Clodifen^® Neuro (Capsules) Instructions for Use

Marketing Authorization Holder

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

Contact Information

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

ATC Code

M01AB55 (Diclofenac in combination with other drugs)

Dosage Form

Clodifen® Neuro

Capsules: 10, 20, 30, or 50 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin size No. 0, opaque, with a body ranging from pinkish-red to brick-red and a yellow cap; the capsule contents are a mixture of powder from almost white to light pink with agglomerates and white particles.

Excipients: lysine hydrochloride – 110.75 mg, microcrystalline cellulose (102) – 150 mg, colloidal silicon dioxide – 4 mg, magnesium stearate – 5 mg.

Composition of the hard gelatin capsule shell No. 0 body – titanium dioxide – 0.944 mg, iron oxide red – 0.177 mg, Ponceau 4R – 0.0527 mg, Brilliant Black – 0.0034 mg, purified water – 8.555 mg, gelatin – 49.265 mg; cap – titanium dioxide – 0.74 mg, iron oxide yellow – 0.0925 mg, Ponceau 4R – 0.0006 mg, purified water – 5.365 mg, gelatin – 30.8025 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

NSAIDs in combination with B vitamins

Pharmacotherapeutic Group

Nonsteroidal anti-inflammatory drug (NSAID) combined (NSAID + B vitamins)

Pharmacological Action

Clodifen^® Neuro is a combination of diclofenac with B vitamins. Diclofenac has a pronounced anti-inflammatory, analgesic, and moderate antipyretic effect.

Pharmacodynamics

The mechanism of action of diclofenac is associated with the inhibition of cyclooxygenase activity, the key enzyme in the metabolism of arachidonic acid, which is a precursor of prostaglandins that play a major role in the pathogenesis of inflammation, pain, and fever.

Thiamine (vitamin B₁) in the human body is converted into cocarboxylase through phosphorylation processes, which is a coenzyme of many enzymatic reactions. Vitamin B₁ plays an important role in carbohydrate, protein, and fat metabolism. It is actively involved in the processes of nerve impulse transmission at synapses.

Pyridoxine (vitamin B₆) is necessary for the normal functioning of the central and peripheral nervous systems. In its phosphorylated form, it is a coenzyme in amino acid metabolism (decarboxylation, transamination). It acts as a coenzyme for the most important enzymes operating in nerve tissues.

Cyanocobalamin (vitamin B₁₂) is necessary for normal hematopoiesis and erythrocyte maturation, and also participates in a number of biochemical reactions that ensure the vital activity of the body – in the transfer of methyl groups, in the synthesis of nucleic acids, protein, and in the metabolism of amino acids, carbohydrates, and lipids.

Pharmacokinetics

Absorption and Distribution

The absorption of diclofenac is rapid and complete; food slows the rate of absorption by 1-4 hours and reduces C_max by 40%. After oral administration of 50 mg, C_max is 1.4 µg/ml, achieved in 2-3 hours. Plasma concentration is linearly dependent on the administered dose.

No changes in the pharmacokinetics of diclofenac were noted during repeated administration; it does not accumulate.

Bioavailability is 50%. Protein binding of diclofenac is more than 99% (most of it binds to albumin). It penetrates into the synovial fluid; C_max in the synovial fluid is observed 2-4 hours later than in plasma. T_1/2 from the synovial fluid is 3-6 hours (the concentration of the active substance in the synovial fluid 4-6 hours after drug administration is higher than in plasma and remains higher for another 12 hours).

Thiamine and pyridoxine are absorbed in the upper part of the small intestine. The absorption of cyanocobalamin largely depends on the presence of intrinsic factor in the body (in the stomach and upper small intestine); further delivery of the vitamin to tissues is determined by the transport protein transcobalamin.

The vitamins included in the Clodifen^® Neuro preparation are water-soluble, which excludes the possibility of their accumulation in the body.

Metabolism

Diclofenac is metabolized in the liver; 50% of the active substance undergoes metabolism during the first pass through the liver. Metabolism occurs as a result of multiple or single hydroxylation and conjugation with glucuronic acid. The cytochrome P450 enzyme system, isoenzyme CYP2C9, is involved in the metabolism of the drug. The pharmacological activity of the metabolites is lower than that of diclofenac. Systemic clearance is 350 ml/min, V_d is 550 ml/kg.

Thiamine and pyridoxine are metabolized in the liver. The degree of absorption is dose-dependent; in case of overdose, the excretion of thiamine and pyridoxine through the intestine increases significantly. Cyanocobalamin is metabolized in the liver.

