Panoxen (Diclofenac + Paracetamol) tablets

The composition and form of issue: 

Tablets, film-coated, 1 tablet contains active substances: 

diclofenac sodium 50 mg

paracetamol 500 mg

excipients: corn starch — 290 mg acetylcellulose (cellacefate) — 15 mg diethyl — 2, 5 mg talc 10 mg magnesium stearate 10 mg titanium dioxide — 13 mg MKC — 70 mg povidone K30 — 18 mg methyl parahydroxybenzoate (methylparaben) — 17, 5 mg parahydroxybenzoate (propyl) — 4 mg 

shell: tablet coating TC1005 (white) — 28, 5 mg (hypromellose (hydroxypropyl methylcellulose) — 5, 5 mg, propylene glycol — 4, 3 mg, talc — 10, 8 mg, titanium dioxide — 7, 98 mg) 

blister aluminum foil/PVC film 10 PCs. in cartons of 2 or 10 blisters.

Description pharmaceutical form:

Pills capsuleline shape, coated white or almost white, scored on one side slight roughness of the surface.

Pharmacokinetics:

Diclofenac

Absorption rapid and complete, food slows the absorption rate. After ingestion of 50 mg Cmax in plasma is 1, 5 µg/ml, Tmax in plasma is 2-3 h. Concentration in plasma is in linear dependence on the dose.

Changes in the pharmacokinetics of diclofenac amid repeated use is not marked. Not koumouliruet in compliance with the recommended interval between meals.

Bioavailability of 50%. Connection with plasma proteins is >99% (most of it binds to albumin). Passes into breast milk, synovial fluid Cmax in synovial fluid is observed in 2-4 hours later than in plasma. T1/2 from synovial fluid — 3-6 h (the concentration of diclofenac in synovial fluid after 4-6 hours after taking it are higher than in plasma, and remain higher in the coming 12 hours).

About 50% of diclofenac metabolized during the first pass through the liver. AUC 2 times less after oral than after parenteral administration of the same dose. Metabolism occurs as a result of repeated or single hydroxylation and subsequent conjugation with glucuronic acid. In the metabolism of diclofenac is also involved isoenzyme CYP2C9. The pharmacological activity of the metabolites less than that of diclofenac.

Systemic clearance is 260 ml/min. T1/2 from plasma is 1-2 h 60% of the dose is excreted as metabolites via the kidneys less than 1% is excreted unchanged, the rest of the dose is excreted as metabolites in the bile.

In patients with severe renal insufficiency (Cl creatinine <10 ml/min) increases the excretion of metabolites in bile, with increase of their concentration in blood is not observed.

In patients with chronic hepatitis or compensated cirrhosis pharmacokinetic parameters are not changed.

Paracetamol

High absorption Tmax — 0, 5-2 h Cmax — 5-20 µg/ml. the Connection with plasma proteins — 15%. Penetrates the GEB. Less than 1% of the accepted nursing mother, the dose of acetaminophen passes into breast milk.

Metabolized in the liver by three main pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation by liver microsomal enzymes. In the latter case produces toxic intermediate metabolites that subsequently conjugium with glutathione, and then with cysteine and mercapturic acid. The major isoenzymes of cytochrome P450 in this pathway is the CYP2E1 isozyme (predominantly), CYP3A4, and CYP1A2 (minor role). Deficiency of glutathione these metabolites can cause damage to and necrosis of hepatocytes.

Additional routes of metabolism are hydroxylation to 3-hydroxypentanal and methoxylamine to 3-methoxypyrazine, which subsequently conjugium with glucuronide or sulfate.

In adults, the predominant glucuronidation, neonates (including premature infants) and young children — sulfation. Conjugated metabolites of paracetamol (glucuronide, sulfate and glutathione conjugates with) have low pharmacological (including toxic) activity. T1/2 — 1-4 h. Excreted by the kidneys as metabolites, primarily conjugates, 3% — in unchanged form. In elderly patients, decreases clearance of acetaminophen and increased T1/2.

Description pharmacological action:

Panoxen is a combined analgesic drug, which is due to its constituent components.

Diclofenac

A derivative of phenylacetic acid, anti-inflammatory, analgesic, antipyretic, antiplatelet effect. Inhibiting COX-1 and -2, violates the metabolism of arachidonic acid, reduces the amount of PG in inflammation and in healthy tissues, inhibits exudative and proliferative phases of inflammation.

Paracetamol

Aniline derivative, inhibits COX mostly in CNS, has little effect on water-salt metabolism and the mucosa of the gastrointestinal tract. In the inflamed tissue peroxidase neutralizes the effect of paracetamol on COX-1 and -2, which explains the almost complete absence of anti-inflammatory effect.

