Each capsule of ARTRODAR contains diacerein 50 mg, lactose monohydrate, croscarmellose sodium, povidone, colloidal silicon dioxide, magnesium stearate.
Pharmacology: Pharmacodynamics: It is now well accepted that the cytokine interleukin-1β (IL-1β) plays a crucial role in triggering the cascade of cartilage degrading events by inducing the production of catabolic factors such as TNF-α, matrix metalloproteinases (MMPs) and nitric oxide (NO). In OA, excessive IL-1β production and activity can enhance catabolic and anti-anabolic processes, resulting in a reduction in cartilage synthesis, an increase in cartilage degradation and subchondral bone remodeling. IL-1β also indirectly stimulates chondrocyte and synoviocyte apoptosis and plays a key role in inflammation, both of which contribute to the loss of cartilage. In addition, by acting in an autocrine or paracrine manner within cartilage, IL-1β can stimulate its own production and thus perpetuate cartilage damage. Blocking IL-1β or its activity has been shown to be effective in preventing cartilage destruction.
In vitro studies show that diacerein and rhein, the active moiety, inhibit the production and activity of the pro-inflammatory and pro-catabolic cytokine IL-1β both in the superficial and deep layers of the cartilage and in the synovial membrane from OA patients.
Diacerein and rhein reduced IL-1β-induced MMP levels and NO by chondrocytes. They also reduced the synthetic activities of OA osteoblasts which could be responsible for the abnormal subchondral bone remodeling occurring during the course of OA. In addition, Boileau et al. (2008) showed that diacerein and rhein reduced, in a dose-dependent manner, IL-1β-induced MMP-13 production in OA subchondral bone. In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K. Moreover, these drugs effectively blocked the IL-1β effect on the osteoclast differentiation process and the survival of mature osteoclasts. Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.
ARTRODAR has a unique mode of action and influences both the anabolism and catabolism of chondrocytes by down-regulating the production of pro-inflammatory cytokines, and thus inflammation and cartilage degradation, while stimulating cartilage repair.
Anti-catabolic effects: By inhibiting IL-1β production and activity at pre- and post-cell membrane levels, ARTRODAR down-regulates IL-1β-induced cartilage degrading events such as the production of pro-catabolic cytokines e.g. TNF-α, MMPs, NO, and other proteases which cause cartilage degradation and also counteracts NO-mediated down-regulation of cartilage repair process.
Anti-inflammatory effects: By inhibiting IL-1β, ARTRODAR acts at an earlier stage in the inflammatory cascade than non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, down-regulating the key mediators responsible for the propagation and exacerbation of inflammation in OA and leading to a reduction in the pain experienced in OA. As ARTRODAR does not negatively affect the arachidonic acid cascade and the synthesis of prostaglandins, unlike NSAIDs, it does not cause gastric damage, cardiovascular side effects, or renal problems. Studies have shown that ARTRODAR does not have a negative effect on the gastric mucosa and may have a gastroprotective effect when taken with an NSAID.
Pro-anabolic effects: ARTRODAR also has pro-anabolic properties. It has been shown to stimulate production of cartilage growth factors such as transforming growth factor-β (TGF-β), even in the presence of IL-1β. This stimulates chondrocyte proliferation, consequently increasing the synthesis of cartilage components such as hyaluronan, collagen and proteoglycans leading to cartilage repair. TGF-β is also an inhibitor of several IL-1β-induced catabolic processes. In addition, TGF-β stimulates the production of tissue inhibitor of metalloproteinases (TIMP), thus inhibiting MMP activity.
In clinical trials, ARTRODAR significantly improved OA symptoms such as pain, joint dysfunction and inflammation. The effect was comparable to that obtained with NSAIDs but with better safety profile. The results from a study in a Thai population found that 90% of patients treated with ARTRODAR reported high satisfaction with treatment, and pain showed a decrease of 70% compared to baseline after 16 weeks of treatment. The beneficial effects of ARTRODAR are observed after 2-4 weeks of treatment, with significant improvements appearing after about 4-6 weeks of treatment, and are still present for at least 2-3 months after treatment has stopped (carry-over effect).
