INSTRUCTION

for medical use of the medicinal product

 

TILDA^®

(TILDA)

 

Composition:

active substances:

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

excipients: corn 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.

Basic physical and chemical properties: yellow, oblong, biconvex, film-coated tablets with a scoreline on one side and smooth on the other side.

 

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Diclofenac, combinations. ATC code M01A B55.

 

Pharmacological properties.

Pharmacodynamics.

Tilda^® is a combined drug with muscle relaxant and analgesic effects.

Paracetamol has analgesic, antipyretic, and moderately expressed anti-inflammatory effects. Paracetamol inhibits cyclooxygenase predominantly in the central nervous system, affecting pain and thermoregulation centers. The analgesic effect is based on the ability to inhibit prostaglandin synthesis due to inhibition of the cyclooxygenase enzyme.

Diclofenac exerts a pronounced anti-inflammatory, analgesic, and moderate antipyretic effect. The mechanism of action is associated with the inhibition of cyclooxygenase activity – the main enzyme in the metabolism of arachidonic acid, which is a precursor of prostaglandins that play a key role in the pathogenesis of inflammation, pain, and fever. The analgesic effect is due to two mechanisms: peripheral (indirectly, by inhibiting prostaglandin synthesis) and central (by inhibiting prostaglandin synthesis in the central and peripheral nervous system). Diclofenac, by blocking prostaglandin synthesis, relieves or significantly reduces inflammation symptoms. Diclofenac reduces prostaglandin-induced increased sensitivity of nerve endings to mechanical stimuli and biologically active substances formed at the site of inflammation; promotes a decrease in body temperature. It reduces the concentration of prostaglandins in menstrual blood and the intensity of pain in primary dysmenorrhea. Diclofenac helps increase the range of motion in affected joints, and reduces pain at rest and during movement. In vitro, diclofenac at a concentration equivalent to that achieved in human tissues during treatment does not inhibit the biosynthesis of proteoglycans 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 inflammatory edema. A stable effect is observed after 1–2 weeks of treatment.

Chlorzoxazone has a muscle relaxant effect, blocking at the spinal cord level the multisynaptic reflexes involved in the occurrence and maintenance of skeletal muscle spasm of various etiologies. Chlorzoxazone in combination with paracetamol causes muscle relaxant and analgesic effects.

The medicinal product Tilda^® does not exert a sedative effect.

Pharmacokinetics.

Diclofenac is rapidly absorbed into the blood; maximum plasma concentration is reached in 1–2 hours. Binding to plasma proteins is over 99 %. Penetrates well into tissues and synovial fluid, where its concentration increases slowly, reaching higher values than in plasma after 4 hours. Food may slow the rate of absorption without affecting the extent of absorption. Bioavailability is about 50 %.

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

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached in 30–60 minutes. Elimination half-life is 1–4 hours. It is evenly distributed throughout all body fluids. Binding to plasma proteins is variable. Paracetamol is metabolized in the liver and excreted mainly by the kidneys in the form of conjugated metabolites.

Chlorzoxazone is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached in 1–2 hours. It is metabolized in the liver, mainly forming conjugates with sulfates and glucuronides and to a minor extent by oxidation to form cysteine and mercapturic acid. It is excreted in urine mostly as metabolites, and only 5 % of the administered dose is excreted unchanged. The elimination half-life is 1–4 hours.

 

Clinical characteristics.

Indications.

Acute pain (muscular, headache, toothache, localized in the spine), in non-articular rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthropathy, acute attacks of gout, primary dysmenorrhea, adnexitis, pharyngotonsillitis, otitis.

Post-traumatic and postoperative pain syndrome.

 

Contraindications.

Hypersensitivity to the active substances or to any other components of the drug.

Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

History of gastrointestinal bleeding or perforation associated with previous treatment with non-steroidal anti-inflammatory drugs (NSAIDs).

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

Hepatic insufficiency.

Renal insufficiency.

