Orcerin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ORCERIN (ORCERIN)

Composition:

Active substance: diacerein;

1 capsule contains 50 mg of diacerein;

Excipients: cyclodextrins, sodium lauryl sulfate, lactose monohydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Capsule shell composition: diamond blue (E 133), ponceau 4R (E 124), quinoline yellow (E 104), titanium dioxide (E 171), sodium lauryl sulfate, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules size №1 with a blue body and dark blue cap, containing light yellow powder.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX21.

Pharmacological properties.

Pharmacodynamics.

Diacerein is a medicinal agent for the treatment of osteoarthritis that possesses analgesic, antipyretic, and anti-inflammatory properties. Diacerein is classified as a slow-acting drug, with its effect becoming apparent within 2–4 weeks of treatment and reaching clinical significance after 4–6 weeks. It has a unique mechanism of action distinct from that of nonsteroidal anti-inflammatory drugs (NSAIDs). Diacerein, as well as its active metabolite rhein, inhibits the synthesis and activity of interleukin-1 (IL-1), which plays a key role in the pathogenesis of osteoarthritis, while simultaneously increasing the production of transforming growth factor beta (TGF-β), which initiates chondrocyte proliferation and stimulates the production of type II collagen, proteoglycans, and hyaluronic acid.

Unlike NSAIDs, diacerein does not inhibit prostaglandin synthesis and therefore lacks gastro-duodenal adverse effects.

Pharmacokinetics.

Absorption of diacerein is slowed when taken concomitantly with food, which is also associated with a 25% increase in the amount of absorbed substance. On the other hand, the occurrence of adverse effects, such as prolonged intestinal transit time, is directly related to the amount of unabsorbed diacerein; therefore, administration on an empty stomach increases the risk of adverse effects. Diacerein is completely converted into the rhein metabolite via deacetylation before entering the systemic circulation. The bioavailability of the rhein metabolite ranges from 35% to 56%. The volume of distribution is approximately 13.2 L. The rhein metabolite is almost 99% bound to plasma proteins, although this binding is not stable. The rhein metabolite is either excreted unchanged by the kidneys (20%), or conjugated in the liver to rhein-glucuronide (60%) or rhein-sulfate (20%), both of which are also excreted in urine. The elimination half-life is approximately 7–8 hours.

No changes in the pharmacokinetic properties of diacerein have been observed in elderly patients.

Clinical characteristics.

Indications.

Treatment of patients with symptoms of hip or knee osteoarthritis, with delayed effect.

Diacerhein treatment is not recommended for patients with rapidly progressive osteoarthritis of the hip joint, as they may have a poor response to diacerhein.

Contraindications.

• Hypersensitivity to the components of the drug or to anthraquinone derivatives in medical history.
• Liver diseases, either present or in medical history.
• Inflammatory bowel diseases (ulcerative colitis, Crohn's disease).
• Intestinal obstruction or pseudo-obstruction.
• Abdominal pain of undetermined origin.
• Pregnancy or breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Diacerhein intake may lead to diarrhea and hypokalemia. When diacerhein is used concomitantly with diuretics (loop and/or thiazide diuretics) and/or cardiac glycosides (digoxin, digitoxin), the risk of developing arrhythmias increases.

Simultaneous intake with antacids (aluminum, calcium and magnesium salts such as oxides and hydroxides) significantly reduces the absorption of diacerhein from the gastrointestinal tract. Therefore, an interval of 1–2 hours should be maintained between the intake of antacids and diacerhein.

No interactions were observed regarding plasma protein binding of rhein (active metabolite of diacerhein) with warfarin, paracetamol, salicylic acid, indometacin, ibuprofen, diclofenac, phenylbutazone, piroxicam, sulindac, tenoxicam, sodium valproate, phenytoin, tolbutamide, glipizide, or chlorpromamide.

Concomitant administration of diacerhein and an H2-histamine receptor blocker (cimetidine) does not lead to modification of pharmacokinetic parameters of rhein in plasma and urine.

Special precautions for use.

Diarrhea. Prolonged use of diacerein may lead to diarrhea, which can cause dehydration and hypokalemia. If diarrhea occurs, treatment with diacerein should be discontinued and a physician should be consulted regarding alternative treatment options.

Caution should be exercised in patients taking diuretics due to the potential risk of dehydration and hypokalemia. Particular caution is also required in patients with hypokalemia who are receiving cardiac glycosides (digoxin, digitoxin) (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with laxatives should be avoided.

Hepatotoxicity. Use of diacerein may result in increased levels of liver enzymes in blood serum and symptomatic acute liver injury (see section "Undesirable effects").