Indications:

pain and inflammation:

• in inflammatory diseases of the musculoskeletal system (rheumatoid arthritis, psoriatic, juvenile chronic arthritis, ankylosing spondylitis, gouty arthritis),
• in acute gouty arthritis
• degenerative diseases of the musculoskeletal system (deforming osteoarthritis, osteochondrosis)
• lumbago, sciatica, neuralgia, myalgia
• diseases of the periarticular tissues (tenosynovitis, bursitis)
• post-traumatic pain syndromes, accompanied by inflammation
• toothache.

Contraindications:

• hypersensitivity to the drug and other derivatives of phenylacetic acid or aniline
• full or partial combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance of acetylsalicylic acid or other NSAIDs (including history)
• erosivno-azwenne defeat stomach and duodenal ulcers, active gastrointestinal bleeding, inflammatory bowel disease
• severe liver failure
• severe heart failure
• since the coronary artery bypass surgery
• severe renal insufficiency (Cl creatinine <30 ml/min), progressive kidney disease
• active liver disease
• hyperkalemia
• pregnancy, lactation
• the children’s age.

Caution: peptic ulcer of stomach and duodenal ulcers (in remission or in history), ulcerative colitis, Crohn’s disease, liver disease, a history of hepatic porphyria, benign hyperbilirubinemia (including Gilbert’s syndrome), viral hepatitis, alcoholic liver disease, chronic heart failure or moderate severity, arterial hypertension, a significant decrease in BCC (including after extensive surgery), elderly patients, bronchial asthma, concomitant use of corticosteroids, anticoagulants, antiplatelet agents and SSRIs, ischemic heart disease, cerebrovascular disease, hyperlipidemia, diabetes mellitus, peripheral artery disease, Smoking, chronic renal failure (Cl creatinine 30-60 ml/min), infection with Helicobacter pylori, prolonged use of NSAIDs, alcoholism, severe somatic disease, the deficit glukozo-6-fosfatdegidrogenaza.

Application of pregnancy and breast-feeding:

The safety of the drug during pregnancy and lactation is not proven. The use of the drug in these groups of patients is contraindicated.

Side effects:

From the digestive system: epigastric pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, anorexia, increased activity of liver aminotransferases, gastritis, proctitis, bleeding from the gastrointestinal tract (vomiting blood, melena, diarrhea mixed with blood), mucosal ulceration of the gastrointestinal tract (bleeding or perforation with or without them), hepatitis, jaundice, abnormal liver function, stomatitis, glossitis, esophagitis, hemorrhagic colitis, aggravation of ulcerative colitis or Crohn’s disease, constipation, pancreatitis, fulminant hepatitis.

From the nervous system: headache, dizziness, drowsiness, disturbance of sensation (including paraesthesia), memory disorders, tremors, convulsions, anxiety, cerebrovascular disorders, aseptic meningitis, confusion, depression, insomnia, nightmares, irritability, mental disorders.

From the senses: vertigo, visual impairment (blurring of visual perception, diplopia), impaired hearing, tinnitus, breach of taste sensations.

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

Organs of hematopoiesis: thrombocytopenia, leukopenia, anemia, including hemolytic or aplastic, agranulocytosis, methemoglobinemia.

Allergic reactions: anaphylactic/anaphylactoid reactions, including marked reduction in blood pressure and shock, angioedema (including facial).

From the CCC: palpitations, chest pain, increased blood pressure, vasculitis, heart failure, myocardial infarction.

The respiratory system: bronchial asthma (including dyspnea) pneumonitis.

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

Other: swelling.

Drug interactions:

Diclofenac

Increases concentration in plasma digoxin, drugs lithium.

Reduces effect of diuretics, against kalisberegath dioretikov increases risk giperkaliemii against the background of anticoagulants, antiplatelet agents, and thrombolytics (alteplase, streptokinase, urokinase) increases the risk of bleeding (often from the gastrointestinal tract).

Reduces effect of hypotensive and hypnotic drugs.

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

Acetylsalicylic acid reduces the concentration of diclofenac in the blood.

Reduces the effect of hypoglycemic agents.

Paracetamol increases the risk of nephrotoxic effects of diclofenac.

Cefamandole, cefoperazone, cefotetan, valproic acid and plicamycin increase the frequency of gipoprotrombinemii.

Cyclosporine and gold drugs increase the effect of diclofenac on the synthesis of PG in the kidney, which is manifested by increased nephrotoxicity.

SSRIs increase the risk of bleeding from the gastrointestinal tract.