Excretion

T_1/2 of diclofenac from plasma is 2 hours. 65% of the administered dose is excreted by the kidneys as metabolites; less than 1% is excreted unchanged, the remainder of the dose is excreted as metabolites with bile. In patients with severe renal failure (creatinine clearance less than 10 ml/min), the excretion of metabolites with bile increases, but no increase in their concentration in the blood is observed.

In patients with chronic hepatitis or compensated liver cirrhosis, the pharmacokinetic parameters of diclofenac do not change.

Diclofenac passes into breast milk.

Thiamine and pyridoxine are excreted by the kidneys (about 8-10% unchanged).

Cyanocobalamin is excreted mainly with bile, the degree of renal excretion is variable – from 6 to 30%.

Indications

• Pain syndrome in inflammations of non-rheumatic nature (after injuries, surgical and dental interventions; in gynecological diseases – primary dysmenorrhea, adnexitis; in inflammatory diseases of the ENT organs – pharyngitis, tonsillitis, otitis);
• Inflammatory and degenerative diseases of the joints and spine (chronic polyarthritis, osteoarthritis, spondyloarthrosis);
• Neuritis and neuralgia (cervical syndrome, lumbago, sciatica);
• Acute gouty arthritis.

ICD codes

Dosage Regimen

To reduce the risk of adverse events from the gastrointestinal tract, the minimum effective dose should be used for the shortest possible course.

The drug should be taken orally with meals, without chewing and with plenty of fluid.

The drug is prescribed 1 capsule 3 times/day at the beginning of treatment, and as a maintenance dose, 1 capsule 1-2 times/day. The duration of therapy is determined by the doctor and depends on the nature and severity of the disease.

Adverse Reactions

The frequency of adverse reactions is presented in accordance with the WHO classification: common – 1-10%; uncommon – 0.1-1%; rare – 0.01-0.1%; very rare – less than 0.001%, including isolated reports.

From the digestive system: common – abdominal pain, feeling of bloating, diarrhea, nausea, constipation, flatulence, increased activity of liver enzymes, peptic ulcer with possible complications (bleeding, perforation), gastrointestinal bleeding; rare – vomiting, jaundice, melena, appearance of blood in the stool, esophageal damage, aphthous stomatitis, dryness of mucous membranes (including mouth), hepatitis (possibly fulminant course), liver necrosis, cirrhosis, hepatorenal syndrome, change in appetite, pancreatitis, cholecystopancreatitis, colitis.

From the hematopoietic organs: rare – anemia (including hemolytic and aplastic anemia), leukopenia, thrombocytopenia, eosinophilia, agranulocytosis, thrombocytopenic purpura.

From the CNS: common – headache, dizziness; rare – sleep disturbance, drowsiness, depression, irritability, aseptic meningitis (more often in patients with systemic lupus erythematosus and other systemic connective tissue diseases), convulsions, general weakness, disorientation, nightmares, feeling of fear.

From the sensory organs: common – tinnitus; rare – blurred vision, diplopia, taste disturbance, reversible or irreversible hearing loss, scotoma.

From the respiratory system: rare – cough, bronchospasm, laryngeal edema, pneumonia.

From the cardiovascular system: rare – increased blood pressure, heart failure, extrasystole, chest pain, myocardial infarction.

From the urinary system: common – fluid retention; rare – nephrotic syndrome, proteinuria, oliguria, hematuria, interstitial nephritis, papillary necrosis, acute renal failure, azotemia.

Dermatological reactions: common – skin itching, skin rash; rare – alopecia, urticaria, eczema, toxic dermatitis, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), increased photosensitivity, petechial hemorrhages, bullous eruptions.

Allergic reactions: rare – anaphylactoid reactions, anaphylactic shock, swelling of the lips and tongue, allergic vasculitis.

Other: rare – worsening of the course of infectious processes.

Contraindications

• Hypersensitivity to the components of the drug (including to other NSAIDs);
• Gastric and duodenal ulcer in the acute phase;
• Gastrointestinal bleeding;
• Intracranial bleeding;
• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nasal mucosa and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in history);
• Hematopoiesis disorders;
• Severe hepatic failure;
• Active liver disease;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Progressive kidney disease;
• Severe heart failure;
• The period after coronary artery bypass grafting;
• Chronic heart failure of functional class IV according to NYHA;
• Confirmed hyperkalemia;
• Hemostasis disorders (including hemophilia);
• Inflammatory bowel diseases in the acute phase;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety have not been established).

