Tilda

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TILDA® (TILDA)

Composition:

Active substances:

One tablet contains: 500 mg of paracetamol, 50 mg of sodium diclofenac, 250 mg of chlorzoxazone;

Excipients: maize starch, purified talc, magnesium stearate, colloidal anhydrous silicon dioxide;

Film coating: hypromellose, polyethylene glycol 6000, purified talc, titanium dioxide (E 171), quinoline yellow dye (E 104).

Pharmaceutical form.

Film-coated tablets.

Main physico-chemical properties: film-coated yellow-colored tablets, elongated, biconvex, with a score line on one side and smooth on the other.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic agents. Diclofenac combinations. ATC code M01AB55.

Pharmacological Properties

Pharmacodynamics

Tilda® is a combination medication with muscle relaxant and analgesic effects.

Paracetamol provides analgesic, antipyretic, and mild anti-inflammatory effects. Paracetamol inhibits cyclooxygenase predominantly within the central nervous system, thereby affecting pain and thermoregulation centers. Its analgesic effect is based on the ability to inhibit prostaglandin synthesis by suppressing the cyclooxygenase enzyme.

Diclofenac exerts pronounced anti-inflammatory, analgesic, and moderate antipyretic effects. Its mechanism of action is related to inhibition of cyclooxygenase activity—the key enzyme in arachidonic acid metabolism, which is a precursor of prostaglandins that play a central role in the pathogenesis of inflammation, pain, and fever. The analgesic effect is mediated via two mechanisms: peripheral (indirectly, by inhibiting prostaglandin synthesis) and central (by suppressing prostaglandin synthesis in both the central and peripheral nervous systems). By blocking prostaglandin synthesis, diclofenac alleviates or significantly reduces inflammation symptoms. Diclofenac decreases prostaglandin-induced hypersensitivity of nerve endings to mechanical stimuli and biologically active substances produced at the inflammatory site and contributes to lowering body temperature. It reduces prostaglandin concentration in menstrual blood and the intensity of pain in primary dysmenorrhea. Diclofenac enhances joint mobility, reduces pain at rest and during movement. In vitro, at concentrations equivalent to those achieved in human tissues during therapy, diclofenac does not inhibit proteoglycan biosynthesis in cartilage tissue. It inhibits platelet aggregation. In traumatic and postoperative pain, the drug reduces pain sensations at rest and during movement, as well as inflammation-related swelling. A sustained effect is observed after 1–2 weeks of treatment.

Chlorzoxazone exerts muscle relaxant effects by blocking polysynaptic reflexes at the spinal cord level, which are involved in the development and maintenance of skeletal muscle spasms of various etiologies. Chlorzoxazone in combination with paracetamol produces muscle relaxant and analgesic effects.

The medicinal product Tilda® does not produce sedative effects.

Pharmacokinetics

Diclofenac is rapidly absorbed into the bloodstream, with peak plasma concentration reached within 1–2 hours. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration increases gradually and reaches higher levels than in plasma after 4 hours. Food may slow the rate of absorption but does not affect the extent of absorption. Bioavailability is approximately 5%.

The elimination half-life from plasma is 1–2 hours and from synovial fluid is 3–6 hours. Approximately 35% is excreted as metabolites in feces; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives, and about 1% is excreted unchanged.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentration is reached within 30–60 minutes. The elimination half-life is 1–4 hours. It is evenly distributed throughout all body fluids. Plasma protein binding is variable. Paracetamol is metabolized in the liver and primarily excreted by the kidneys as conjugated metabolites.

Chlorzoxazone is rapidly absorbed from the gastrointestinal tract. Peak plasma concentration is achieved within 1–2 hours. It is metabolized in the liver, primarily forming sulfate and glucuronide conjugates, and to a lesser extent via oxidation, producing cysteine and mercaptopyruvic acid. It is excreted in urine mostly as metabolites, with only 5% of the administered dose excreted unchanged. The elimination half-life is 1–4 hours.

Clinical characteristics.

Indications.

Acute pain (muscular, headache, toothache, spinal pain), in non-articular rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, acute gout attacks, primary dysmenorrhea, adnexitis, pharyngotonsillitis, otitis.

