Panoxen^® (Tablets) Instructions for Use

Marketing Authorization Holder

Oxford Laboratories, Pvt. Ltd. (India)

Contact Information

Oxford Laboratories Pvt. Ltd. (India)

ATC Code

M01AB55 (Diclofenac in combination with other drugs)

Active Substances

Paracetamol (Rec.INN registered by WHO)

Diclofenac (Rec.INN registered by WHO)

Dosage Form

Panoxen®

Film-coated tablets, 50 mg+500 mg: 20 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, capsule-shaped, with a score on one side; slight roughness is allowed.

Excipients: corn starch – 290 mg, cellacephate – 15 mg, diethyl phthalate – 2.5 mg, talc – 10 mg, magnesium stearate – 10 mg, titanium dioxide – 13 mg, microcrystalline cellulose – 70 mg, povidone K30 – 18 mg, methylparaben – 17.5 mg, propylparaben – 4 mg; tablet coating TS 1005 (white) – 28.5 mg [hypromellose – 5.5 mg, propylene glycol – 4.3 mg, talc – 10.8 mg, titanium dioxide – 7.98 mg].

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

Clinical-Pharmacological Group

NSAID in combination with an analgesic-antipyretic

Pharmacotherapeutic Group

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

Pharmacological Action

A combined analgesic drug, the action of which is due to the effects of its constituent components.

Diclofenac – a phenylacetic acid derivative, has anti-inflammatory, analgesic, antipyretic, and antiplatelet effects. By inhibiting COX-1 and COX-2, it disrupts arachidonic acid metabolism, reduces the amount of prostaglandins both at the site of inflammation and in healthy tissues, and suppresses the exudative and proliferative phases of inflammation.

Paracetamol – an aniline derivative, inhibits COX predominantly in the CNS, has little effect on water-salt metabolism and the gastrointestinal mucosa. In inflamed tissues, peroxides neutralize the effect of paracetamol on COX-1 and COX-2, which explains the almost complete absence of anti-inflammatory effect.

Pharmacokinetics

Diclofenac

Absorption

Absorption is rapid and complete, food slows down the rate of absorption. After oral administration of 50 mg, C_max in plasma is 1.5 µg/ml, T_max in plasma is 2-3 hours. Plasma concentration is linearly dependent on the dose. Bioavailability is 50%. AUC is 2 times lower after oral administration than after parenteral administration at the same dose.

Distribution

Binding to plasma proteins is more than 99% (most of it is bound to albumin).

Penetrates into breast milk, synovial fluid; C_max in synovial fluid is reached 2-4 hours later than in plasma. T_1/2 from synovial fluid is 3-6 hours (diclofenac concentrations in synovial fluid 4-6 hours after its administration are higher than in plasma and remain higher for another 12 hours).

No changes in the pharmacokinetics of diclofenac during repeated use have been noted. Does not accumulate if the recommended interval between meals is observed.

Metabolism

About 50% of diclofenac undergoes first-pass metabolism in the liver. Metabolism occurs as a result of multiple or single hydroxylation and subsequent conjugation with glucuronic acid. The isoenzyme CYP2C9 is also involved in the metabolism of diclofenac. The pharmacological activity of the metabolites is less than that of diclofenac.

Excretion

Systemic clearance is 260 ml/min. T_1/2 from plasma is 1-2 hours. 60% 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 in the bile.

Pharmacokinetics in special clinical cases

In patients with severe renal failure (creatinine clearance <10 ml/min), the excretion of metabolites with bile increases, while no increase in their concentration in the blood is observed.

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

Paracetamol

Absorption and Distribution

Absorption is high. C_max in blood plasma is 5-20 µg/ml, T_max is 0.5-2 hours.

Binding to plasma proteins is 15%.

Penetrates the blood-brain barrier.

Less than 1% of the paracetamol dose taken by a nursing mother penetrates into breast milk.

Metabolism

It is metabolized in the liver through three main pathways: conjugation with glucuronides, conjugation with sulfates, and oxidation by microsomal liver enzymes. In the latter case, toxic intermediate metabolites are formed, which are subsequently conjugated with glutathione, and then with cysteine and mercapturic acid. The main cytochrome P450 isoenzymes for this metabolic pathway are isoenzyme CYP2E1 (predominantly), CYP1A2 and CYP3A4 (secondary role). In glutathione deficiency, these metabolites can cause damage and necrosis of hepatocytes.

