Osteorin

Rx                 OSTEORIN

COMPOSITION:

OSTEORIN 1 TAB

Each Capsule contains:

Diacerein       50mg

DESCRIPTION:

Osteoarthritis is one of the most common arthritic disorders with a global prevalence of 60% in men & 70% in women beyond the age of 65 years. The current treatment of OA involves symptomatic relief of pain using non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors. However, these drugs do not inhibit the progression of disease, and their prolonged use, especially in elderly, may lead to major gastrointestinal, renal and cardiovascular adverse events.

Diacerein, a semisynthetic anthrquinone derivative extracted from certain plants belongs to a new class of anti-osteoarthritis drugs, known as disease modifying osteoarthritis drug (DMOAD). It inhibits interleukin-1 (IL-1), an important cytokine implicated in Osteoarthritis. Diacerein has beneficial effects on the anabolic processes that occur in the cartilage. It increases the production of transforming growth factor- β (TGF-β) that triggers chondrocytes proliferation and stimulates the production of collagen, proteoglycans and hyluronan. Furthermore, since Diacerein does not inhibit prostaglandin synthesis, it has better safety profile compared to NSAIDs.

Several randomized controlled trials have demonstrated beneficial role of Diacerein in knee & hip OA, with pain relieving action starting around 4 weeks of therapy and persisting for 1-2 months after discontinuation.

PHARMACOLOGY:

PHARMACODYNAMICS:

Osteoarthritis is a multifactorial disease characterized by a progressive degradation of articular cartilage. Articular cartilage is an avascular tissue in which the chondrocytes are embedded in an abundant extracellular matrix, composed mainly of type II collagen and glycoproteins. The integrity of the tissue structure is maintained by a balanced control between anabolic and catabolic processes, which is regulated by ambient growth factors and cytokines. Numerous studies have demonstrated the key role of IL-1 in the osteoarthritis process. Several cells including macrophages, synovial cells and chondrocytes in articular joint tissues produce IL-1. This cytokine contributes to the degeneration of articular cartilage by stimulating the cells to produce proteolytic enzymes and by decreasing the anabolism of chondrocytes. Diacerein, specially its active diacetyl derivative rhein, cause inhibition of interleukin-1 and protease activity, phagocytosis and macrophage migration. It does not affect prostaglandin synthesis in macrophages and neither stimulates its synthesis in chondrocytes. Diacerein is known to exert chondroprotective effects in cultured articular cartilage and reduce the severity of cartilage, bone, and synovial membrane damage in OA. It also inhibits superoxide production, chemotaxis and phagocytic activity of neutrophils in addition to effect on macrophage migration and phagocytosis. In contrast to NSAIDS, Diacerein does not block the synthesis of prostaglandins, thromboxanes, or leukotrienes but may actually stimulate prostaglandin synthesis, especially PGF-2 alpha, a prostaglandin with cytoprotective effect on the gastric mucosa and thus is devoid of gastrointestinal toxicity. Diacerein does not alter renal or platelet cyclo-oxygenase activity and may therefore be tolerated by patients with prostaglandin-dependent renal function.

Anabolic effects of Diacerein

Diacerein has beneficial effects on the anabolic processes that occur in the cartilage. It increases the production of transforming growth factor-β (TGF-β) that triggers chondrocytes proliferation and stimulates the production of collagen II, proteoglycans, hyaluronan proteoglycans and hyaluronan.

PHARMACOKINETICS:

Absorption:

 Diacerein is entirely converted into rhein before reaching the systemic circulation. Apparent bioavailability of rhein is 35%-56%. The steady state is reached by the third administration and the mean elimination half-life is around 7-8 hours. Taking Diacerein with a standard meal delays systemic absorption, but is associated with a 25% increase in the amount absorbed. After oral administration, the peak plasma concentration (Cmax) of 3.2mg/L is reached after 2.2 hours.

Distribution:

The volume of distribution (Vd) after oral administration of single dose of Diacerein 50 mg in 12 healthy volunteers was 13.2L. Rhein is highly bound to plasma proteins i.e. 99%, but this binding is not saturable so that no drug interactions are likely to occur, in contrast to those widely reported with nonsteroidal anti-inflammatory drugs.

Metabolism and Excretion:

Oral Diacerein undergoes complete deacetylation to its active metabolite rhein before reaching the systemic circulation. Rhein is either eliminated by renal route (20%) or conjugated in liver to rhein glucuronide (60%) and rhein sulphate (20%); these metabolites are mainly eliminated by kidney. After administration of a single oral dose of Diacerein 50 mg, terminal elimination half-life (t1/2) is 4.3 hours, apparent total plasma clearance is 1.6L/h and renal clearance (CLR) is 0.13L/h.

