Diacerein

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

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:

Benefit-risk assessment of diacerein in the treatment of osteoarthritis.

Author:

Panova E

Year:

2015

Bibliographic source:

Drug Saf. 2015; 38(3): 245-52.

Materials and methods

Test material

Test material information

Details on test material:

The SMILES included in the reference substance linked in Section 1 (General information) was used as model input.

Results and discussion

Results:

TOLERABILITY:

all shorter-duration randomized clinical trials (RTCs) found that the numbers of patients experiencing any AE were similar in the diacerein and comparator (placebo or active) groups. In the longer 3-year trial, there were higher adverse events (AEs) rates in the diacerein group (95 %) versus placebo (84 %), P = 0.001. This was largely due to a higher rate of diarrhoea (46 % in the diacerein group versus 12 % in the placebo group) and a statistically significant higher rate of skin and appendage disorders (P = 0.024). Similar findings were reported in the 1-year study by Pham et al., where diarrhoea occurred in 41 %of the diacerein group and in 8 % of the placebo group, while the skin disorder rates were 8 and 1 %, respectively. Only those two longer duration studies reported skin disorders as a significant AE. It seems likely that longer exposure to diacerein might trigger skin reactions in some patients. In the majority of the key RCTs, the most common side effects with diacerein were diarrhoea and urine discolouration. Diarrhoea occurred within the first 2 weeks, and the rates ranged from 8 to 13.6 %in the placebo/comparator groups and from 15.5 to 46 % in the diacerein groups. The wide range of diarrhoea rates in the diacerein groups may have reflected differences in reporting but are most likely due to the lengths of the studies, with a lower percentage in the short term and the highest percentage in the 3-year study. The literature suggests that diarrhoea is a class effect with IL-1 blockade. A possible explanation for increased gut motility is an increase in prostaglandin levels, as diacerein has been shown to induce its synthesis. All trials classified diarrhoea as mild to moderate and, except in the 3-year trial, it did not result in higher discontinuation rates. ECHODIAH reported a 12 % discontinuation rate due to diarrhoea in the diacerein group, compared with 2 % in the placebo group. In terms of the dose, there was a higher rate of diarrhoea in the 150 mg/day diacerein group, and diarrhoea was categorized as “severe” in 13 patients in that group versus 2 in the placebo group and 2 in the 100 mg/day diacerein group. The same trial reported higher withdrawal rates due to diarrhoea in the 150 mg/day group versus the placebo and 100 mg/day diacerein groups, with 12, 3 and 3 withdrawals, respectively. Those observations lead to a conclusion that diarrhoea worsens with longer treatment duration and higher daily dosing. Another common AE was urine discolouration; up to half of the participants experienced it, but it is a known class event due to elimination of diacerein metabolites via the kidney and is not of clinical significance. All of the key trials collected blood and urine for various evaluations, including liver and kidney functions; all found no clinically relevant differences between the diacerein and comparator groups. The Zhang et al. meta-analysis reported diarrhoea as a significant problem; the RR versus placebo was 3.51 (95 % CI 2.55, 4.83). The Cochrane Collaboration meta-analysis summarized evidence from seven trials and concluded that the rate of AEs, mainly diarrhoea after 2–36 months, was significantly higher in the diacerein group than in the placebo group (RR 3.52; 95 % CI 2.42, 5.11), with an absolute risk increase of 24 % (95 % CI 12–35 %) and a number-needed- to-treat for an additional harmful outcome (NNTH) of 4 (95 % CI 3, 7). With regard to comparisons with NSAIDs, three studies were reviewed, with 505 patients in total. Diacerein caused more lower gastrointestinal tract problems (diarrhoea RR 3.20; 95 % CI 1.58, 6.49) and less upper gastrointestinal tract problems (dyspepsia RR 0.67; 95 % CI 0.41, 1.11). The Cochrane review did not find a statistical difference between the diacerein and comparator groups in participant withdrawals due to AEs. For the comparison of diacerein with placebo, the RR for dropout due to AEs was 1.29 (95 % CI 0.83, 2.01). For diacerein versus NSAIDs, the RR was 0.96 (95 % CI 0.38, 2.44). With regard to hepatotoxicity, only two case reports were identified: one case of fatal hepatitis, published in 2001, and one case of acute hepatitis, published in 1997. These were both in French, with no abstracts available.