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

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

Contraindicated in patients in whom attacks of bronchial asthma ("aspirin asthma"), angioedema, urticaria, or acute rhinitis, nasal polyps, and other allergic symptoms occur in response to the use of ibuprofen, diclofenac, paracetamol, acetylsalicylic acid, or other NSAIDs.

Blood diseases, unexplained origin blood formation 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 in coronary artery bypass graft surgery (or when using a cardiopulmonary bypass machine).

Ischemic heart disease in patients with angina, a history of myocardial infarction.

Cerebrovascular disease in patients with a history of stroke or episodes of transient ischemic attacks.

Peripheral arterial disease.

Alcoholism.

 

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Lithium, digoxin.

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

Diuretics and antihypertensive agents.

Concomitant use of diclofenac, like other NSAIDs, with diuretics and antihypertensive agents [e.g., β-blockers, angiotensin-converting enzyme inhibitors (ACEIs)] may lead to a reduction in their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such a combination should be used with caution, and patients, especially the elderly, should be carefully monitored for blood pressure. Patients should be adequately hydrated, and monitoring of renal function is also recommended after initiation of concomitant therapy and regularly thereafter, especially when using diuretics and ACE inhibitors, due to an increased risk of nephrotoxicity.

Drugs causing hyperkalemia.

Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels, so patient monitoring should be performed more frequently.

Concomitant use of the drug Tilda^® leads to a reduction in the effect of furosemide and antihypertensive agents.

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

Concurrent administration with non-steroidal anti-inflammatory drugs, glucocorticosteroids increases the frequency of adverse gastrointestinal events, including gastrointestinal bleeding or ulcers. Concomitant use of the drug with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to the absence of any evidence of possible benefit from synergistic action.

Anticoagulants and antiplatelet agents.

Regular concomitant use of the drug with anticoagulants, especially warfarin and other coumarins, and antiplatelet drugs may lead to an increased risk of bleeding. Therefore, in the case of such a combination of drugs, careful and regular monitoring of patients is recommended, and to be confident that no changes in anticoagulant dosing are needed, careful monitoring of such patients is recommended. Like other non-steroidal anti-inflammatory drugs, diclofenac in high doses can temporarily inhibit platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs).

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

Antidiabetic drugs.

With concomitant use of the drug and antidiabetic drugs, the effectiveness of the latter does not change. However, there are isolated reports of both hypoglycemia and hyperglycemia in such cases, necessitating a change in the dose of hypoglycemic drugs during the use of the drug. Therefore, blood glucose levels should be monitored during therapy.

Methotrexate.
Diclofenac may inhibit the renal tubular clearance of methotrexate, leading to increased methotrexate levels.

Caution should be exercised when using NSAIDs less than 24 hours before or after methotrexate administration, as in such cases the concentration of methotrexate in the blood may increase and its toxic effect may be enhanced. There are data on cases of serious toxicity when the interval between methotrexate and NSAID use, including diclofenac, was within 24 hours. This interaction is mediated through the accumulation of methotrexate due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine.
The effect of diclofenac, like other NSAIDs, on prostaglandin synthesis in the kidneys may enhance the nephrotoxicity of cyclosporine; therefore, diclofenac should be used in lower doses than for patients not using cyclosporine.

Tacrolimus.
When using NSAIDs with tacrolimus, an increased risk of nephrotoxicity is possible, which may be mediated through the renal antiprostaglandin effects of NSAIDs and the calcineurin inhibitor.

Antibacterial quinolones.

There is a potential risk of seizures in patients using quinolone derivatives concomitantly with NSAIDs. This can be observed in patients with and without a history of epilepsy and seizures. Therefore, caution should be exercised when deciding on the use of a quinolone in patients already receiving NSAIDs.

Phenytoin.
When using phenytoin concurrently with diclofenac, monitoring of plasma phenytoin concentration is recommended due to the expected increase in phenytoin effect.

Cholestipol and cholestyramine.