ARTRODAR also has shown disease-modifying properties in animal models and in a clinical study in patients with hip osteoarthritis. Daily treatment with ARTRODAR for 3 years significantly reduced radiographic progression of OA with a cartilage sparing effect of 32% compared with placebo. Moreover, the results from this long-term study showed that requirement for total hip replacement during the study and during the 3 months following treatment discontinuation was lower in the ARTRODAR group (14.5%) compared with the placebo group (19.8%). It also had a good safety profile during this continuous, 3-year treatment period.
Pharmacokinetics: After oral administration of ARTRODAR, diacerein is rapidly converted to rhein, the active moiety. Clinical pharmacokinetics studies carried out in healthy adults (40 to 60 years) and elderly volunteers (over 60 years of age), showed that peak levels of rhein were reached 2.6 hours after multiple oral dose administration of 50 mg diacerein twice a day with an elimination half-life of 7 to 8 hours. Therefore, no change in the usual recommended dose is necessary in elderly patients. In patients with severe renal insufficiency, a significant increase in the elimination half-life, AUC and renal clearance were observed. A dose reduction is recommended in these patients. No changes in plasmatic or urinary parameters of diacerein were observed in patients with compensated or decompensated mild or moderate hepatic insufficiency and no changes in the posology are required in these cases. However, ARTRODAR is contraindicated in patients with severe liver disease.
Treatment of degenerative joint diseases (osteoarthritis and related diseases). Relief or improvement of osteoarthritis (OA) symptoms such as pain, inflammation and joint impairment. Long term treatment with ARTRODAR can slow down disease progression and preserve articular cartilage. It can be recommended as an alternative medication for patients who do not respond to other OA treatments and/or patients who present contraindications to joint replacement/surgery, NSAIDs and those with cardiovascular problems in whom NSAIDs are contraindicated.
The usual dosage regimen for ARTRODAR is one capsule taken orally once or twice a day (depending on the disease severity and the patient's body weight) with the main meals for prolonged periods (at least 3 months). However, as diacerein may cause an acceleration of intestinal transit time resulting in loose stools and/or diarrhea in some patients at the start of treatment, it is recommended that treatment be started with one capsule per day taken orally with the main meal for 2-4 weeks. Any loose stools and/or diarrhea will abate on continuing treatment. Once the patient has become accustomed to the medication, the dose should be increased to 2 capsules per day (1 capsule two times a day), taken orally with meals.
Duration of treatment should be considered depending on expected outcome. For symptomatic treatment, ARTRODAR should be taken continuously for at least 3 months and treatment can be repeated when symptoms reappear. Clinical data have demonstrated that the beneficial symptomatic effects persisted for at least 3 months after a 3-month treatment period. Long term treatment is recommended for preservation of articular cartilage and to delay disease progression.
However, due to its late onset of action (after 2-4 weeks of treatment) in terms of pain relief, ARTRODAR may be co-prescribed with a non-steroidal anti-inflammatory drug or analgesics for the first 2-4 weeks of treatment.
The accidental or voluntary ingestion of high doses of diacerein could produce diarrhea. No specific antidotes exist. If diarrhea persists, please see the doctor. Emergency treatment consists of restoring the hydroelectrolytic balance if necessary.
Diacerein should not be administered to patients with known hypersensitivity to the drug itself or to those with previous episodes of hypersensitivity to anthraquinone derivatives. Temporary treatment suspension must be considered in case of antibiotic therapy, which may affect intestinal flora and kinetics. As diacerein may cause acceleration in intestinal transit time in some patients in the early period of treatment, it should be used with caution in those with previous episodes of enterocolic disturbances such as irritable colon. ARTRODAR is contraindicated in patients with inflammatory intestinal disease (e.g. ulcerative colitis, Crohn's disease), intestinal obstruction or pseudo-obstruction, painful abdominal syndromes of undetermined cause and severe liver disease.
Pregnancy and lactation: Although animal studies did not reveal any toxic effects on fertility or fetal development (Pregnancy category B), ARTRODAR should not be administered during pregnancy. In addition, ARTRODAR should not be prescribed to lactating women due to reports that small amounts of diacerein derivatives pass into the maternal milk.
ARTRODAR should not be prescribed to children below 18 years old as no clinical studies have been undertaken in this age group.