Applicant's summary and conclusion

Executive summary:

TOLERABILITY:

all shorter-duration randomized clinical trials (RTCs) found that the numbers of patients experiencing any AE were similar in the diacerein and comparator (placebo or active) groups. In the longer 3-year trial, there were higher adverse events (AEs) rates in the diacerein group (95 %) versus placebo (84 %), P = 0.001. This was largely due to a higher rate of diarrhoea (46 % in the diacerein group versus 12 % in the placebo group) and a statistically significant higher rate of skin and appendage disorders (P = 0.024). Similar findings were reported in the 1-year study by Pham et al., where diarrhoea occurred in 41 %of the diacerein group and in 8 % of the placebo group, while the skin disorder rates were 8 and 1 %, respectively. Only those two longer duration studies reported skin disorders as a significant AE. It seems likely that longer exposure to diacerein might trigger skin reactions in some patients. In the majority of the key RCTs, the most common side effects with diacerein were diarrhoea and urine discolouration. Diarrhoea occurred within the first 2 weeks, and the rates ranged from 8 to 13.6 %in the placebo/comparator groups and from 15.5 to 46 % in the diacerein groups. The wide range of diarrhoea rates in the diacerein groups may have reflected differences in reporting but are most likely due to the lengths of the studies, with a lower percentage in the short term and the highest percentage in the 3-year study. The literature suggests that diarrhoea is a class effect with IL-1 blockade. A possible explanation for increased gut motility is an increase in prostaglandin levels, as diacerein has been shown to induce its synthesis. All trials classified diarrhoea as mild to moderate and, except in the 3-year trial, it did not result in higher discontinuation rates. ECHODIAH reported a 12 % discontinuation rate due to diarrhoea in the diacerein group, compared with 2 % in the placebo group. In terms of the dose, there was a higher rate of diarrhoea in the 150 mg/day diacerein group, and diarrhoea was categorized as “severe” in 13 patients in that group versus 2 in the placebo group and 2 in the 100 mg/day diacerein group. The same trial reported higher withdrawal rates due to diarrhoea in the 150 mg/day group versus the placebo and 100 mg/day diacerein groups, with 12, 3 and 3 withdrawals, respectively. Those observations lead to a conclusion that diarrhoea worsens with longer treatment duration and higher daily dosing. Another common AE was urine discolouration; up to half of the participants experienced it, but it is a known class event due to elimination of diacerein metabolites via the kidney and is not of clinical significance. All of the key trials collected blood and urine for various evaluations, including liver and kidney functions; all found no clinically relevant differences between the diacerein and comparator groups. The Zhang et al. meta-analysis reported diarrhoea as a significant problem; the RR versus placebo was 3.51 (95 % CI 2.55, 4.83). The Cochrane Collaboration meta-analysis summarized evidence from seven trials and concluded that the rate of AEs, mainly diarrhoea after 2–36 months, was significantly higher in the diacerein group than in the placebo group (RR 3.52; 95 % CI 2.42, 5.11), with an absolute risk increase of 24 % (95 % CI 12–35 %) and a number-needed- to-treat for an additional harmful outcome (NNTH) of 4 (95 % CI 3, 7). With regard to comparisons with NSAIDs, three studies were reviewed, with 505 patients in total. Diacerein caused more lower gastrointestinal tract problems (diarrhoea RR 3.20; 95 % CI 1.58, 6.49) and less upper gastrointestinal tract problems (dyspepsia RR 0.67; 95 % CI 0.41, 1.11). The Cochrane review did not find a statistical difference between the diacerein and comparator groups in participant withdrawals due to AEs. For the comparison of diacerein with placebo, the RR for dropout due to AEs was 1.29 (95 % CI 0.83, 2.01). For diacerein versus NSAIDs, the RR was 0.96 (95 % CI 0.38, 2.44). With regard to hepatotoxicity, only two case reports were identified: one case of fatal hepatitis, published in 2001, and one case of acute hepatitis, published in 1997. These were both in French, with no abstracts available.