Concurrent use with ethanol, colchicine, corticotropin, and drugs St. John’s wort increases the risk of bleeding from the gastrointestinal tract.

Means for causing photosensitization, increase the sensitizing action of diclofenac to UV irradiation.

Agents that block tubular secretion, increase in plasma concentration of diclofenac, thereby increasing its efficacy and toxicity.

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

Paracetamol

Reduces the effectiveness of uricosuric drugs.

Simultaneous application of paracetamol in high doses increases the effect of anticoagulants (decreased synthesis of coagulation factors in the liver).

Inductors of microsomal liver enzymes (phenytoin, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants), ethanol, and hepatotoxic agents increase the production of hydroxylated active metabolites, resulting in the possibility of development of heavy intoxications even at small overdose.

Prolonged use of barbiturates reduces the effectiveness of paracetamol.

Ethanol contributes to the development of acute pancreatitis.

Inhibitors of microsomal liver enzymes (e.g. cimetidine) reduce the risk of hepatotoxicity.

Prolonged concurrent use of acetaminophen and NSAIDs increases the risk of analgesic nephropathy and papillary necrosis of the kidneys, occurrence of ESRD.

Prolonged concurrent use of paracetamol in high dozes and salitsilatov raises risk of development of kidney cancer or urinary bladder.

Was diflunisal increases the plasma concentration of acetaminophen by 50%, which increases the risk of hepatotoxicity.

Mielotoksicnae drugs increase the manifestation gematotoksichnosti of paracetamol.

Method of application and dose:

Inside.

Panoxen accept, without chewing, during or after delivery, squeezed small amounts of water. 1 table. 2-3 times a day. The maximum daily dose — 3 table. (150 mg in terms of diclofenac).

The duration of use of the medicinal product depends on Panoxen indications. In acute conditions, can be quickly compensated conditions apply within several days. In chronic inflammatory or degenerative diseases of connective tissue the prolonged use Panaxea.

Long-term use of the drug should be monitor regularly for possible occurrence of erosion of gastrointestinal mucosa with subsequent development of gastrointestinal bleeding, and conduct liver function tests for early detection of potential hepatotoxicity of the drug.

Overdose:

Paracetamol

Symptoms: during the first 24 h after admission — pallor, nausea, vomiting, anorexia, abdominal pain, violation of glucose metabolism, metabolic acidosis. Symptoms of liver function abnormalities can occur after 12-48 h after overdose. In severe overdose — hepatic failure with advanced encephalopathy, coma, death, acute renal failure with tubular necrosis (including in the absence of severe liver disease) arrhythmia, pancreatitis. Hepatotoxic effects in adults manifests itself during the ingestion of 4 g or more.

Treatment: the introduction of aid donors SH-groups and precursor to the synthesis of glutathione — methionine for 8-9 hours after the overdose and acetylcysteine within 8 h. the Need for additional therapeutic measures (further introduction of methionine, in/in the introduction of acetylcysteine) is determined depending on concentration of paracetamol in the blood, and the time elapsed after its reception.

Diclofenac

Symptoms: vomiting, bleeding from the gastrointestinal tract, epigastric pain, diarrhoea, dizziness, tinnitus, lethargy, seizures rarely — increased blood pressure, acute renal failure, hepatotoxic effects, respiratory depression, coma.

Treatment: gastric lavage, activated charcoal, symptomatic therapy, aimed at addressing the increase in BP, renal dysfunction, seizures, irritation of the gastrointestinal tract, respiratory depression. Forced diuresis, haemodialysis ineffective because of the high Association with plasma proteins and intense metabolism.

Precautions:

To reduce the risk of adverse effects from the blood should use the minimum effective dose Panoxen and minimum possible short course.

Due to the important role of PG in maintaining renal blood flow should be particularly careful in the appointment of Panaxea patients with cardiac or renal insufficiency and in the treatment of elderly people taking diuretics, and patients who, for any reason, a decrease in BCC (e.g. after extensive surgery). If in such cases appoint Panoxen, recommended as a precaution to monitor kidney function.

In order to quickly achieve the desired therapeutic effect Proxen take 30 minutes before a meal. In other cases, taking before, during or after meals is not chewed, with sufficient quantity of water.

In patients with liver disease (chronic hepatitis, compensated cirrhosis) pharmacokinetics and metabolism Panoxen not differ from those in patients with normal hepatic function.

Panoxen deforms parameters of laboratory researches at quantitative definition of glucose and uric acid in plasma.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. Be careful when driving and occupation of other types of activities, require high concentration and psychomotor speed reactions.