Post-traumatic and postoperative pain syndrome.

Contraindications.

Hypersensitivity to the active substances or to any other components of the medicinal product.

Acute gastric or intestinal ulcer; gastrointestinal hemorrhage or perforation.

History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

Active peptic ulcer/bleeding or recurrent disease/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding).

Hepatic failure.

Renal failure.

Congestive heart failure (functional class II–IV according to NYHA classification — New York Heart Association).

High risk of postoperative bleeding, coagulation disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular hemorrhage.

Contraindicated in patients who experience attacks of bronchial asthma (‘aspirin-induced asthma’), angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to ibuprofen, diclofenac, paracetamol, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Blood disorders, unexplained hematopoietic disorders, leukopenia.

Severe anemia.

Congenital hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase deficiency.

Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis).

Not to be used for the treatment of perioperative pain associated with coronary artery bypass grafting (or use of cardiopulmonary bypass).

Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.

Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.

Peripheral arterial disease.

Alcoholism.

Interaction with other medicinal products and other types of interactions.

Diclofenac.

Lithium, digoxin.

The medicinal product may increase plasma concentrations of lithium and digoxin. Monitoring of plasma levels of lithium and digoxin is recommended.

Diuretics and antihypertensive agents.

Concomitant use of diclofenac, as with other NSAIDs, with diuretics and antihypertensive agents [e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors] may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly, should be closely monitored for blood pressure. Adequate hydration is required, and monitoring of renal function is recommended upon initiation of concomitant therapy and regularly thereafter, particularly when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia.

Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is required.

Concomitant administration of the medicinal product Tilda® reduces the effect of furosemide and antihypertensive agents.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids.

Concomitant administration with nonsteroidal anti-inflammatory drugs and glucocorticoids increases the frequency of adverse gastrointestinal events, including gastrointestinal bleeding or ulcers. Concomitant use of the medicinal product with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for any potential benefit from synergistic effects.

Anticoagulants and antiplatelet agents.

Regular concomitant use of the medicinal product with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents may increase the risk of bleeding. Therefore, in such combinations, close and regular monitoring of patients is recommended, and careful monitoring is advised to ensure no dosage adjustments of anticoagulants are needed. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use of systemic NSAIDs and SSRIs increases the risk of gastrointestinal bleeding.

Antidiabetic agents.

The efficacy of antidiabetic agents is not altered when used concomitantly with the medicinal product. However, isolated reports of both hypoglycemia and hyperglycemia have been documented, necessitating dosage adjustments of antidiabetic agents during treatment. Therefore, blood glucose levels should be monitored during therapy.

Methotrexate.

Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels.

Caution should be exercised when using NSAIDs less than 24 hours before or after methotrexate administration, as this may increase methotrexate plasma concentrations and enhance its toxic effects. Cases of severe toxicity have been reported when the interval between methotrexate and NSAIDs, including diclofenac, was within 24 hours. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine.

The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be used at lower doses than in patients not receiving cyclosporine.

Tacrolimus.

Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors.

Antibacterial quinolones.

Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Phenytoin.

When phenytoin is used concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to the expected increased effect of phenytoin.

Cholestyramine and colestipol.

These agents may delay or reduce absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4–6 hours after cholestyramine/colestipol.

Cardiac glycosides.

Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate (GFR), and increase glycoside levels in plasma.

Mifepristone.

NSAIDs should not be used within 8–12 days after administration of mifepristone, as NSAIDs may reduce the efficacy of mifepristone.

Potent CYP2C9 inhibitors.

Caution is advised when co-administering diclofenac with potent CYP2C9 inhibitors (e.g., voriconazole), which may lead to significant increases in maximum plasma concentrations and exposure of diclofenac due to inhibition of diclofenac metabolism.

Medicinal products that induce drug-metabolizing enzymes.

Medicinal products that induce enzymes, such as rifampicin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum), etc., may theoretically reduce plasma concentrations of diclofenac.

Paracetamol.

