Flecetin

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

Composition:

Active ingredient: diacerhein;

1 capsule contains 50 mg of diacerhein;

Excipients: lactose monohydrate, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Hard gelatin capsule: gelatin, indigocarmine (indigotine) (E 132), quinoline yellow (E 104), titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: hard gelatin capsules with a green cap and body. The capsule contents are yellow granular powder.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AX21.

Pharmacological Properties.

Pharmacodynamics.

Flecerin is a medicinal product for the treatment of osteoarthritis and osteoarthrosis, possessing analgesic, antipyretic, and anti-inflammatory properties. Diacerhein is classified as a slow-acting drug, whose effect appears within 2–4 weeks of treatment and reaches clinical significance after 4–6 weeks. It has a unique mechanism of action distinct from that of nonsteroidal anti-inflammatory drugs (NSAIDs). Diacerhein, 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 nonsteroidal anti-inflammatory drugs, diacerhein does not inhibit prostaglandin synthesis and therefore does not cause gastroduodenal adverse effects.

Pharmacokinetics.

Absorption of diacerhein is slowed when administered concomitantly with food. Diacerhein is completely converted into the active rhein metabolite via deacetylation prior to entering the systemic circulation. The bioavailability of the rhein metabolite ranges between 35–56%. 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.

When diacerhein is administered to elderly patients, no changes in its pharmacokinetic properties have been observed.

Clinical characteristics.

Indications.

Rheumatic joint diseases (osteoarthritides, osteoarthroses).

Contraindications.

• Hypersensitivity to the components of the medicinal product or to anthraquinone derivatives in medical history.
• Liver diseases, 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 types of interactions.

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

Concomitant administration 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 due to plasma protein binding between reumycin (active metabolite of diacerhein) and warfarin, paracetamol, salicylic acid, indometacin, ibuprofen, diclofenac, phenylbutazone, piroxicam, sulindac, tenoxicam, sodium valproate, phenytoin, tolbutamide, glibenclamide, or chlorpropamide have been observed.

Concomitant administration of diacerhein and an H2-histamine receptor blocker (cimetidine) does not lead to modification of pharmacokinetic parameters of reumycin 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 is required in patients taking diuretics due to the potential risk of dehydration and hypokalemia. Particular caution should also be exercised 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 laxative medicinal products should be avoided.

Hepatotoxicity. Use of diacerein may lead to 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 possible concomitant diseases, particularly liver disorders (current or in medical history), and appropriate examinations should be performed. Diagnosed liver disease is a contraindication for the use of diacerein (see section "Contraindications").

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

Treatment with diacerein should be discontinued if liver enzyme levels increase or signs of liver injury develop, including neurological symptoms. If symptoms of liver injury occur, immediate medical consultation is required.

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

Metabolites of diacerein may impart a color ranging from brown to red to the urine depending on pH; this color change is not clinically significant, 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 Flectorin is used for prolonged periods.

Flectorin capsules contain lactose. Patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

Use during pregnancy or breastfeeding.

Due to lack of data, Flectorin is contraindicated during pregnancy.

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

Ability to influence reaction speed when driving or operating machinery.

There are no reports on the effect of diacerein on the ability to drive or operate machinery.

Dosage and Administration

During the first 2–4 weeks of treatment, Flecserin should be administered to adults at a dose of 1 capsule (50 mg) once daily at night after a meal. Starting from the 2nd to 4th week 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, each taken after a meal).

The medication should be used for a prolonged period (at least 6 months). The total duration of treatment is determined individually by the physician.

Elderly Patients

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

No significant changes in pharmacokinetic parameters have been observed when diacerhein is administered to elderly patients; therefore, no dosage adjustment is required (see section "Pharmacological Properties"). Nevertheless, caution should be exercised. If diarrhea occurs, treatment with diacerhein should be discontinued.

Patients with Chronic Renal Impairment

The pharmacokinetics of diacerhein may be altered in patients with renal impairment. In such cases, the dose should be reduced to 1 capsule per day (creatinine clearance < 30 mL/min).

Children

The efficacy and safety of the medication in children have not been established; therefore, diacerhein is contraindicated in this age group.

Overdose

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

Adverse Reactions

The drug is generally well tolerated; however, gastrointestinal disturbances such as frequent defecation, soft stools, flatulence, diarrhea, and abdominal pain may occasionally occur. These symptoms usually resolve 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 reported, which are not of clinical significance. Unlike other nonsteroidal anti-inflammatory drugs, diacerein does not have ulcerogenic effects on the gastrointestinal tract.

Adverse reactions are listed according to MedDRA terminology, classified by system organ classes and absolute frequency. Frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated based on available data).

Gastrointestinal disorders:
Very common — diarrhea, abdominal pain;
Common — frequent defecation, flatulence;
Rare — pigmentation of the intestinal mucosa (pseudomelanosis).

Hepatobiliary disorders:
Uncommon — increased levels of liver enzymes in blood serum.

Renal and urinary disorders:
Very common — change in urine color.

Skin and subcutaneous tissue disorders:
Common — pruritus, rash, eczema.

General disorders:
Frequency not known — headache.

Disorders of the hepatobiliary system have been reported.

Cases of acute liver injury, including elevated liver enzymes in blood serum and hepatitis, have been observed during diacerein treatment. Most cases occurred within the first months of treatment. Patients should monitor for symptoms of liver injury (see section "Special Warnings and Precautions for Use").

Reporting of Adverse Reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

PJSC "KYIV VITAMIN PLANT"

Manufacturer's address and location of its business activities.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua