Dolaren^® (Tablets) Instructions for Use

Marketing Authorization Holder

Nabros Pharma, Pvt. Ltd. (India)

ATC Code

N02BE51 (Paracetamol in combination with other drugs, excluding psycholeptics)

Active Substances

Paracetamol (Rec.INN registered by WHO)

Diclofenac (Rec.INN registered by WHO)

Dosage Form

Dolaren®

Tablets 50 mg+500 mg: 10 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, two-layered, white to almost white on one side and orange with white and dark orange specks on the other side.

Excipients: starch, talc, magnesium stearate, sodium starch glycolate, gelatin, sodium methylparaben, sodium propylparaben, microcrystalline cellulose, sunset yellow FCF (E110).

10 pcs. – blisters (1) – cartons.
10 pcs. – blisters (10) – cartons.

Clinical-Pharmacological Group

NSAID in combination with an analgesic-antipyretic

Pharmacotherapeutic Group

Combined analgesic agent (NSAID + non-narcotic analgesic agent)

Pharmacological Action

The drug’s action is due to the properties of its constituent components. Diclofenac has anti-inflammatory, analgesic, antiplatelet, and antipyretic effects. By non-selectively inhibiting cyclooxygenase 1 and 2, it disrupts arachidonic acid metabolism, reducing the amount of prostaglandins at the site of inflammation. In rheumatic diseases, the anti-inflammatory and analgesic effects of diclofenac contribute to a significant reduction in pain severity, morning stiffness, and joint swelling, which improves the joint’s functional state. In injuries and the postoperative period, diclofenac reduces pain and inflammatory edema.

Paracetamol is a non-narcotic analgesic that blocks cyclooxygenase 1 and 2 primarily in the CNS, affecting pain and thermoregulation centers. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on cyclooxygenases, which explains the almost complete absence of an anti-inflammatory effect.

Pharmacokinetics

Absorption and Distribution

Absorption of the active components (diclofenac and paracetamol) is rapid and complete; food slows the rate of diclofenac absorption by 1-4 hours and reduces the maximum concentration by 40%. The plasma concentration of the active components is linearly dependent on the administered dose; they do not accumulate.

Plasma protein binding of diclofenac is more than 99% (most binds to albumin); paracetamol binds to blood proteins by 15%. Both components penetrate into breast milk in insignificant amounts. Diclofenac penetrates into the synovial fluid; the maximum concentration in the synovial fluid is observed 2-4 hours later than in plasma. The half-life 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). The relationship between the drug concentration in the synovial fluid and the clinical efficacy of the drug has not been established.

Metabolism

Diclofenac – 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 CYP2C9 is involved in the drug’s metabolism. The pharmacological activity of the metabolites is lower than that of diclofenac.

Systemic clearance is 350 ml/min, volume of distribution is 550 ml/kg. Plasma half-life 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 blood concentration is observed.

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

Paracetamol – metabolized in the liver (90-95%): 80% undergoes conjugation reactions with glucuronic acid and sulfates to form inactive metabolites; 17% undergoes hydroxylation to form 8 active metabolites, which conjugate with glutathione to form inactive metabolites. With glutathione deficiency, these metabolites can block hepatocyte enzyme systems and cause their necrosis. The isoenzyme CYP2E1 is also involved in the drug’s metabolism. T_1/2 is 1-4 hours. It is excreted by the kidneys as metabolites, mainly conjugates, with only 3% unchanged. In elderly patients, the drug clearance decreases and T_1/2 increases.

Indications

• Short-term therapy of pain syndrome in rheumatic diseases (rheumatoid arthritis, osteoarthritis);
• Neuralgia, myalgia, lumbosacral radiculopathy, post-traumatic pain syndrome accompanied by inflammation, postoperative pain, headache, migraine, dysmenorrhea, adnexitis, proctitis, toothache;
• As part of the complex therapy of infectious-inflammatory diseases of the ear, throat, nose with severe pain and fever syndrome (pharyngitis, tonsillitis, otitis);

ICD codes

Dosage Regimen

Take orally. Do not chew. Administer during or after meals. Swallow with a small amount of water.

For adults, the standard dose is one tablet taken two to three times daily.

Maintain a minimum interval of 4 to 6 hours between consecutive doses.

Do not exceed the maximum daily dose of three tablets (equivalent to 150 mg diclofenac and 1500 mg paracetamol).

Use the lowest effective dose for the shortest duration necessary to control symptoms.

The total treatment course should not exceed seven days unless directed by a physician.

Discontinue use and consult a doctor if symptoms persist or worsen.

In elderly patients and those with renal or hepatic impairment, use with particular caution and consider a reduced dosage.

Avoid concurrent use with other paracetamol-containing products or NSAIDs.

Adverse Reactions

Gastrointestinal tract

> 1% – abdominal pain, feeling of abdominal distension, diarrhea, nausea, constipation, flatulence, increased levels of “liver” enzymes, peptic ulcer with possible complications (bleeding, perforation), gastrointestinal bleeding;

< 1% – vomiting, jaundice, melena, presence of blood in stool, esophageal lesions, aphthous stomatitis, dryness of mucous membranes (including mouth), hepatitis (possibly fulminant), liver necrosis, cirrhosis, hepatorenal syndrome, change in appetite, pancreatitis, cholecystopancreatitis, colitis.

Nervous system

> 1% – headache, dizziness;

< 1% – 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.

Sensory organs

> 1% – tinnitus;

< 1% – blurred vision, diplopia, taste disturbance, reversible or irreversible hearing loss, scotoma.

Skin

> 1% – skin itching, skin rash;

< 1% – alopecia, urticaria, eczema, toxic dermatitis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), increased photosensitivity, petechiae.

Urinary system

> 1% – fluid retention;

< 1% – nephrotic syndrome, proteinuria, oliguria, hematuria, interstitial nephritis, papillary necrosis, acute renal failure, azotemia.

Hematopoietic and immune system

< 1% – anemia (including hemolytic and aplastic anemia), leukopenia, thrombocytopenia, eosinophilia, agranulocytosis, thrombocytopenic purpura, worsening of infectious processes (including development of necrotizing fasciitis).

Respiratory system

< 1% – cough, bronchospasm, laryngeal edema, pneumonitis.

Cardiovascular system

< 1% – increased blood pressure; congestive heart failure, extrasystole, chest pain.

Allergic reactions

< 1% – anaphylactoid reactions, anaphylactic shock (usually develops rapidly), swelling of the lips and tongue, allergic vasculitis.

Contraindications

• Hypersensitivity (including to other NSAIDs);
• Erosive and ulcerative lesions of the gastrointestinal tract (in the acute phase);
• Gastrointestinal bleeding;
• History of bronchospasm attack, rhinitis, urticaria after taking acetylsalicylic acid or another NSAID (complete or incomplete acetylsalicylic acid intolerance syndrome – rhinosinusitis, urticaria, nasal mucosal polyps, bronchial asthma);
• Period after coronary artery bypass grafting;
• Inflammatory bowel diseases in the acute phase;
• Severe hepatic insufficiency or active liver disease;
• Severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney diseases;
• Hematopoiesis disorders, hemostasis disorders (including hemophilia);
• Pregnancy;
• Childhood;
• Lactation period.

With caution: coronary artery disease, cerebrovascular diseases, anemia, bronchial asthma, congestive heart failure, dyslipidemia/hyperlipidemia, arterial hypertension, edematous syndrome, hepatic or renal insufficiency, benign hyperbilirubinemias (including Gilbert’s syndrome), alcoholism, erosive and ulcerative diseases of the gastrointestinal tract outside the acute phase, diabetes mellitus, peripheral arterial diseases, condition after extensive surgical interventions, inducible porphyria, elderly age, systemic connective tissue diseases.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency or active liver disease.

Use with caution in hepatic insufficiency.

Use in Renal Impairment

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

Use with caution in renal insufficiency.

Pediatric Use

Contraindicated in children.

Geriatric Use

With caution in the elderly.

Special Precautions

During treatment with the drug, peripheral blood picture, liver function, kidney function should be monitored, and stool should be examined for the presence of blood.

Additional NSAIDs should not be taken simultaneously due to an increased risk of adverse reactions.

When using the drug, distortion of laboratory parameters during the quantitative determination of glucose and uric acid in plasma is possible.

Effect on ability to drive vehicles and mechanisms

Patients taking the drug should refrain from activities requiring increased attention and rapid mental and motor reactions, and from consuming alcohol.

Overdose

The severity of overdose is primarily due to the presence of paracetamol in the drug.

Symptoms within the first 24 hours after ingestion – pale skin, nausea, vomiting, anorexia, abdominal pain; impaired glucose metabolism, metabolic acidosis. Symptoms of liver dysfunction may appear 12-48 hours after overdose. In severe overdose – liver failure with progressive encephalopathy, coma, death; acute renal failure with tubular necrosis (including in the absence of severe liver damage); arrhythmia, pancreatitis. Hepatotoxic effect in adults manifests when taking 10 g or more.

Treatment: administration of SH-group donors and glutathione synthesis precursors – methionine 8-9 hours after overdose and acetylcysteine – after 12 hours. The need for additional therapeutic measures (further administration of methionine, intravenous administration of acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as the time elapsed after its intake.

Drug Interactions

Interaction is due to the active components included in the drug: diclofenac and paracetamol.

Diclofenac

• Increases plasma concentration of digoxin, lithium preparations;
• Reduces the effect of diuretics; against the background of potassium-sparing diuretics, the risk of hyperkalemia increases; against the background of anticoagulants, antiplatelet and thrombolytic drugs (alteplase, streptokinase, urokinase), the risk of bleeding (more often gastrointestinal) increases;
• Reduces the effect of antihypertensive and hypnotic drugs;
• Increases the likelihood of side effects of other NSAIDs and glucocorticosteroids (gastrointestinal bleeding), toxicity of methotrexate and nephrotoxicity of cyclosporine (due to an increase in their plasma concentration);
• Acetylsalicylic acid reduces the concentration of diclofenac in the blood;
• Reduces the effect of hypoglycemic drugs;
• Cefamandole, cefoperazone, cefotetan, valproic acid and plicamycin increase the frequency of hypoprothrombinemia;
• Cyclosporine and gold preparations enhance the effect of diclofenac on prostaglandin synthesis in the kidneys, which is manifested by increased nephrotoxicity;
• Selective serotonin reuptake inhibitors increase the risk of gastrointestinal bleeding;
• Concomitant administration with ethanol, colchicine, corticotropin and St. John’s wort preparations increases the risk of gastrointestinal bleeding;
• Drugs causing photosensitization increase the sensitizing effect of diclofenac to ultraviolet radiation;
• Drugs blocking tubular secretion increase the plasma concentration of diclofenac, thereby increasing its efficacy and toxicity;
• Antibacterial drugs from the quinolone group increase the risk of seizures.

Paracetamol

• Reduces the effectiveness of uricosuric drugs;
• Concomitant use of paracetamol in high doses enhances the effect of anticoagulant drugs (reduction of procogulant factor synthesis in the liver);
• Inducers of microsomal oxidation in the liver (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants), ethanol and hepatotoxic drugs increase the production of hydroxylated active metabolites, which determines the possibility of severe intoxication even with a small overdose;
• Long-term use of barbiturates reduces the effectiveness of paracetamol;
• Ethanol contributes to the development of acute pancreatitis and liver damage;
• Inhibitors of microsomal oxidation (including cimetidine) reduce the risk of hepatotoxic action;
• Simultaneous long-term administration of paracetamol in high doses and salicylates increases the risk of kidney or bladder cancer;
• Diflunisal increases the plasma concentration of paracetamol by 50% – risk of hepatotoxicity;
• Myelotoxic drugs enhance the manifestations of hematotoxicity of paracetamol.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 4 years.

Dispensing Status

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.