Indications:

Diacerein is indicated for the treatment of symptomatic relief in long-term treatment of both major forms of osteoarthritis: coxarthrosis and gonarthrosis

CONTRAINDICATIONS:

It is contraindicated in patients with hypersensitivity to Diacerein and anthraquinone derivatives. Temporary treatment suspension must be considered in case of antibiotic therapy, which may affect intestinal flora and kinetics.

WARNING AND PRECAUTIONS:

A reduction (50%) in the initial dosage of Diacerein should be considered in severe renal failure as renal insufficiency modifies the pharmacokinetics of Diacerein and therefore a dose reduction is recommended in such cases (creatinine clearance<30 ml/min).

Mild to severe liver cirrhosis does not change the kinetics of Diacerein. The pharmacokinetics of Diacerein following a single oral dose of 50 mg were studies in 10 patients with a mild liver cirrhosis (child Pugh’s grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh’s grade B to C). It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of Diacerein need be proposed in liver cirrhosis.

When Diacerein is taken with food, there is an increase (about 25%) in its absorption; on the other hand, severe nutritional deficiencies decrease the bioavailability of Diacerein. As the incidence of collateral effects, such as accelerated intestinal transit time, is directly proportional to the amount of unabsorbed Diacerein, the intake of the product in a fasting state or after very small amounts of food cause an increase of collateral effects. Laxatives should not be taken with Diacerein.

Pediatric Use: Diacerein should not be prescribed to children below 15 years age as no clinical studies have been undertaken in this age-group. Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: The pharmacokinetics of Diacerein is about the same in young healthy volunteers and elderly people with normal renal function, both after a single (50 mg) or repeated doses (25-75 mg twice daily). Elderly patients with congestive heart failure, with or without hepatic failure, had similar plasma rhein concentrations (after administration of Diacerein 50 mg twice daily for 5 days) to otherwise healthy elderly patients with osteoarthritis. AUC values of Diacerein are age-dependently increased by 40 to 50% in elderly patients (>60 years).

USE IN PREGNANCY AND LACTATION:

Diacerein should not be administered during pregnancy and lactation.

DRUG INTERACTIONS:

Diacerein must not be administered at the same time with drugs that modify intestinal transit and /or the quality of the intestinal content (e.g. excess fibers or phylates). The concomitant administration of products containing aluminum hydroxide and/or magnesium hydroxide antacids should be avoided in order to maximize the bioavailability of Diacerein. Treatment with Diacerein may cause and increase in enterocolic events in patients undergoing antibiotic and/or chemotherapy, which could affect the intestinal flora.

                  

ADVERSE EFFECTS:

·         Diarrhea.

·         Stomach pain

·         Nausea

·         Vomiting

·         Intense yellow coloring of urine.

·         Epigastric pain

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DOSAGE AND ADMINISTRATION:

The usual recommended dose is one capsule (50 mg) orally twice a day with the main meals for prolonged periods. However, as Diacerein may cause acceleration in intestinal transit time during the first 2 weeks of treatment. It is recommended that treatment be started with one capsule per day taken orally with the evening meal for 4 weeks. Once the patient has become accustomed to the medication, the dose should be increased to 2 capsules (100 mg) per day, taken orally with meals. The doctor should decide the duration of treatment as a function of outcome. As with prolonged treatment with any other medication, a complete blood test, including liver enzymes, and urinalysis should be conducted every 6 months. Due to its late onset of action (after 2-4 weeks of treatment) and its gastroduodenal tolerability, Diacerein may be associated with a non-steroidal anti-inflammatory drug or analgesic for the first 2-4 weeks of treatment.

SAFETY PROFILE:

Drug watch data and clinical trials have confirmed the safety and tolerability of Diacerein. So there is no limitation on the duration of its use. The optimal daily dose which relief symptoms in osteoarthritis knee calculated from effect on VAS assessment criteria of pain on movement was found to be 100mg/day. Diacerein is well tolerated, the predominant adverse effect include transient change in bowel habits. It seems neither responsible for gastrointestinal bleeding nor for renal, liver nor hematological toxicities. Non significant discoloration of urine occurs during treatment because of urinary elimination of metabolites of Diacerein.

No allergic cutaneous reactions were reported in knee osteoarthritis trial. In 3 year hip osteoarthritis trial, rash or pruritis was noted in 3% patients on placebo and in 7% patients on Diacerein100mg daily. No severe allergic reaction has been reported till date.

STORAGE:
Store in a cool dry place, protect from light.

COMMERCIAL PACKAGING:

OSTEORIN is available in a strip of 10 Capsules