Effects on ability to drive and use machines: No sedative effect, which may affect the ability to handle machines, is known for diacerein.
Severe renal insufficiency modifies the pharmacokinetics of diacerein and therefore a dose reduction is recommended in such cases (creatinine clearance <30 ml/min). In patients with moderate renal insufficiency (creatinine clearance 30-49 ml/min), no change in the usual recommended dose is necessary. When diacerein is taken with food, there is an increase (about 24%) in its absorption; on the other hand, severe nutritional deficiencies decrease the bioavailability of diacerein.
Intake of ARTRODAR may lead to loose stool and/or diarrhea at the start of treatment, however, these symptoms would disappear spontaneously with continuing treatment. Taking ARTRODAR with meals and starting treatment with 1 capsule/day can decrease these symptoms. However, if the patient still has unusually frequent liquid or watery stools, which could lead to dehydration and hypokalemia, treatment should be stopped and the patient should consult his/her physician. During the first 2-4 weeks of treatment, caution should be exercised in patients receiving diuretics, because dehydration and hypokalemia may occur. Particular caution should also be exercised in case of hypokalemia in patients treated with cardiac glycosides (digitoxin, digoxin).
Laxatives should not be taken concomitantly with ARTRODAR especially during the first 2-4 weeks of treatment.
Before treatment with ARTRODAR is initiated, the patient should be questioned about possible comorbid conditions and past or concurrent liver disease and screened for major causes of active hepatic disease. A diagnosis of severe liver disease is a contraindication to diacerein use. Signs of hepatic injury should be monitored and caution should be exercised when diacerein is used concomitantly with other medicinal products associated with hepatic injury.
Patients should be advised to limit their alcohol intake while on treatment with ARTRODAR. Treatment should be discontinued if symptoms suggestive of liver damage arise (abdominal pain, jaundice, pruritus, and increases in liver enzyme).
Use with caution in patients aged 65 years and above, or in patients with liver disease or history of liver disease.
Although animal studies did not reveal any toxic effects on fertility or fetal development (Pregnancy category B), ARTRODAR should not be administered during pregnancy. In addition, ARTRODAR should not be prescribed to lactating women due to reports that small amounts of diacerein derivatives pass into the maternal milk.
Diarrhea, abdominal pain, frequent bowel movements and flatulence are the most frequently reported side effects associated with ARTRODAR treatment. As a rule, these effects abate with continuing treatment. In some cases, diarrhea was severe with complications such as dehydration and disorders of fluid and electrolyte balance. However, results from a clinical study showed that starting treatment with one capsule per day with meals for the first 4 weeks can decrease the undesirable effects of accelerated intestinal transit time.
The intake of ARTRODAR may sometimes result in a more intense yellow coloring of the urine. This is typical of the type of compound (anthraquinone) and is of no clinical significance. Thus, it is recommended to drink a lot of water which will decrease the intensity of urine discoloration.
Based on pharmacovigilance data, a few cases of liver disorders such as elevated serum liver enzymes including hepatitis have been reported. Most of them occurred during the first months of treatment. Although the incidence is very rare, patients should be monitored for signs and symptoms of hepatic injury.
Cutaneous effects: some cases of pruritus, rash and eczema have been reported.
Diacerein must not be administered at the same time as drugs that modify intestinal transit and/or the quality of the intestinal content (e.g. excess fibers or phytates) especially during the first 2-4 weeks of treatment. In case of concomitant use of magnesium, aluminium or calcium-based antacids, there should be a minimum time interval of 2 hours between the intake of any of these preparations and ARTRODAR, in order to maximize the bioavailability of diacerein. Treatment with diacerein may cause an increase in enterocolic events in patients undergoing treatment with some antibiotics such as amoxicillin/clavulanic acid and/or chemotherapy which could affect the intestinal flora. During the first 2-4 weeks of treatment, intake of diacerein can in some cases lead to severe diarrhea and hypokalemia. Caution must be exercised in the concomitant administration of diuretics (high-ceiling loop and thiazides) and/or cardiac glycosides (digitoxin, digoxin), as the risk of arrhythmia is increased.
Store at room temperature (15 to 25°C).
M01AX21 - diacerein ; Belongs to the class of other non-steroidal antiinflammatory and antirheumatic products.