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone, and decreased when used with cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effects of paracetamol by increasing its conversion to hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the risk of hepatotoxicity.

Concomitant use of high-dose paracetamol with isoniazid and rifampicin increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Paracetamol should be used with caution concomitantly with flucloxacillin, as such concomitant use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Do not use concomitantly with alcohol.

Effect on laboratory tests

Paracetamol may interfere with blood glucose testing by the glucose oxidase-peroxidase method. Paracetamol may affect blood uric acid tests performed by the phosphotungstic acid method. Cholestyramine may reduce the absorption rate of paracetamol.

Chlorzoxazone.

The effect of chlorzoxazone is enhanced by ethanol and other agents with central nervous system depressant effects. Use with caution together with phenytoin, barbiturates, rifampicin, phenylbutazone, and tricyclic antidepressants due to the risk of intoxication. Concomitant use with diuretics reduces the effectiveness of the latter; therefore, these agents should be administered with several hours apart. Concomitant use of chlorzoxazone with disulfiram reduces the plasma clearance of chlorzoxazone by 85%, resulting in a doubling of peak plasma concentration and prolongation of its elimination half-life from an average of 0.92 hours to 5.1 hours. When chlorzoxazone is used concomitantly with isoniazid in slow acetylators, a 56% reduction in chlorzoxazone clearance is observed, accompanied by enhanced sedative effects, headache, and nausea. Two days after discontinuation of concomitant use of chlorzoxazone and isoniazid, a reverse reaction occurs—an increase in chlorzoxazone clearance by 56% compared to baseline. Similar, but less pronounced, effects were observed in fast acetylators, where pharmacokinetic parameters of chlorzoxazone returned to baseline values within 2 days.

Special precautions for use.

For diclofenac.

To minimize adverse effects, treatment should be initiated with the lowest effective dose and continued for the shortest duration necessary to control symptoms.

Concomitant use of diclofenac with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to the lack of evidence for synergistic effect and the potential for additive adverse effects.

Caution is required in elderly patients. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Allergic reactions, including anaphylactic/anaphylactoid reactions, may occur with diclofenac, as with other NSAIDs, even in the absence of prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction. Symptoms of this reaction may include chest pain resulting from an allergic reaction to diclofenac.

Due to its pharmacodynamic properties, diclofenac may mask signs and symptoms of infection.

Gastrointestinal effects.

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported, which may be fatal and may occur at any time during treatment, with or without warning symptoms or history of serious gastrointestinal events. These events are usually more severe in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

Use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic insufficiency. Caution and close medical monitoring are recommended when using diclofenac after gastrointestinal surgery.

As with other NSAIDs, including diclofenac, medical supervision and special caution are required for patients with symptoms indicating gastrointestinal (GI) disturbances. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs likely to increase GI adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

Hepatic effects.

Close medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function impairment persists or worsens, and if clinical signs or symptoms may be related to progressive liver disease or other manifestations (e.g., eosinophilia, rash), the drug should be discontinued. Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when the drug is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, history of hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with the use of NSAIDs, including diclofenac. The highest risk of these reactions occurs early in the course of treatment, with most cases appearing within the first month of therapy. The drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue diseases.

Patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases may have an increased risk of aseptic meningitis.

Cardiovascular and cerebrovascular effects.

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAID use, including diclofenac.

Clinical trial data and epidemiological evidence suggest that use of diclofenac, particularly at high doses (150 mg/day) and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful risk/benefit assessment and at a dose not exceeding 100 mg/day. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes, smokers).

Patients should be informed about the possibility of serious thrombotic events (chest pain, dyspnea, weakness, speech disturbances), which may occur at any time. In such cases, immediate medical attention is required.

Hematological effects.

With prolonged use of this drug, as with other NSAIDs, monitoring of complete blood count is recommended.

Diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostatic disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma.

Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (e.g., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience reactions to NSAIDs, such as asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautions (readiness for emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, pruritus, or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm in patients with bronchial asthma or a history of bronchial asthma.

For paracetamol.

Consult a physician before use if the patient is taking warfarin or similar anticoagulant agents.