These drugs may cause a delay or decrease in the absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4-6 hours after cholestipol/cholestyramine use.

Cardiac glycosides.

Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce GFR, and increase plasma glycoside levels.

Mifepristone.
NSAIDs should not be used for 8–12 days after mifepristone administration, as NSAIDs may reduce the effect of mifepristone.

Potent CYP2C9 inhibitors.

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

Drugs that induce drug-metabolizing enzymes.

Drugs that induce enzymes, e.g., rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), etc., are theoretically capable of reducing plasma concentrations of diclofenac.

Paracetamol.

The absorption rate of paracetamol may increase with the use of metoclopramide and domperidone and decrease with the use of cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced with long-term regular daily concomitant use of paracetamol, increasing the risk of bleeding. Occasional intake has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine) that stimulate the activity of hepatic microsomal enzymes may enhance the toxic effect of paracetamol on the liver due to increased conversion of the drug into hepatotoxic metabolites. When paracetamol is used concomitantly with hepatotoxic agents, the toxic effect of the drugs on the liver increases.

Concomitant use of high doses of paracetamol with isoniazid, rifampicin increases the risk of developing a hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Do not use concurrently with alcohol.

Effect on laboratory tests

The use of paracetamol may affect the results of blood glucose analysis performed by the glucose oxidase-peroxidase method. The use of paracetamol may affect uric acid blood tests performed by the phosphotungstate method. The absorption rate of paracetamol may be decreased by cholestyramine.

Chlorzoxazone.

The effect of chlorzoxazone is enhanced by ethanol and other agents that have a depressant effect on the central nervous system. Prescribe with caution together with phenytoin, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants, because there is a risk of intoxication. Concomitant use with diuretic drugs reduces the effectiveness of the latter, so the drugs should be taken several hours apart. Concomitant use of chlorzoxazone with disulfiram leads to an 85% reduction in plasma clearance of chlorzoxazone, resulting in a doubling of the peak plasma concentration of chlorzoxazone and prolongation of its half-life on average from 0.92 h to 5.1 h. When chlorzoxazone and isoniazid are used concomitantly in slow acetylators, a 56% reduction in chlorzoxazone clearance is noted, accompanied by increased sedative effect, 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 the baseline value. Similar, but less pronounced effects were also recorded in rapid acetylators, in whom the pharmacokinetic parameters of chlorzoxazone returned to baseline within 2 days.

 

Precautions for use.

For diclofenac.

To minimize adverse effects, treatment should be started with the lowest effective dose and continued for the shortest time 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 any evidence of synergistic effect and due to potential additive side effects.

Caution is required regarding elderly patients. In particular, it is recommended to use the lowest effective dose in debilitated elderly patients or those with low body weight.

When using diclofenac, as with other NSAIDs, allergic reactions may be observed, including anaphylactic/anaphylactoid reactions, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome – a serious allergic reaction that can lead to myocardial infarction. Symptoms of this syndrome reaction may include chest pain that occurs as a result of an allergic reaction to diclofenac.

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

Effect on the digestive tract.

With the use of all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (cases of hematemesis, melena), ulcer formation or perforation have been reported, which may be fatal and occur at any time during treatment with or without warning symptoms or a history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If patients receiving diclofenac experience gastrointestinal bleeding or ulcer formation, use of the drug must be discontinued.

The use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic leakage. When using diclofenac after gastrointestinal surgery, caution is recommended and careful medical supervision should be carried out.

As with the use of other NSAIDs, including diclofenac, medical supervision and special caution are mandatory for patients with symptoms indicative of gastrointestinal (GI) disorders. The risk of GI bleeding, ulcer, or perforation increases with increasing doses of NSAIDs, including diclofenac.

Elderly patients have an increased frequency of adverse reactions to NSAID use, especially regarding gastrointestinal bleeding and perforation, which can be fatal.

