ART 50 mg Capsule B/30

Diacerein .................................................................................................................................................... 50 mg

For one capsule.

Excipient with known effect: lactose (240 mg).

Symptomatic slow-acting treatment of osteoarthritis of the hip and knee.

Treatment with diacerein is not recommended in patients with rapidly destructive coxarthrosis, as they are likely to show a weaker response to this medicine.

Treatment must be initiated by physicians experienced in the treatment of osteoarthritis.

Oral use.

FOR ADULTS ONLY (over 15 years).

Diacerein is not recommended in patients over 65 years of age.

As some patients may experience loose stools or diarrhoea, the recommended initial dose is 50 mg once a day at dinner during the first 2 to 4 weeks of treatment, then the recommended daily dose is 50 mg twice a day.

The treatment must be taken with food, one capsule at breakfast and the other capsule at dinner. The capsules must be swallowed whole, without opening them, with a glass of water.

In elderly patients, and in patients with moderate renal impairment, there is no need to modify the dosage.

In patients with severe renal impairment (creatinine clearance less than 30 ml/min), daily doses should be halved.

This medicine is contraindicated in cases of:

• organic inflammatory bowel disease (ulcerative colitis, Crohn's disease...),

• occlusive or sub-occlusive syndrome,

• abdominal pain syndromes of undetermined cause,

• hypersensitivity to rhein and to substances with similar activity,

• hypersensitivity to any of the excipients,

• current episode and/or history of liver disease.

Diarrhoea

Taking diacerein frequently causes diarrhoea (see section Adverse effects) which can lead to dehydration and hypokalaemia.

In case of diarrhoea, patients are advised to stop treatment with diacerein and contact their doctor in order to consider other therapeutic alternatives.

Patients treated with diuretics require particular precautions because of the risks of dehydration and hypokalaemia.

Patients treated with cardiac glycosides (digitoxin, digoxin) should also be the subject of particular precautions in case of hypokalaemia (see section Interactions).

Avoid concomitant use of laxatives.

Hepatotoxicity

Elevated serum liver enzyme levels and symptomatic acute liver injury have been observed with diacerein in the post-marketing period (see section Adverse effects).

Before initiating treatment with diacerein, the doctor must question the patient about possible comorbidities, ongoing liver diseases, and liver history, and screen for major causes of active liver damage. A diagnosis of liver disease is a contraindication to the use of diacerein (see section Contraindications).

Signs of liver damage must be monitored and diacerein must be used with caution in case of concomitant treatment with other medicines causing liver damage. Patients are advised to limit their alcohol consumption during treatment with diacerein.

Treatment with diacerein must be stopped in case of elevation of serum liver enzymes or suspected signs or symptoms of liver damage. Patients must be informed of the signs and symptoms of hepatotoxicity and that they must contact their doctor immediately if symptoms suggestive of liver damage appear.

Other warnings

ART 50 mg, capsule must not be administered to children under 15 years.

This medicine is not recommended during pregnancy and breastfeeding.

This medicine contains lactose. Its use is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases).

Associations requiring precautions for use

+ Gastrointestinal topicals (aluminium, calcium and magnesium salts, oxides and hydroxides)

Decreased digestive absorption of diacerein.

Take gastrointestinal topicals at a distance from diacerein (more than 2 hours, if possible).

+ Diuretics and/or cardiac glycosides

Taking diacerein may cause diarrhoea and hypokalaemia. Concomitant administration of diuretics (loop diuretics and thiazides) and/or cardiac glycosides (digitoxin, digoxin) requires particular precautions due to the increased risk of arrhythmia (see section Warnings and precautions).

Pregnancy

In animals, an experimental study showed delayed ossification in the foetus, due to a maternotoxic effect at high doses.

In clinical practice, there is currently no sufficiently relevant data to assess a possible teratogenic or foetotoxic effect of diacerein when administered during pregnancy.

Consequently, the use of this medicine is not recommended during pregnancy.

Breast-feeding

It is not recommended to administer this product to women during breastfeeding, as the passage of anthraquinone derivatives into breast milk in minimal proportions has been demonstrated in the literature.

