Doctor leaflet Art50-DL-March2012-01 ART 50 Capsules 1. NAME OF THE MEDICINAL PRODUCT Art 50 mg, capsule. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule of ART 50 contains Diacerein 50 mg. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Capsule. 4. CLINICAL PARTICULARS 4.1. Therapeutic Indications Symptomatic treatment of functional symptoms and signs of osteoarthritis. Note: action onset is deferred: a period of 30 to 45 days precedes analgesic effect onset. Treatment may therefore have to be initiated with standard immediate action onset analgesics/antiinflammatories. 4.2. Posology and Method of Administration ADULTS( aged over 15 years). Oral route. The capsules should be swallowed whole, without chewing, with a glass of water, preferably during a meal. The recommended dosage is 2 capsules daily, 1 in the morning, 1 in the evening. In elderly subjects or those suffering from moderate liver or kidney failure, there is no need to adjust the dosage. In patients suffering from severe kidney failure (creatinine clearance less than 30ml/min), the daily dosage should be halved. 4.3. Contraindications This medicinal product is contraindicated in case of: Inflammatory organic bowel disease (ulcerative colitis, Crohn s disease) Intestinal obstruction or partial obstruction Abdominal pain syndromes of indeterminate etiology Known allergy to rhein and substances with similar activity Hypersensitivity to one of the excipients Severe liver failure 1
4.4. Special warnings and precautions for use ART 50 mg, capsule must not be administered to children under the age of 15 years. This medicinal product should not be taken during pregnancy or lactation. Taking into account frequency of diarrhoea, beware of dehydration risk, especially for elderly and/or for subjects receiving ACE inhibitors or diuretics, due to an increase of salt and water depletion risk. Treatment with Art 50 mg, hard capsule should be stopped in case of symptoms suggesting a hepatic disorder. Due to the presence of lactose, this medicinal product must not be administered in the event of congenital galactosemia, glucose or galactose malabsorption syndrome or lactase deficiency. 4.5. Interactions with other medicinal products and other forms of interactions Association involving precautions for use + Antacids (aluminum, calcium, and magnesium salts, oxides or hydroxides): Decreased of digestive absorption of diacerein. Antacids should be taken separately from diacerein, allowing for an interval of greater than 2 hours if possible. 4.6. Pregnancy and lactation Pregnancy Animal studies have shown retarded foetal ossification due to a maternotoxic effect at high doses. In clinical practice, no sufficiently pertinent data are currently available for evaluation of a potential malformative or fetotoxic effect of diacerein administered during pregnancy. Therefore, the use of this medicinal product during pregnancy is not advised. Lactation This product should not be administered to lactating women, minimal excretion of anthraquinone derivatives in breast milk has been reported in the literature. 4.7. Effects on ability to drive and use machines 4.8. Undesirable effects Gastrointestinal effects: The most frequently reported adverse effects were diarrhoea, soft stools, abdominal pain. Pigmentation of the colorectal mucosa (colonic melanosis) has been rarely observed. Urine dark coloration related to the molecule structure and without pathological account may be noticed. Cutaneous effects: Cases of pruritus, rash, and eczema have been reported. 2
Hepatobiliary affections: Cases of hepatic disorder, especially cytolytic (see chapter 4.4) have been reported since marketing of the medicinal product. 4.9. Overdose Profuse diarrhoea may occur in the event of overdose. Symptomatic treatment should then be instituted and electrolyte disorders and dehydration corrected if necessary. 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties ANTI-ARTHROSIQUE (M: MUSCLE AND SKELETON) Diacerein is an anthraquinone derivative which has moderate anti-inflammatory activity. It is anti-inflammatory at high doses and devoid of any irritant effect on the stomach. Action onset is slow, beginning towards day 30 of treatment and becoming significant after about 45 days. It has an additive effect in combination with NSAIDs. In vitro, diacerein has the following properties: inhibition of phagocytosis and macrophage migration inhibition of interleukin-1 synthesis reduction of collagenolytic activity In some models, diacerein stimulates production of proteoglycans, glycosaminoglycans and hyaluronic acid. A positive effect on cartilage has been demonstrated in a number of animal models. A multicentre, randomized, double-blind, placebo-controlled, three year study (ECHODIAH study) assessing the eefect of diacerein on the radiological Joint Space (JSW) has been conducted on 507 patients with an osteoarthritis of the hip. Patients received either 50 mg of deacerein (n=255) or placebo (n=252) twice a day, i.e. in the morning and in the evening. Main efficacy criteria were: percentage of the patients with a radiological impairment (radiological joint space width decreased more than 0.5 mm). Joint Space Narrowing (JSN) rate per year (mm/year). 269 patients copleted the trial. At 3 years, the Intend-To-Treat (ITT) analysis shows that: The percentage of patients with a radiological impairment of more than 0.5 mm is significantly lower with diacerein group compared to placebo (50.7% versus 60.4 for placebo, p=0.036). JSN rate (0.39 mm/year) is not statistically different between the 2 groups. Art50-DL-Dec2011-01 3
5.2. Pharmacokinetic properties Orally administered diacerein undergoes a hepatic first-pass effect and is totally deacetylated to the sulphoconjugated metabolite, rhein. After a single 50 mg dose, plasma diacerein concentrations peak arises at a mean 2.5 hours and the maximal concentration is of the order of 3 mg/l. ART 50 mg capsule intake with food increases the bioavailability (the area under the curve increases by nearly 25%) and delays absorption. The pharmacokinetic parameters of single doses of ART 50 mg, capsule ranging from 50 to 200 mg are dose-independent. Protein binding is very strong (99%) and mainly consists in high-affinity binding to albumin. The elimination half-life of rhein is approximately 4.5 hours. The total quantity excreted in the urine is around 30%. 80% of the rhein excreted in urine is in sulpho- and glucuroconjugated form and 20% is excreted in unchanged form. Repeated administration of ART 50 mg, capsule (50 mg twice daily) results in slight accumulation. In patients with severe kidney failure (creatinine clearance less than 30 ml/min), the area under the curve and elimination half-life are doubled and urinary elimination halved. Given the good clinical safety profile of the drug, doses do not need to be adjusted in elderly patients despite the slower elimination. 5.3. Preclinical safety data 6. PHARMACEUTICALS PARTICULARS 6.1. List of excipients Lactose monohydrate, magnesium stearate. Composition of empty capsule shell: titanium dioxide, indigotine, gelatin. 6.2. Incompatibilities 6.3. Shelf life 3 years. 6.4. Special precautions for storage Store at room temperature. 6.5. Nature and contents of container 30 capsules in heat-formed blister packs (PVC/aluminium). 6.6. Special precautions for disposal 4
7. REGISTRATION HOLDER: Rafa Laboratories Ltd, POB 405, Jerusalem 91003. Registration no: 1075328783 Manufacturer: Negma, France The format of this leaflet has been determined by the Ministry of Health and its content has been examined and approved by it in March 2012. 5