Zotek®-200

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOTEK®-200 (ZOTEK®-200) ZOTEK®-300 (ZOTEK®-300) ZOTEK®-400 (ZOTEK®-400)

Composition:

Active substance: dexibuprofen;

One film-coated tablet contains dexibuprofen 200 mg or 300 mg or 400 mg;

Excipients: microcrystalline cellulose, anhydrous colloidal silicon dioxide, talc, carmellose calcium; coating composition: hypromellose, titanium dioxide (E 171), talc, dichloromethane, isopropyl alcohol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

ZOTEK®-200: white, round, biconvex, film-coated tablets.

ZOTEK®-300 and ZOTEK®-400: white, oval, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Dexibuprofen. ATC code M01A E14.

Pharmacological properties.

Pharmacodynamics.

Dexibuprofen is the pharmacologically active isomer of racemic ibuprofen and belongs to non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). Its mechanism of action is associated with inhibition of prostaglandin synthesis. The drug possesses antipyretic, analgesic, and anti-inflammatory properties.

Results of comparative clinical studies in the treatment of osteoarthritis, dysmenorrhea, and pain (including dental pain) indicate that dexibuprofen at a dose twice lower than that of ibuprofen has comparable efficacy.

Pharmacokinetics.

After oral administration, dexibuprofen is rapidly and completely absorbed from the small intestine. Maximum plasma concentration is reached approximately 2 hours after oral administration of 200 mg of the drug. Plasma protein binding is approximately 99%.

Dexibuprofen is metabolized in the liver (via hydroxylation and carboxylation) and subsequently excreted as inactive metabolites, primarily (90%) via the kidneys, and the remainder via bile. The elimination half-life ranges from 1.8 to 3.5 hours.

Clinical characteristics.

Indications.

Symptomatic therapy of mild to moderate pain of various origins: headache, toothache, back pain, joint pain, muscle pain, rheumatic pain, dysmenorrhea.

Contraindications.

Hypersensitivity to dexibuprofen, other NSAIDs, or to any component of the drug; use in patients in whom substances with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, bronchospasm, acute rhinitis, or lead to the development of nasal polyps, urticaria, or angioedema; bleeding or gastrointestinal perforation in medical history associated with the use of NSAIDs; active phase of peptic ulcer disease/gastrointestinal bleeding, peptic ulcer disease/gastrointestinal bleeding in medical history (no fewer than two confirmed episodes of ulcer or bleeding); Crohn’s disease or active phase of ulcerative colitis; cerebrovascular hemorrhage or other active bleeding; disorders of blood formation or blood coagulation; severe hepatic insufficiency, severe renal insufficiency, severe heart failure.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of dexibuprofen with the following medicinal products is not recommended

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin. In case of concomitant use, monitoring of coagulation parameters is recommended, and the dose of anticoagulants should be adjusted if necessary.

Other NSAIDs, including acetylsalicylic acid (in doses exceeding 100 mg per day). Concomitant use of other NSAIDs, including selective COX-2 inhibitors, may increase the risk of gastrointestinal ulcers and bleeding.

Lithium. NSAIDs may increase plasma lithium levels by reducing its renal clearance. In case of concomitant use, frequent monitoring of plasma lithium levels is required, and dose reduction should be considered if necessary.

Methotrexate when administered at a dose of 15 mg/week or higher. When NSAIDs are used within 24 hours before or after methotrexate administration, the plasma levels of the latter may increase due to reduced renal clearance, thereby increasing its toxic effects.

Concomitant use of dexibuprofen with the following medicinal products should be performed with caution

Aminoglycosides, tacrolimus, sirolimus, cyclosporine. Concomitant use with NSAIDs may increase the risk of nephrotoxicity due to reduced synthesis of prostaglandins. Continuous monitoring of kidney function is required during concomitant use, especially in elderly patients.

Antihypertensive agents. NSAIDs may reduce the effectiveness of beta-blockers, possibly due to inhibition of vasodilatory prostaglandin synthesis.

Concomitant use of NSAIDs with ACE inhibitors may increase the risk of acute renal failure, particularly in patients with pre-existing kidney dysfunction, elderly patients, and patients with dehydration. Monitoring of kidney function should be initiated at the beginning of treatment.

Antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs). Concomitant use with NSAIDs may increase the risk of gastrointestinal bleeding.

Acetylsalicylic acid (at doses below 100 mg per day). Concomitant use with NSAIDs may impair the ability of low-dose acetylsalicylic acid to inhibit platelet aggregation.

Digoxin. NSAIDs may increase plasma digoxin levels and enhance its toxicity.

Agents that increase plasma potassium levels (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, cyclosporine, tacrolimus, trimethoprim, heparin). NSAIDs may increase plasma potassium levels. Monitoring of plasma potassium levels is recommended during concomitant use.

Zidovudine. Concomitant use of NSAIDs and zidovudine increases the risk of hemarthrosis and hematoma in patients with hemophilia.

Potassium-sparing, loop, and thiazide diuretics. Concomitant use with NSAIDs may increase the risk of renal failure due to reduced renal blood flow.