Patients who take analgesics daily for mild arthritis should consult a physician.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism) treated with therapeutic doses of paracetamol over a long period or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring of the patient are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the primary cause of HAGMA in patients with multiple risk factors.

Consult a physician regarding the possibility of using the drug in patients with impaired renal or hepatic function.

Note that the risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic liver disease; the drug may affect laboratory test results for blood glucose and uric acid levels.

Do not exceed the recommended doses.

Do not take the drug with other products containing paracetamol.

If symptoms persist, consult a physician.

For chlorzoxazone.

Should not be prescribed to patients with impaired liver function and should be discontinued if signs of hepatotoxicity appear. Patients who develop symptoms such as fever, rash, jaundice, dark urine, loss of appetite, nausea, or vomiting should seek medical advice. Should not be prescribed to patients with porphyria.

Like other NSAIDs, the drug may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostatic disorders.

Do not exceed the recommended doses.

Note that the risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic non-cirrhotic liver disease; the drug may affect laboratory test results for blood glucose and uric acid levels.

Do not take simultaneously with other products containing paracetamol or diclofenac.

Alcohol should not be consumed during treatment.

Excipients.

The medicinal product contains the colorant quinoline yellow (E 104), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy or breastfeeding.

Use of diclofenac from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of diclofenac.

After exposure to diclofenac for several days starting from the 20th week of pregnancy, fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors, including diclofenac, may cause:

in the fetus:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above);

in the mother and newborn at the end of pregnancy:

• possible prolongation of bleeding time, antiaggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed and prolonged labor.

Fertility in women.

Use of diclofenac may impair fertility in women and is not recommended for women wishing to become pregnant. For women experiencing difficulties with conception or undergoing infertility investigations, discontinuation of the drug should be considered.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, drowsiness, or other central nervous system effects during treatment should refrain from driving or operating machinery.

Dosage and Administration

The dosage is determined individually by a physician for each patient, depending on the patient's age, nature and course of the disease, individual tolerance, and therapeutic efficacy of the drug. The medication should be used at the lowest effective doses for the shortest duration necessary, taking into account the treatment goals for each individual patient.

For adults and children aged 14 years and older, the recommended dose is 1 tablet 2–3 times daily after meals.

Do not chew the tablets; swallow them with sufficient amount of water (0.5–1 glass).

The interval between doses should be at least 4 hours.

The treatment duration should not exceed 5–7 days and depends on the symptom dynamics.

The maximum daily dose of the drug for adults and children aged 14 years and older is 3 tablets.

The maximum duration of use without medical consultation is 3 days.

Children

The medication is contraindicated in children under 14 years of age.

Overdose

Diclofenac

Symptoms

There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, and seizures. Acute renal failure and liver damage are possible in cases of severe intoxication.

Treatment

Management of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes management of arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because the active substances of these drugs are highly protein-bound and undergo extensive metabolism. After ingestion of potentially toxic doses, activated charcoal may be administered. Following ingestion of potentially life-threatening doses, gastrointestinal decontamination (e.g., induced emesis, gastric lavage) should be considered.

Paracetamol

Hepatic injury may occur in adults who ingest 10 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., malnutrition, AIDS, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage. Symptoms of overdose within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may result in death. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported. With prolonged use of the drug in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop from the hematopoietic system. From the nervous system: dizziness, psychomotor agitation, and disorientation; from the urinary system: nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis); from the digestive system: hepatonecrosis.

Treatment

Emergency supportive and symptomatic therapy is required.

In case of overdose, immediate medical assistance is necessary. The patient should be taken to hospital immediately, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting, or may not reflect the severity of overdose or risk of organ damage.

If an excessive dose was ingested within the past hour, administration of activated charcoal should be considered. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to the established dosing regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, as the active substances of the drug are highly bound to plasma proteins and undergo extensive metabolism.

