	Magnesium stearate	Magnesium stearate	Magnesium stearate
	Lactose	Lactose	Lactose
	Corn starch	Corn starch	Sucrose
	Talc	Talc	Povidon
	Titanium dioxide G	Titanium dioxide G	Erythrosine aluminum lake
	Ponceau 4R lake	Ponceau 4R lake
	Stearic acid	Sugar
	Opadry® II red 85F250030	Ewax
	Kollidon® VA64	Primojel®
	FD&C yellow #6 aluminum lake	Gum arabic
	Polyvinyl alcohol
	Polyethylene glycol

[14,15].

Table 4. Pharmacokinetic properties of different colchicine preparations after a single dose in patients with normal renal and hepatic functions.

Study	Method	Dose (mg)	Form	Cmax (ng/mL)	Tmax (h)	AUC0–Last (ng h/mL)	Last Measurement (h)	Brand (Company, Country)
Achtert et al. [16]	RIA	0.76	Coated tablet	4.15 ± 2.35	1.15 ± 0.38	23.95 ± 12.1	72	Colchicum-Dispert® (Kali-Chemie, Hannover, Germany)
		1	Oral solution	4.88 ± 3.9	1.13 ± 0.42	28.01 ± 14.74
Girre et al. [23]	RIA	1	Tablet	3.9a	1a	26.3 ± 3.52	48	Colchicine Houde® (Houde-ISH, Paris, France)
Rochdi et al. [24]	RIA	1	Tablet	5.5 ± 1.4	1.03 ± 0.5	N/P	48	Colchicine Houde® (Houde-ISH, Paris, France)
Amanova et al. [17]	HPLC	1	Coated tablet	0.13 ± 0.02	3.3 ± 1	2.12 ± 0.64	24	Kolsin® (I.E. Ulagay, İstanbul, Turkey)

shows pharmacokinetic studies performed in healthy volunteers or FMF patients with normal renal and hepatic function by measuring plasma colchicine for at least 24 h with different colchicine preparations after single oral doses. Studies on the steady-state pharmacokinetics of colchicine have shown high interindividual variability in peak plasma colchicine concentrations (Cmax), the time to Cmax (Tmax), and the area under the plasma colchicine concentration–time curve (AUC), which reflects the actual exposure to colchicine [16,17,18]. The variations in CYP3A4 and P-glycoprotein expression and polymorphisms in enterocytes—the cells where oral colchicine is metabolized and reabsorbed into the intestinal lumen—could account for this variability [19]. This theory may be supported by the finding that the colchicine response is linked to certain polymorphisms in the MDR1 gene, which codes for P-glycoprotein, in both FMF and Behçet’s disease [20]. Previous research has shown that plasma colchicine concentrations are lower in FMF patients with insufficient colchicine response than in those who respond well to colchicine [21]. Toxicity may be seen at therapeutic doses and plasma concentrations since colchicine is concentrated in leukocytes; therefore, plasma concentrations do not reflect therapeutic activity or toxicity [20]. Colchicine varies among individuals depending on many variables, and its pharmacokinetic properties vary between studies (Table 4). Although coating the tablets improves their physical properties, the oral forms of many excipients slow down disintegration and dissolution rates, resulting in a decrease in the Tmax and AUC [22]. In our opinion, using compressed colchicine tablets may result in a reduced rate of switching to biological therapies due to resistance or intolerance and using lower drug doses for treatment efficacy.

Our study had some limitations. This was a single-center and retrospective study. Moreover, this study lacked a direct comparison of different pharmaceutical colchicine preparations and plasma or leukocyte colchicine measurements. However, our patient number was higher than in other studies. Additionally, the resistance and intolerance rates and evaluation of negative effects against the compressed tablet form of colchicine were superior to those in other studies.

5. Conclusions

In conclusion, current guidelines recommend anti-IL-1 therapy, which is an expensive and parenteral treatment, in patients with persistent attacks or intolerance to coated colchicine tablet preparations. In this large-scale study, compressed oral colchicine tablets were used as a treatment option before anti-IL-1 therapy. The difference in therapeutic efficacy between these different colchicine preparations may be explained by their different pharmacokinetic properties. Conducting prospective studies with more patients will further contribute to the literature.