Additional pathways of metabolism are hydroxylation to 3-hydroxyparacetamol and methoxylation to 3-methoxyparacetamol, which are subsequently conjugated with glucuronides or sulfates. In adults, glucuronidation predominates; in newborns (including premature infants) and young children, sulfation predominates. Conjugated metabolites of paracetamol (glucuronides, sulfates, and glutathione conjugates) have low pharmacological (including toxic) activity.

Excretion

T_1/2 is 1-4 hours. It is excreted by the kidneys as metabolites, mainly conjugates, only 3% unchanged.

Pharmacokinetics in special clinical cases

In elderly patients, the clearance of paracetamol decreases and T_1/2 increases.

Indications

• To reduce pain and inflammation at the time of use in inflammatory diseases of the musculoskeletal system (rheumatoid arthritis, psoriatic, juvenile and chronic arthritis, ankylosing spondylitis, acute gouty arthritis);
• Degenerative diseases of the musculoskeletal system (osteoarthritis deformans, osteochondrosis);
• Lumbago, sciatica, neuralgia, myalgia;
• Diseases of periarticular tissues (tenosynovitis, bursitis);
• Post-traumatic pain syndromes accompanied by inflammation;
• Toothache.

ICD codes

Dosage Regimen

Panoxen^® is taken orally, without chewing, during or after meals, with a small amount of water.

Prescribe 1 tablet 2-3 times/day. The maximum daily dose is 3 tablets (150 mg in terms of diclofenac).

The duration of use of the drug Panoxen^® depends on the indication for use. For acute conditions, quickly resolved conditions, the drug is used for several days. For chronic inflammatory or degenerative connective tissue diseases, long-term use of the drug Panoxen^® is possible.

With long-term use of the drug, regular monitoring should be carried out for the possible occurrence of erosion of the gastrointestinal mucosa with the subsequent development of gastrointestinal bleeding, and liver function tests should be performed for the early detection of possible hepatotoxicity of the drug.

Adverse Reactions

From the digestive system epigastric pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, anorexia, increased activity of liver aminotransferases, gastritis, proctitis, gastrointestinal bleeding (vomiting blood, melena, diarrhea with blood), ulceration of the gastrointestinal mucosa (with or without bleeding or perforation), hepatitis, jaundice, liver dysfunction, stomatitis, glossitis, esophagitis, hemorrhagic colitis, exacerbation of ulcerative colitis or Crohn’s disease, constipation, pancreatitis, fulminant hepatitis.

From the nervous system headache, dizziness, drowsiness, sensitivity disorders (including paresthesia), memory disorders, tremor, convulsions, anxiety, cerebrovascular disorders, aseptic meningitis, disorientation, depression, insomnia, nightmares, irritability, mental disorders.

From the sensory organs: vertigo, visual impairment (blurred vision, diplopia), hearing impairment, tinnitus, taste disturbance.

From the urinary system acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

From the hematopoietic system thrombocytopenia, leukopenia, anemia, including hemolytic or aplastic, agranulocytosis, methemoglobinemia.

Allergic reactions urticaria, allergic purpura, anaphylactic/anaphylactoid reactions (including severe hypotension and shock), angioedema (including facial).

From the cardiovascular system palpitations, chest pain, increased blood pressure, vasculitis, heart failure, myocardial infarction.

From the respiratory system bronchial asthma (including shortness of breath), pneumonitis.

From the skin skin rash (including bullous), erythema, including multiforme and Stevens-Johnson syndrome, Lyell’s syndrome, exfoliative dermatitis, itching, hair loss, photosensitivity, purpura.

Other edema.

Contraindications

• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including history);
• Erosive and ulcerative lesions of the gastrointestinal tract (including duodenal ulcer);
• Active gastrointestinal bleeding;
• Inflammatory bowel diseases;
• Severe hepatic failure;
• Severe heart failure;
• The period after coronary artery bypass grafting;
• Severe renal failure (creatinine clearance <30 ml/min);
• Progressive kidney disease;
• Active liver disease;
• Hyperkalemia;
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other derivatives of phenylacetic acid or aniline.

With caution gastric and duodenal ulcer (in remission or history), ulcerative colitis, Crohn’s disease, history of liver disease, hepatic porphyria, benign hyperbilirubinemias (including Gilbert’s syndrome), viral hepatitis, alcoholic liver disease, chronic heart failure of mild or moderate severity, arterial hypertension, significant decrease in circulating blood volume (including after extensive surgery), bronchial asthma, coronary artery disease, cerebrovascular diseases, 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, glucose-6-phosphate dehydrogenase deficiency, simultaneous use of glucocorticosteroids, anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors, in elderly patients.