Chlorzoxazone

After chlorzoxazone overdose, gastrointestinal disturbances, drowsiness, dizziness, headache, malaise, lethargy, followed by pronounced loss of muscle tone, hypotonia, hypotension, and respiratory depression may occur. Cases of coma after chlorzoxazone overdose have been reported, one of which occurred after intravenous administration of flumazenil. Hepatotoxicity with fatal outcomes and one case of torticollis have been occasionally reported after chlorzoxazone overdose.

Treatment

Emergency supportive and symptomatic therapy is required. Gastric lavage and administration of activated charcoal should be performed. Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, as the active substances of the drug are highly bound to plasma proteins and undergo extensive metabolism.

Adverse reactions.

Metabolism and nutrition disorders: Frequency unknown – metabolic acidosis with high anion gap.

Gastrointestinal disorders: Nausea, vomiting, diarrhea, epigastric pain, heartburn, anorexia, increased liver transaminase activity, dyspepsia, abdominal pain, flatulence, gastritis; gastrointestinal bleeding, hemorrhages and perforations, sometimes fatal, especially in elderly patients; vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with or without bleeding or perforation (sometimes fatal, especially in elderly patients), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation; stomatitis, including ulcerative stomatitis, glossitis; esophageal disorders, diaphragm-like intestinal stricture; pancreatitis.

Nervous system disorders: Sensory disturbances, headache, dizziness, somnolence, fatigue, excitement, paresthesia, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, cerebral circulation disorders, stroke, visual disturbances, blurred vision, general malaise.

Psychiatric disorders: Hallucinations, disorientation, depression, memory impairment, sleep disorders, nightmares, insomnia, irritability, restlessness, fear, psychotic disorders, confusion, psychomotor agitation.

Eye disorders: Visual disturbances, blurred vision, diplopia, optic neuritis.

Ear and labyrinth disorders: Vertigo, tinnitus, ear noise, hearing disturbances.

Cardiac and vascular disorders: Palpitations, tachycardia, dyspnea, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; frequency unknown – Kounis syndrome.

Blood and lymphatic system disorders: Thrombocytopenia, leukopenia, neutropenia, anemia, including aplastic anemia; hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency), agranulocytosis, pancytopenia, sulfhemoglobinemia, methemoglobinemia (cyanosis, dyspnea, chest pain).

Respiratory, thoracic and mediastinal disorders: Bronchospasm (especially in patients sensitive to acetylsalicylic acid and other NSAIDs), bronchial asthma (including dyspnea), chest pain, pneumonitis.

Renal and urinary disorders: Change in urine color, hematuria, acute nephritis, acute renal failure, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

Endocrine disorders: Hypoglycemia, up to hypoglycemic coma.

Immune system disorders: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions, including arterial hypotension and anaphylactic shock, Quincke’s edema, angioneurotic edema (including facial edema).

Hepatobiliary disorders: Elevated transaminase levels, liver failure, liver function disorders, hepatitis, liver necrosis, jaundice, fulminant hepatitis.

Skin and subcutaneous tissue disorders: Itching, skin rashes, redness, mucosal rashes, urticaria, bullous rashes, eczema, exudative polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, allergic dermatitis, alopecia, photosensitivity reactions, purpura, including allergic purpura.

General disorders: Fluid retention, general weakness, fatigue, increased sweating.

Reproductive system and breast disorders: Impotence.

Diclofenac, especially at high doses (150 mg/day) and with prolonged use, may increase the risk of arterial thromboembolic events (e.g., myocardial infarction or stroke).

Paracetamol may cause such adverse reactions as bruising and bleeding.

Chlorzoxazone may cause such adverse reactions: hyperstimulation, petechiae, ecchymosis, hepatotoxicity, sometimes fatal, rarely torticollis, somnolence, dizziness, sometimes gastrointestinal irritation, occasionally gastrointestinal bleeding, headache, rarely hypersensitivity reactions, including skin rashes, bruising, urticaria, itching, Quincke’s edema, anaphylactoid reactions. In some patients, jaundice and liver damage have occurred after taking the drug.

Description of selected adverse reactions

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

4 tablets per strip; 1 strip per envelope, 50 envelopes per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Genome Biotech Pvt. Ltd.

Manufacturer’s address and place of business.

Plot No. D-121, 122, 123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra State, India.