Gastrointestinal effects:

• Very common (>1/10): diarrhoea, abdominal pain.

• Common (>1/100 and <1/10): frequent stools, flatulence.

As a general rule, these effects decrease during treatment. In some cases, diarrhoea is severe, with complications such as dehydration and disturbances of fluid and electrolyte balance.

Pigmentation of the recto-colonic mucosa (melanosis coli) has rarely been observed.

Hepato-biliary disorders:

• Rare (≥1/1000 and <1/100): cases of elevated serum liver enzymes.

Renal and urinary disorders :

• Frequency not known: chromaturia.

Skin and subcutaneous reactions:

• Common (>1/100 and <1/10): pruritus, rashes, eczema.

Data from post-marketing surveillance

Cases of acute liver injury, with elevated liver enzyme levels, have been reported in the post-marketing period with diacerein. Most cases occurred during the first months of treatment. Patients should be monitored to detect signs and symptoms of liver injury (see section Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

In case of overdose, profuse diarrhoea may occur. Symptomatic treatment will be instituted: correct fluid and electrolyte disturbances if necessary.

Pharmacotherapeutic class: ANTI-ARTHROSIS AGENT (M: MUSCULOSKELETAL SYSTEM).

Diacerein is an anthraquinone derivative that possesses moderate anti-inflammatory activity. It is anti-inflammatory at high doses, without irritant effect on the stomach.

Its action is slow and appears around the 30th day of treatment and is significant around the 45th day. The effect is additive when combined with NSAIDs.

In vitro, diacerein has shown the following properties:

• inhibition of phagocytosis and migration of macrophages,

• inhibition of the production of interleukin 1,

• a reduction of collagenolytic activity.

In certain models, diacerein stimulates the synthesis of proteoglycans, glycosaminoglycans and hyaluronic acid.

A favourable action on cartilage has been demonstrated in several animal models.

A multicentre, randomised, double-blind study (ECHODIAH study) aimed at evaluating the effect of diacerein on the progression of joint space narrowing was conducted over a period of 3 years in 507 patients suffering from coxarthrosis. It compared the morning and evening intake of 50 mg of diacerein (n=255) with that of a placebo (n=252).

Efficacy was assessed according to the two following main criteria:

• percentage of patients radiologically worsened (defined as a radiological decrease of more than 0,5 mm in the joint space).

• annual rate of joint space narrowing (mm/year).

269 patients completed the study.

At 3 years, according to the intention-to-treat analysis:

• the proportion of patients experiencing a radiological progression of more than 0,5 mm is significantly lower in the diacerein group than in the placebo group (50,7% versus 60,4%, p = 0,036);

• the annual rate of narrowing (0,39 mm/year) is not significantly different between the two groups.

The clinical significance of these results in terms of prognosis is not known.

• Diacerein, after oral administration, undergoes the hepatic first-pass effect and is completely deacetylated into rhein. The latter is sulfoconjugated.

• After absorption of a single dose of 50 mg of diacerein, the plasma peak occurs on average after 2,5 hours and the Cmax is of the order of 3 mg/L.

• Intake of ART 50 mg, capsule during a meal increases bioavailability (the area under the curve increases by nearly 25%) and absorption is delayed.

• For doses between 50 and 200 mg of ART 50 mg, capsule as a single intake, all pharmacokinetic parameters are independent of the dose.

• Protein binding is very high (99 %). It is essentially a high-affinity binding to albumin.

• The elimination half-life of rhein is approximately 4,5 hours. The total amount excreted in the urine is approximately 30%. Rhein is eliminated in the urine at 80 % as sulfo- and glucuro-conjugates and at 20 % in unchanged form.

• At repeated doses (50 mg x 2 per day), ART 50 mg, capsule shows low accumulation.

• In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the areas under the curve and the elimination half-life are doubled and urinary elimination is halved.

• In elderly subjects, given the good tolerability of the product, it is not necessary to modify the dose, despite the slower elimination.

3 years.

No special precautions for storage.

No special requirements.