With caution

Gastric and duodenal ulcer, ulcerative colitis, Crohn’s disease in remission; history of liver disease; hepatic porphyria; chronic hepatic insufficiency; chronic heart failure (functional class I-III according to NYHA); arterial hypertension; significant reduction in circulating blood volume (including after extensive surgical intervention); elderly patients (including those receiving diuretics, debilitated patients and those with low body weight); bronchial asthma; simultaneous use of glucocorticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including acetylsalicylic acid, clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); coronary artery disease; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; peripheral artery diseases; smoking; chronic renal failure (creatinine clearance 30-60 ml/min); presence of Helicobacter pylori infection; long-term use of NSAIDs; alcoholism; severe somatic diseases.

Use in Pregnancy and Lactation

The use of the drug during pregnancy and breastfeeding is contraindicated.

Due to the negative effect on fertility, the drug is not recommended for women wishing to become pregnant. In patients with infertility (including those undergoing examination), it is recommended to discontinue the drug.

Use in Hepatic Impairment

Contraindicated in severe hepatic failure, active liver disease.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney disease.

Pediatric Use

Contraindicated for use under the age of 18 years.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

During treatment with the drug, systematic monitoring of the peripheral blood picture, liver and kidney function, and examination of feces for occult blood should be carried out.

Due to the important role of prostaglandins in maintaining renal blood flow, special caution should be exercised when prescribing to patients with heart failure, as well as during therapy for elderly patients taking diuretics, and patients who, for any reason, have a reduced circulating blood volume (including after extensive surgical intervention). If diclofenac is prescribed in such cases, monitoring of renal function is recommended as a precaution.

If an increase in the activity of liver transaminases is observed after using the drug, or clinical symptoms of hepatotoxicity (including nausea, fatigue, drowsiness, diarrhea, skin itching, jaundice) are noted, treatment must be discontinued and should not be repeated subsequently.

Diclofenac (like other NSAIDs) can cause hyperkalemia.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: vomiting, gastrointestinal bleeding, epigastric pain, diarrhea, dizziness, tinnitus, lethargy, convulsions; rarely – increased blood pressure, acute renal failure, hepatotoxic effect, respiratory depression, coma.

Treatment: gastric lavage, activated charcoal, symptomatic therapy aimed at eliminating increased blood pressure, impaired renal function, convulsions, gastrointestinal irritation, respiratory depression. Forced diuresis and hemodialysis are not very effective (due to significant protein binding and intensive metabolism).

Drug Interactions

When used simultaneously with Clodifen^® Neuro

• The effect of diuretics is reduced; against the background of potassium-sparing diuretics, the risk of hyperkalemia increases;
• The plasma concentration of digoxin, methotrexate, lithium preparations and cyclosporine increases;
• The effects of antihypertensive and hypnotic drugs are reduced;
• The risk of bleeding (more often gastrointestinal bleeding) increases during therapy with anticoagulants and thrombolytic agents (alteplase, streptokinase, urokinase);
• The likelihood of adverse reactions of other NSAIDs and glucocorticosteroids (gastrointestinal bleeding), the toxicity of methotrexate and the nephrotoxicity of cyclosporine increase;
• The effect of hypoglycemic agents is reduced;
• The antiparkinsonian effectiveness of levodopa is reduced;
• Cefamandole, cefoperazone, cefotetan, valproic acid increase the frequency of hypoprothrombinemia;
• Ethanol, colchicine, corticotropin, serotonin reuptake inhibitors and St. John’s wort preparations increase the risk of gastrointestinal bleeding;
• Diclofenac enhances the effect of drugs that cause photosensitization.

Concomitant use with paracetamol increases the risk of nephrotoxic effects of diclofenac.

Acetylsalicylic acid reduces the concentration of diclofenac in the blood.

Cyclosporine and gold preparations enhance the effect of diclofenac on the synthesis of prostaglandins in the kidneys, which increases the risk of nephrotoxicity.

Drugs that block tubular secretion increase the plasma concentration of diclofenac, thereby increasing its toxicity.

Ethanol sharply reduces the absorption of thiamine (blood levels may decrease by 30%).

Long-term treatment with anticonvulsant drugs can lead to thiamine deficiency.

The use of colchicine and biguanides reduces the absorption of cyanocobalamin.

During the drug intake, it is not recommended to take multivitamin complexes that include B vitamins.

Storage Conditions

The drug should be stored in a light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

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.