Prior to initiating treatment with diacerein, patients should be questioned about concomitant diseases, particularly liver disorders (current or in medical history), and appropriate examinations should be performed. Diagnosed liver disease is a contraindication to the use of diacerein (see section "Contraindications").

Monitoring for signs of liver damage is necessary during the first 2 months of treatment. Caution should also be exercised when diacerein is used concomitantly with other medicinal products associated with potential liver injury. Patients should be advised to limit alcohol consumption during treatment with diacerein.

Treatment with diacerein should be discontinued if liver enzyme levels rise or if signs of liver injury develop, including neurological symptoms. In case of symptoms indicating liver injury, immediate medical consultation is required.

Due to the delayed onset of action (after 2–4 weeks), during the first month of treatment with diacerein, concomitant use of nonsteroidal anti-inflammatory drugs and analgesics may be considered.

Metabolites of diacerein may impart a color to urine ranging from brown to red, depending on pH; this color change has no clinical significance but may interfere with diagnostic tests based on colorimetry (e.g. glucose urine test strips).

Since urine discoloration may mask microhematuria, regular laboratory assessment of renal function, including urine sediment analysis, should be performed, especially if Oracerin is used for prolonged periods.

Oracerin capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Oracerin.

Use during pregnancy or breastfeeding.

Due to lack of data, use of Oracerin during pregnancy is contraindicated.

Diacerein should not be used in women who are breastfeeding, as small amounts of the drug have been detected in breast milk.

Ability to affect reaction speed when driving or operating machinery.

There are no reports indicating that diacerein affects the ability to drive or operate machinery.

Method of administration and dosage.

Treatment should only be initiated by physicians experienced in the management of osteoarthritis.

During the first 2–4 weeks of treatment, adults should take 1 capsule (50 mg) once daily with the evening meal, taken with water. From week 2 to 4 of treatment, the dose should be increased to 100 mg per day in two divided doses (1 capsule in the morning and 1 capsule in the evening, taken with meals). Diacerhein has a slow onset of action with a delayed initial effect and a residual effect after discontinuation of treatment; therefore, Oracerin should be administered for at least 2–4 weeks before the first positive effect becomes apparent. The beneficial symptomatic effect persists for up to 3 months after the end of treatment. Considering the chronic nature of the disease, a prolonged course of treatment—at least 3 months—is recommended, which may be repeated if symptoms reappear.

The duration of treatment should be individually determined by the physician.

Elderly patients.

Diacerhein is not recommended for patients aged 65 years and older due to increased susceptibility of this population to complications associated with diarrhea.

No significant changes in pharmacokinetic parameters have been observed when diacerhein is administered to elderly patients; therefore, there is no need to adjust the recommended dose (see section "Pharmacological properties"). However, caution is required when prescribing Oracerin to elderly patients. If diarrhea occurs, treatment with diacerhein should be discontinued.

Patients with chronic renal impairment.

Patients with mild to moderate renal impairment do not require dose adjustment. However, in patients with severe renal impairment (creatinine clearance < 30 mL/min), the daily dose should be reduced by 50% of the recommended dose (corresponding to 50 mg per day).

Children.

The safety and efficacy of the drug in children under 18 years of age have not been established.

Overdose.

In cases of accidental or intentional ingestion of large doses of diacerhein, diarrhea may occur. There is no specific antidote. Immediate treatment consists of restoring electrolyte balance.

Adverse Reactions

The drug is usually well tolerated; however, gastrointestinal disturbances such as frequent defecation, soft stools, flatulence, diarrhea, and abdominal pain may occasionally occur. These symptoms usually diminish with continued treatment. In some cases, prolonged diarrhea may lead to complications such as dehydration and disturbances in water-electrolyte balance.

Changes in urine color have also been observed, which are clinically insignificant. Unlike nonsteroidal anti-inflammatory drugs, diacerhein does not have ulcerogenic effects on the gastrointestinal tract.

Gastrointestinal system: Very common – diarrhea, abdominal pain; common – frequent defecation, flatulence; rare – pigmentation of the intestinal mucosa (pseudomelanosis).

Hepatobiliary system: Uncommon – cases of increased levels of liver enzymes in blood serum.

Renal and urinary system: Very common – change in urine color.

Skin and subcutaneous tissue: Common – pruritus, rash, eczema.

General disorders: Unknown frequency – headache.

There is data regarding disorders of the hepatobiliary system.

Cases of acute liver injury, including increased levels of liver enzymes in blood serum and hepatitis, have been reported during diacerhein use. Most of these cases occurred within the first months of treatment. Patients should monitor for symptoms of liver injury (see section "Dosage and Administration").

Shelf life.

3 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister pack; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

MACLEOD'S PHARMACEUTICALS LIMITED.

Manufacturer's address and place of business.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.