Actasulid (Tablets) Instructions for Use

Marketing Authorization Holder

Zdravlje-Leskovac Pharmaceutical and Chemical Industry (Serbia and Montenegro)

ATC Code

M01AX17 (Nimesulide)

Active Substance

Nimesulide (Rec.INN registered by WHO)

Dosage Form

Actasulid

Tablets 100 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, flat, light yellow in color, with a score line on one side.

Excipients: lactose monohydrate, corn starch, silicon dioxide, povidone K-30, magnesium stearate.

10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID from the sulfonanilide class. It is a selective competitive inhibitor of cyclooxygenase-2 (COX-2), an enzyme involved in the synthesis of prostaglandins – mediators of edema, inflammation, and pain. It has anti-inflammatory, analgesic, and pronounced antipyretic effects.

It reversibly inhibits the formation of prostaglandin E₂ both at the site of inflammation and in the ascending pathways of the nociceptive system, including the pathways for pain impulse transmission in the spinal cord.

It reduces the concentration of short-lived prostaglandin H₂, from which prostaglandin E₂ is formed under the action of prostaglandin isomerase. The decrease in the concentration of prostaglandin E₂ leads to a reduction in the degree of activation of EP-type prostanoid receptors, which is manifested in analgesic and anti-inflammatory effects.

It has a minor effect on COX-1, practically not preventing the formation of prostaglandin E₂ from arachidonic acid under physiological conditions, thereby reducing the number of side effects of the drug. The drug also suppresses platelet aggregation by inhibiting the synthesis of endoperoxides and thromboxane A₂, inhibits the synthesis of platelet aggregation factor, and inhibits plasminogen activation by increasing the concentration of inhibitor-1. It suppresses the release of histamine and also reduces the degree of bronchospasm caused by exposure to histamine and acetaldehyde. It inhibits the release of tumor necrosis factor α, which causes the formation of cytokines.

It has been shown that Nimesulide is capable of suppressing the synthesis of interleukin-6 and urokinase, thereby preventing the destruction of cartilage tissue. It inhibits the synthesis of metalloproteinases (elastase, collagenase), preventing the destruction of proteoglycans and collagen in cartilage tissue.

It has antioxidant properties, inhibits the formation of toxic oxygen breakdown products by reducing myeloperoxidase activity. It interacts with glucocorticoid receptors, activating them through phosphorylation, which also enhances the anti-inflammatory effect of the drug.

Pharmacokinetics

Absorption after oral administration is high. Food intake reduces the rate of absorption without affecting its extent. The time to reach C_max of the active substance in blood plasma is 1.5-2.5 hours. Protein binding is 95%, with erythrocytes – 2%, with lipoproteins -1%, with acidic α1-glycoproteins – 1%.

The dose of the drug does not affect the degree of its binding to blood proteins. C_max of nimesulide in blood plasma reaches 3.5-6.5 mg/l. V_d – 0.19-0.35 l/kg. It penetrates into the tissues of the female genital organs, where after a single dose its concentration is about 40% of the plasma concentration. It penetrates well into the acidic environment of the inflammation site (40%), synovial fluid (43%). It easily passes through histohematic barriers.

It is metabolized in the liver by tissue monooxygenases. The main metabolite, 4-hydroxynimesulide (25%), has similar pharmacological activity.

T_1/2 of nimesulide is 1.56-4.95 hours, of 4-hydroxynimesulide – 2.89-4.78 hours. 4-hydroxynimesulide is excreted by the kidneys (65%) and with bile (35%). In patients with renal failure (creatinine clearance 1.8-4.8 l/h or 30-80 ml/min), as well as in children and the elderly, the pharmacokinetic profile of nimesulide does not change significantly.

Indications

• Rheumatoid arthritis;
• Osteoarthritis;
• Arthritis of various etiologies;
• Arthralgia;
• Myalgia;
• Postoperative and post-traumatic pain;
• Bursitis;
• Tendinitis;
• Algodysmenorrhea;
• Toothache and headache.

ICD codes

Dosage Regimen

Orally, 1 tab. (100 mg) 2 times/day. The tablets should be taken with a sufficient amount of water, preferably before meals. In the presence of gastrointestinal diseases, the drug is advisable to take at the end of a meal or after eating.

For children over 12 years old, it is prescribed at a single dose of 1.5 mg/kg of the child’s body weight 2-3 times/day, the maximum daily dose of the drug is 5 mg/kg. For adolescents weighing over 40 kg – 100 mg no more than 2 times/day.

Adverse Reactions

Frequency is classified by categories, depending on the incidence of the case: very common (>1/10), common (<1/10, but >1/100), uncommon (<1/100, but >1/1000), rare (<1/1000, but >1/10000), very rare (<1/10000).