Use in Pregnancy and Lactation

The safety of the drug during pregnancy and breastfeeding has not been established, therefore the prescription of Panoxen^® to this category of patients is contraindicated.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic failure, active liver disease.

The drug should be prescribed with caution in case of a history of liver disease, hepatic porphyria, viral hepatitis, alcoholic liver disease.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney disease.

The drug should be prescribed with caution in chronic renal failure (creatinine clearance 30-60 ml/min).

Pediatric Use

The use of the drug is contraindicated in children.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

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

Due to the important role of prostaglandins in maintaining renal blood flow, special caution should be exercised when prescribing to patients with cardiac or renal failure, as well as when treating elderly patients receiving diuretics, and patients who, for any reason, have a decrease in circulating blood volume (for example, after extensive surgery). When prescribing Panoxen^® in such cases, it is recommended to monitor renal function as a precaution.

To quickly achieve the desired therapeutic effect, the drug is taken 30 minutes before meals. In other cases, it is taken before, during or after meals without chewing, with a sufficient amount of water.

In patients with hepatic insufficiency (chronic hepatitis, compensated liver cirrhosis), the kinetics and metabolism do not differ from those in patients with normal liver function.

During the use of the drug, the results of laboratory tests for the quantitative determination of glucose and uric acid in plasma are distorted.

Effect on the ability to drive vehicles and mechanisms

Caution must be exercised when driving vehicles and engaging in other activities that require increased concentration and speed of psychomotor reactions.

Overdose

Diclofenac

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, hemodialysis are not very effective (due to the high degree of binding to plasma proteins and intensive metabolism).

Paracetamol

Symptoms: within the first 24 hours after administration – 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 occurs when taking 4 g or more.

Treatment: administration of SH-group donors and a precursor of glutathione synthesis – methionine within 8-9 hours after overdose and acetylcysteine – within 8 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 administration.

Drug Interactions

Diclofenac

Increases the 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 agents and thrombolytics (alteplase, streptokinase, urokinase), the risk of bleeding (more often from the gastrointestinal tract) increases.

It reduces the effects of antihypertensive and hypnotic drugs.

It increases the likelihood of side effects from other NSAIDs and corticosteroids (gastrointestinal bleeding), the toxicity of methotrexate, and the nephrotoxicity of cyclosporine (by increasing their plasma concentration).

Acetylsalicylic acid reduces the concentration of diclofenac in the blood.

It reduces the effect of hypoglycemic agents.

Paracetamol increases the risk of developing nephrotoxic effects of diclofenac.

Cefamandole, cefoperazone, cefotetan, valproic acid, and plicamycin increase the incidence 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 use with ethanol, colchicine, corticotropin, and St. John’s wort preparations increases the risk of gastrointestinal bleeding.

Agents causing photosensitization increase the sensitizing effect of diclofenac to UV radiation.

Agents blocking tubular secretion increase the plasma concentration of diclofenac, thereby increasing its efficacy and toxicity.

Antibacterial agents from the quinolone group increase the risk of seizures.

Paracetamol

It reduces the efficacy of uricosuric agents.

Concomitant use of paracetamol in high doses enhances the effect of anticoagulants (by reducing the synthesis of blood clotting factors in the liver).

Inducers of liver microsomal enzymes (phenytoin, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants), ethanol, and hepatotoxic agents increase the production of hydroxylated active metabolites, which may lead to severe intoxication even with a slight overdose.

Long-term use of barbiturates reduces the efficacy of paracetamol.

Concomitant intake of ethanol contributes to the development of acute pancreatitis.

Inhibitors of liver microsomal enzymes (including cimetidine) reduce the risk of hepatotoxic action.

Long-term concomitant use of paracetamol and NSAIDs increases the risk of “analgesic” nephropathy and renal papillary necrosis, and the onset of end-stage renal failure.

Long-term concomitant use of paracetamol in high doses and salicylates increases the risk of kidney or bladder cancer.

Diflunisal increases the plasma concentration of paracetamol by 50%, which increases the risk of hepatotoxicity.

Myelotoxic agents enhance the manifestations of the hematotoxicity of paracetamol.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

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.