To reduce the risk of such toxic effects on the GI tract, treatment is initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of medicinal products containing low doses of acetylsalicylic acid (ASA/aspirin) or other drugs that are likely to increase the risk of adverse GI effects, consideration should be given to combination 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 (especially GI bleeding). Warnings are also required for patients receiving concomitant medications that may increase the risk of ulcer or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antithrombotic agents (e.g., ASA), or selective serotonin reuptake inhibitors.

Effect on the liver.

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

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

During long-term treatment with the drug, regular monitoring of liver function and liver enzyme levels is prescribed as a precautionary measure. If liver function impairment persists or worsens and if clinical signs or symptoms may be associated with progressive liver disease or if other manifestations occur (e.g., eosinophilia, rash), use of the drug should be discontinued. The course of diseases such as hepatitis may proceed without prodromal symptoms. Precautions are necessary if the drug is used in patients with hepatic porphyria, due to the possibility of provoking an attack.

Effect on the kidneys.

Since cases of fluid retention and edema have been reported with NSAID treatment, including diclofenac, special attention should be paid to patients with impaired heart or kidney function, a history of arterial hypertension, elderly patients, patients receiving concomitant therapy with diuretics or drugs that significantly affect kidney function, as well as patients with a significant decrease in extracellular fluid volume for any reason, for example, before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to a return to the pre-treatment state.

Effect on the skin

In connection with the use of NSAIDs, including diclofenac, very rare cases of serious skin reactions (some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) have been reported. In patients, the highest risk of developing these reactions is observed at the beginning of the treatment course: the onset of the reaction is noted in most cases within the first month of treatment. Use of the drug must be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue diseases.

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases, there may be an increased risk of developing aseptic meningitis.

Cardiovascular and cerebrovascular effects.

For patients with a history of arterial hypertension and/or mild or moderate congestive heart failure, appropriate monitoring and recommendations are necessary, since cases of fluid retention and edema have been reported in connection with the use of NSAIDs, including diclofenac.

Clinical trial data and epidemiological data indicate that the use of diclofenac, especially in high doses (150 mg/day) and with long-term treatment, may be associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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

Patients should be informed about the possibility of serious antithrombotic incidents (chest pain, shortness of breath, weakness, speech impairment), which may occur at any time. In this case, a doctor should be consulted immediately.

Effect on hematological parameters.

With long-term use of this drug, as with other NSAIDs, monitoring of a complete blood count is recommended.

Diclofenac may temporarily inhibit platelet aggregation. Patients with hemostasis disorders, hemorrhagic diathesis, or hematological disorders should be carefully observed.

History of asthma.

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms), reactions to NSAIDs such as asthma exacerbation (so-called analgesic intolerance/analgesic asthma), angioedema, or urticaria occur more frequently. In this regard, special precautions (readiness to provide emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, itching, or urticaria.

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

For paracetamol.

Before using the drug, it is necessary to consult a doctor if the patient is using warfarin or similar drugs that have an anticoagulant effect.

Patients who take analgesics daily for mild forms of arthritis need to consult a doctor. In patients with severe infections, such as sepsis, accompanied by reduced glutathione levels, taking paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis are deep, rapid, or labored breathing, nausea, vomiting, loss of appetite. A doctor should be consulted immediately if these symptoms appear.

It is necessary to consult a doctor regarding the possibility of using the drug in patients with impaired kidney and liver function.

Consider that in patients with alcoholic liver damage, the risk of hepatotoxic effects of paracetamol increases; the drug may affect the results of laboratory tests regarding blood glucose and uric acid content.

Do not exceed the indicated doses.

Do not take the drug with other products containing paracetamol.

If symptoms do not disappear, consult a doctor.

For chlorzoxazone.

Should not be prescribed to patients with impaired liver function and should be discontinued if signs of hepatotoxicity appear. Patients, who develop signs after use, such as fever, rash, jaundice, dark urine, loss of appetite, nausea, vomiting, should consult a doctor. It should not be prescribed to patients with porphyria.