From the digestive system common – diarrhea, nausea, vomiting; uncommon – constipation, flatulence, gastritis; very rare – abdominal pain, stomatitis, tarry stools, gastrointestinal bleeding, ulcer and/or perforation of the stomach or duodenum.

From the CNS: uncommon – dizziness; rare – feeling of fear, nervousness, nightmares; very rare – headache, drowsiness, encephalopathy (Reye’s syndrome).

From the respiratory system uncommon – shortness of breath; very rare – bronchial asthma, bronchospasm.

From the cardiovascular system: uncommon – arterial hypertension; rare – tachycardia, hemorrhages, “hot flashes”.

From the sense organs rare – blurred vision, very rare – dizziness.

From the skin and mucous membranes uncommon – itching, rash, increased sweating; rare – erythema, dermatitis; very rare – urticaria, angioedema, facial swelling, multiform exudative erythema, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

From the liver and biliary system common – increased liver transaminases; very rare – hepatitis, fulminant hepatitis, jaundice, cholestasis.

From the kidneys and urinary system uncommon – edema; rare – dysuria, hematuria, urinary retention, hyperkalemia; very rare – renal failure, oliguria, interstitial nephritis.

From the hematopoietic system rare – anemia, eosinophilia; very rare – thrombocytopenia, pancytopenia, purpura, prolonged bleeding time.

Allergic reactions rare – hypersensitivity reactions; very rare – anaphylactoid reactions.

General reactions rare – general weakness; very rare – hypothermia.

If other, not mentioned above, side effects occur or if you feel worse, you should immediately consult a doctor.

Contraindications

• Hypersensitivity;
• Erosive and ulcerative lesions of the gastrointestinal tract (in the acute phase);
• Gastrointestinal bleeding;
• Intracranial hemorrhages;
• “aspirin” asthma;
• Hepatic insufficiency;
• Renal insufficiency (creatinine clearance less than 30 ml/min);
• Severe heart failure;
• Pregnancy;
• Lactation period;
• Children’s age (under 12 years).

With caution arterial hypertension, heart failure, type 2 diabetes mellitus.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

The drug is contraindicated in hepatic insufficiency.

Use in Renal Impairment

The drug is contraindicated in renal insufficiency (creatinine clearance less than 30 ml/min).

Pediatric Use

The drug is contraindicated in children under 12 years of age.

For children over 12 years old, it is prescribed at a single dose of 1.5 mg/kg of the child’s body weight 2-3 times/day, the maximum daily dose of the drug is 5 mg/kg. For adolescents weighing over 40 kg – 100 mg no more than 2 times/day.

Special Precautions

Actasulid should be used with caution in patients with a tendency to bleeding, patients with diseases of the upper gastrointestinal tract, or patients taking drugs that reduce blood clotting, or drugs that suppress platelet aggregation.

Since Actasulid is partially excreted by the kidneys, the dose for patients with impaired renal function should be reduced depending on the level of urine output.

Given reports of visual disturbances in patients taking other NSAIDs, treatment should be discontinued immediately if any visual disturbance occurs, and the patient should be examined by an ophthalmologist.

The drug may cause fluid retention in tissues, so patients with high blood pressure and cardiac disorders should use Actasulid with particular caution. Patients should undergo regular medical supervision if they are taking drugs that affect the gastrointestinal tract along with Actasulid.

Influence on the ability to drive vehicles and mechanisms

Patients whose work requires concentration (constant attention) should be aware that the drug may cause drowsiness or dizziness.

Overdose

Symptoms apathy, drowsiness, nausea, vomiting. They are generally reversible with supportive patient care. Gastrointestinal bleeding, arterial hypertension, acute renal failure, and respiratory depression may occur.

Treatment symptomatic treatment of the patient and supportive care are required. There is no specific antidote. If the overdose occurred within the last 4 hours, it is necessary to induce vomiting, provide intake of activated charcoal (60-100 g for an adult), and osmotic laxatives. Forced diuresis and hemodialysis are not effective due to the high protein binding of the drug.

Drug Interactions

The effect of drugs that reduce blood clotting is enhanced when used simultaneously with nimesulide.

Nimesulide may reduce the effect of furosemide.

Nimesulide may increase the possibility of adverse reactions when taken simultaneously with methotrexate.

The level of lithium in plasma increases with the simultaneous administration of lithium preparations and nimesulide.

Due to the high degree of binding of nimesulide to plasma proteins, patients simultaneously treated with hydantoins and sulfonamides should be under medical supervision, undergoing examination at short intervals.

Nimesulide may enhance the effect of cyclosporine on the kidneys.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F), in a place protected from light and out of the reach of children.

Shelf Life

Shelf life – 3 years. The drug should not be used after the expiration date indicated on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.