potassium;4,5-diacetoxy-9,10-dioxo-anthracene-2-carboxylate

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

review article or handbook

Title:

Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO.

Author:

Pavelka K

Year:

2016

Bibliographic source:

Drugs Aging. 2016; 33(2): 75-85.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Diacerein

EC Number:

237-310-2

EC Name:

Diacerein

Cas Number:

13739-02-1

Molecular formula:

C19H12O8

IUPAC Name:

4,5-diacetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Results and discussion

Results:

ADVERSE EFFECTS:

GASTROINTESTINAL
Regarding the risk of gastrointestinal disorders, the most frequently reported events with diacerein were loose stools and diarrhoea. The laxative effect of diacerein is well known and results from its anthraquinone chemical structure. Bartels et al. calculated that the risk ratio (RR) for developing diarrhoea under diacerein versus placebo treatment was 3.51 (95 % CI 2.55–4.83). Fidelix et al. obtained an RR of 3.52 (95 % CI 2.42–5.11) for diacerein versus placebo, with an absolute risk increase of 24 % (95 % CI 12–35). Well in line with these meta-analyses, Rintelen and co-authors summarised that 39 % of patients treated with diacerein versus 12 % of patients receiving placebo experienced at least one episode of loose stool or diarrhoea. Diarrhoea was mentioned to be generally mild to moderate in all publications that make reference to the severity, and occurred in the first 2 weeks of treatment. No particular pattern of associated disorders could be detected. In all cases, the diacerein-induced diarrhoea was reversible after cessation of treatment. Furthermore, diarrhoeal symptoms decreased in most cases after continuous treatment. The post-marketing surveillance of diacerein showed that 25 serious cases of diarrhoea were reported. Three of them concerned elderly patients, who experienced dehydration and electrolyte disorders; one case was fatal and occurred in a 79-year-old female with a medical history of arterial hypertension and cardiac arrhythmia.
CUTANEOUS
The skin was not a target organ for toxicity in short- and long-term animal toxicology studies. Nevertheless, the incidence of cutaneous events in the 15 published clinical trials evaluating diacerein ranged between 1.8 % and 9.4 %. The present review identified rash, pruritus and eczema as the most common cutaneous reactions reported in clinical trials. They are appropriately reflected in the product information with a frequency of >1/100 and <1/10. Furthermore, the available post-marketing data revealed a few severe cases of cutaneous events: four erythema multiform, two Stevens-Johnson syndrome (SJS) and three toxic epidermal necrolysis (TEN).
HEPATIC
Among the 15 published clinical trials evaluating diacerein, only Zheng et al. reported the occurrence of a hepatic adverse event: one treatment discontinuation due to increase in hepatic enzymes. The PRAC performed a more complete analysis of available data and retrieved seven clinical trials showing abnormalities of liver tests. These were mostly characterised by mild/moderate liver enzyme increase (ALT, AST<5 ULN) without increases in bilirubin. A total of 89 cases within the post-marketing surveillance were considered as hepatic reactions. The most frequent reactions were liver function test abnormalities (41 cases). One case of hepatic failure had a fatal outcome and a close temporal association with diacerein. The extensive preclinical animal toxicology data with diacerein indicated that the liver was not a target organ for toxicity. The mechanism of action of this hepatic toxicity is not fully understood, but an idiosyncratic mechanism is suggested.
CARDIOVASCULAR
Diacerein does not appear to show cardiovascular toxicity. Indeed, a toxicology study designed in accordance with ICH S7A guidelines demonstrated that diacerein at 5 and 30 mg/kg/day for 7 consecutive days, and at 60 and 200 mg/kg/day for 4 and 3 consecutive days, respectively, did not affect the cardiovascular system in the conscious dog. The doses used in this study were between 3.6 times and about 143 times the recommended dose in humans (1.4 mg/kg/day based on a 70 kg person). More significantly, no signal from post-marketing surveillance for acute coronary syndromes or myocardial infarctions was reported in more than 20 years of experience with diacerein.

Applicant's summary and conclusion

Executive summary:

ADVERSE EFFECTS:

GASTROINTESTINAL

Regarding the risk of gastrointestinal disorders, the most frequently reported events with diacerein were loose stools and diarrhoea. The laxative effect of diacerein is well known and results from its anthraquinone chemical structure. Bartels et al. calculated that the risk ratio (RR) for developing diarrhoea under diacerein versus placebo treatment was 3.51 (95 % CI 2.55–4.83). Fidelix et al. obtained an RR of 3.52 (95 % CI 2.42–5.11) for diacerein versus placebo, with an absolute risk increase of 24 % (95 % CI 12–35). Well in line with these meta-analyses, Rintelen and co-authors summarised that 39 % of patients treated with diacerein versus 12 % of patients receiving placebo experienced at least one episode of loose stool or diarrhoea. Diarrhoea was mentioned to be generally mild to moderate in all publications that make reference to the severity, and occurred in the first 2 weeks of treatment. No particular pattern of associated disorders could be detected. In all cases, the diacerein-induced diarrhoea was reversible after cessation of treatment. Furthermore, diarrhoeal symptoms decreased in most cases after continuous treatment. The post-marketing surveillance of diacerein showed that 25 serious cases of diarrhoea were reported. Three of them concerned elderly patients, who experienced dehydration and electrolyte disorders; one case was fatal and occurred in a 79-year-old female with a medical history of arterial hypertension and cardiac arrhythmia.

CUTANEOUS

The skin was not a target organ for toxicity in short- and long-term animal toxicology studies. Nevertheless, the incidence of cutaneous events in the 15 published clinical trials evaluating diacerein ranged between 1.8 % and 9.4 %. The present review identified rash, pruritus and eczema as the most common cutaneous reactions reported in clinical trials. They are appropriately reflected in the product information with a frequency of >1/100 and <1/10. Furthermore, the available post-marketing data revealed a few severe cases of cutaneous events: four erythema multiform, two Stevens-Johnson syndrome (SJS) and three toxic epidermal necrolysis (TEN).

HEPATIC

Among the 15 published clinical trials evaluating diacerein, only Zheng et al. reported the occurrence of a hepatic adverse event: one treatment discontinuation due to increase in hepatic enzymes. The PRAC performed a more complete analysis of available data and retrieved seven clinical trials showing abnormalities of liver tests. These were mostly characterised by mild/moderate liver enzyme increase (ALT, AST<5 ULN) without increases in bilirubin. A total of 89 cases within the post-marketing surveillance were considered as hepatic reactions. The most frequent reactions were liver function test abnormalities (41 cases). One case of hepatic failure had a fatal outcome and a close temporal association with diacerein. The extensive preclinical animal toxicology data with diacerein indicated that the liver was not a target organ for toxicity. The mechanism of action of this hepatic toxicity is not fully understood, but an idiosyncratic mechanism is suggested.

CARDIOVASCULAR

Diacerein does not appear to show cardiovascular toxicity. Indeed, a toxicology study designed in accordance with ICH S7A guidelines demonstrated that diacerein at 5 and 30 mg/kg/day for 7 consecutive days, and at 60 and 200 mg/kg/day for 4 and 3 consecutive days, respectively, did not affect the cardiovascular system in the conscious dog. The doses used in this study were between 3.6 times and about 143 times the recommended dose in humans (1.4 mg/kg/day based on a 70 kg person). More significantly, no signal from post-marketing surveillance for acute coronary syndromes or myocardial infarctions was reported in more than 20 years of experience with diacerein.