Like other NSAIDs, the drug may temporarily inhibit platelet aggregation. Patients with hemostasis disorders should be carefully observed.

Do not exceed the indicated doses.

Consider that in patients with alcoholic non-cirrhotic liver damage, the risk of hepatotoxic effects of paracetamol increases; the drug may affect the results of laboratory tests regarding blood glucose and uric acid content.

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

Do not consume alcohol during use.

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

 

Pregnancy and lactation.

The drug is contraindicated during pregnancy or breastfeeding.

Fertility in women.

Use of diclofenac may lead to impaired fertility in women and is not recommended for women trying to conceive. For women who may have difficulty conceiving or who are undergoing infertility investigation, discontinuation of the drug should be considered.

 

Effects on ability to drive and use machines.

Patients who experience visual disturbances, dizziness, drowsiness, or other central nervous system disorders during treatment with the drug should refrain from driving vehicles and working with other machinery.

 

Method of administration and dosage.

The dose is determined by the doctor for each patient individually, depending on the patient's age, nature and course of the disease, individual tolerance, and therapeutic effectiveness of the drug. The drug should be used in the lowest effective doses for the shortest period of time, taking into account the treatment goals for each individual patient.

Adults and children aged 14 years and older: 1 tablet 2–3 times a day after meals.

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

The interval between doses is at least 4 hours.

The duration of the treatment course is no more than 5–7 days and depends on 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 consulting a doctor is 3 days.

 

Children.

The drug 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, agitation, coma, drowsiness, tinnitus, and convulsions. Acute renal failure and liver damage are possible in case of severe intoxication.

Treatment.
Treatment of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This applies to manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, respiratory depression. It is unlikely that specific therapeutic measures such as forced diuresis, dialysis, or hemoperfusion will be effective for removing NSAIDs, including diclofenac, because the active substances of these drugs are largely bound to blood proteins and undergo intensive metabolism. After potentially toxic doses, activated charcoal can be used, and after potentially life-threatening doses, gastric decontamination (e.g., inducing vomiting, gastric lavage) can be performed.

Paracetamol.

Liver damage may occur in adults who have taken 10 g or more of paracetamol, and in children who have taken more than 150 mg/kg body weight. In patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other liver enzyme-inducing drugs; alcohol abuse; glutathione system deficiency, e.g., malnutrition, AIDS, starvation, cystic fibrosis, cachexia), taking 5 g or more of paracetamol may lead to liver damage. Overdose symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12-48 hours after overdose. Glucose metabolism disorders and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and lead to death. Acute renal failure with acute tubular necrosis may manifest as severe pain in the lumbar region, hematuria, proteinuria, and develop even in the absence of severe liver damage. Cardiac arrhythmia and pancreatitis have also been noted. With long-term use of the drug in large doses, from the hematopoietic organs, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia may develop. From the nervous system with large doses: 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 measures.

In case of overdose, prompt medical assistance is necessary. The patient should be taken to the hospital immediately, even if there are no early symptoms of overdose. Symptoms may be limited to nausea and vomiting, or may not reflect the severity of the overdose or the risk of organ damage.

If an excessive dose of the drug was taken within 1 hour, the advisability of using activated charcoal should be considered. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be applied within 24 hours of ingestion, but the maximum protective effect is obtained if applied within 8 hours of ingestion. The effectiveness of the antidote sharply decreases after this time. If necessary, administer N-acetylcysteine intravenously to the patient according to the established dosage regimen. In the absence of vomiting, methionine orally may be used as an appropriate alternative in remote areas outside the hospital.

Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective for removing NSAIDs, because the active substances of the drug are largely bound to plasma proteins and undergo intensive metabolism.

Chlorzoxazone.

After chlorzoxazone overdose, gastrointestinal disorders, drowsiness, dizziness, headache, malaise, lethargy with subsequent pronounced loss of muscle tone, hypotension, respiratory depression may occur. Isolated cases of coma following chlorzoxazone overdose have been reported; in one case, coma occurred after intravenous administration of flumazenil. Cases of hepatotoxicity with fatal outcome and one case of torticollis after chlorzoxazone overdose have sometimes been recorded.

Treatment.
Emergency supportive and symptomatic therapy measures. Gastric evacuation by lavage, and use of activated charcoal. Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective for removing NSAIDs, because the active substances of the drug are largely bound to plasma proteins and undergo intensive metabolism.

 

Adverse reactions.

Gastrointestinal disorders: nausea, vomiting, diarrhea, epigastric pain, heartburn, anorexia, increased liver transaminase activity, dyspepsia, abdominal pain, flatulence, gastritis; gastrointestinal bleeding, bleeding and perforations, sometimes fatal, especially in elderly patients; hematemesis, hemorrhagic diarrhea, melena, gastric or intestinal ulcer, with or without accompanying 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 dysfunction, diaphragmatic-like intestinal stenosis; pancreatitis.

Nervous system disorders: sensitivity disorders, headache, dizziness, drowsiness, fatigue, agitation, paresthesia, convulsions, anxiety, tremor, aseptic meningitis, taste disorders, cerebrovascular disorders, stroke, visual disturbances, blurred vision, general malaise.

Psychic disorders: hallucinations, disorientation, depression, memory impairment, sleep disorders, nightmares, insomnia, irritability, anxiety, feeling of fear, psychotic disorders, confusion, psychomotor agitation.

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

Ear disorders: vertigo, ringing in the ears, tinnitus, hearing disorders.

Cardiovascular system disorders: palpitations, tachycardia, shortness of breath, pain in the heart area, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; unknown – Kounis syndrome.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, neutropenia, anemia, including aplastic anemia; hemolytic anemia (especially for patients with glucose-6-phosphate dehydrogenase deficiency), agranulocytosis, pancytopenia, sulfhemoglobinemia, methemoglobinemia (cyanosis, shortness of breath, heart pain).

Respiratory system, thoracic and mediastinal organs disorders: bronchospasm (especially in patients sensitive to acetylsalicylic acid and to other NSAIDs), bronchial asthma (including shortness of breath), chest pain, pneumonitis.

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

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Immune system disorders: hypersensitivity reactions, anaphylactic/anaphylactoid reactions, including arterial hypotension and anaphylactic shock, angioedema, angioneurotic edema (including facial edema).

Hepatobiliary system disorders: increased transaminase levels, liver failure, impaired liver function, hepatitis, liver necrosis, jaundice, fulminant hepatitis.

Skin and subcutaneous tissue disorders: itching, skin rash, redness, rash on mucous membranes, urticaria, bullous eruptions, eczema, exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, allergic dermatitis, hair loss, photosensitivity reactions, purpura, including allergic.

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

Reproductive system and mammary glands disorders: impotence.

Diclofenac, especially in high doses (150 mg/day) and with long-term use, may increase the risk of arterial thromboembolism (e.g., myocardial infarction or stroke).

Paracetamol may cause adverse reactions such as bruising and bleeding.

Chlorzoxazone may cause the following adverse reactions: hyperstimulation, petechiae, ecchymosis, hepatotoxicity, sometimes fatal, rarely torticollis, drowsiness, dizziness, sometimes gastrointestinal irritation, sometimes gastrointestinal bleeding, headache, rarely hypersensitivity reactions, including skin rash, bruising, urticaria, itching, angioedema, anaphylactoid reactions. In some patients, jaundice and liver damage occurred as a result of taking the drug.

 

Shelf-life. 3 years.

 

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

 

Packaging.

4 tablets in a blister; 1 blister in a cardboard envelope, 50 cardboard envelopes in a cardboard box.

 

Terms of dispensing.

On prescription.

 

Manufacturer.

Genom Biotech Pvt. Ltd.

 

Location of the manufacturer and address of its activity.

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