Corticosteroids. Concomitant use with NSAIDs may increase the risk of gastrointestinal bleeding and ulcers.

Methotrexate when administered at a dose less than 15 mg/week. Dexibuprofen may increase plasma methotrexate levels. During concomitant use of dexibuprofen and low-dose methotrexate (less than 15 mg/week), monitoring of blood parameters is required, especially at the beginning of treatment. This combination should be used with particular caution in patients with impaired renal function (even of moderate degree), particularly elderly patients, and continuous monitoring of kidney function is recommended.

Pemetrexed. High doses of NSAIDs may increase plasma pemetrexed levels. Patients with impaired renal function should avoid using NSAIDs for 2 days before and 2 days after pemetrexed administration.

Oral antidiabetic agents. Concomitant use of NSAIDs with sulfonylureas may lead to fluctuations in plasma glucose levels. Monitoring of plasma glucose levels may be required.

Thrombolytics, antiaggregants. Dexibuprofen enhances the antithrombotic effect of the latter by inhibiting platelet aggregation.

Phenytoin. Some NSAIDs may increase plasma phenytoin levels and enhance its toxicity. Monitoring of plasma phenytoin levels is required during concomitant use, and dose adjustment should be considered if necessary.

Phenytoin, phenobarbital, rifampicin. Concomitant use may reduce the effectiveness of dexibuprofen.

Alcohol. Excessive alcohol consumption during NSAID use may increase the risk of gastrointestinal adverse effects.

Special precautions for use.

Adverse reactions associated with the use of dexibuprofen can be minimized by using the lowest effective dose required to control symptoms for the shortest possible duration.

Patients undergoing long-term treatment with dexibuprofen should have regular monitoring of kidney, liver, and hematological functions.

Chronic use of analgesics, particularly combinations of different painkillers, may lead to severe kidney damage and development of renal failure (analgesic nephropathy).

Concomitant use of dexibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Gastrointestinal effects.

Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported during NSAID therapy at any stage of treatment, regardless of the presence of warning signs or a history of severe gastrointestinal disorders.

Elderly patients are at increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

The risk of gastrointestinal bleeding, perforation, and ulceration increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, in patients with alcoholism, and in elderly patients. These patients should initiate treatment with the lowest possible doses.

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated.

NSAIDs should be used cautiously in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid). For these patients, as well as for those with a history of peptic ulcer, especially if complicated by bleeding or perforation, patients with alcoholism, and elderly patients, physicians should consider the appropriateness of combination therapy with misoprostol or proton pump inhibitors.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment.

If gastrointestinal bleeding or ulceration occurs, dexibuprofen should be discontinued immediately.

Cardiovascular effects.

Patients with a history of arterial hypertension and/or heart failure (mild to moderate) should begin treatment with caution (medical consultation required), as fluid retention and edema have been reported during NSAID therapy.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen (particularly at high doses of 2400 mg daily) and long-term treatment may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤1200 mg daily) increases the risk of myocardial infarction. However, there is insufficient data to exclude this risk with dexibuprofen use.

Long-term treatment in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be prescribed by a physician only after careful evaluation.

Long-term NSAID treatment in patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed only after careful assessment.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen treatment. Kounis syndrome presents with cardiovascular symptoms due to coronary artery spasm caused by an allergic or hypersensitivity reaction, which may lead to myocardial infarction.

Effects on the blood system.

Like other NSAIDs, dexibuprofen may reversibly inhibit platelet aggregation and prolong bleeding time. Use with caution in patients with hemorrhagic diathesis, other coagulation disorders, and when dexibuprofen is used concomitantly with oral anticoagulants.

Experimental data suggest that concomitant use of ibuprofen may suppress the effect of low-dose acetylsalicylic acid on platelet aggregation. However, the limited nature of these data and uncertainty regarding extrapolation of ex vivo findings to clinical situations prevent definitive conclusions about regular ibuprofen use; effects are considered unlikely with occasional use.

Effects on the urinary system.

Like other inhibitors of prostaglandin synthesis, dexibuprofen may adversely affect kidney function, potentially leading to glomerular or interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and acute renal failure.

Like other NSAIDs, dexibuprofen may increase plasma concentrations of blood urea nitrogen and creatinine.

Dexibuprofen should be used with caution in patients with impaired renal function, using the lowest effective dose. The risk of fluid retention, edema, and worsening renal function should be considered, and regular monitoring of renal function is recommended.

Effects on the hepatobiliary system.

As with other NSAIDs, mild increases in certain liver function parameters, as well as significant elevations in AST and ALT, are possible. If significant increases in ALT and AST levels occur, dexibuprofen should be discontinued.

Dexibuprofen should be used with caution in patients with impaired liver function, using the lowest effective dose, and regular monitoring of liver function is recommended.

Effects on the skin and subcutaneous tissue.

Severe skin reactions have been reported with ibuprofen use, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis, which may be life-threatening or fatal (see section "Adverse reactions"). Most such reactions occurred within the first month of treatment.

If signs or symptoms suggestive of these reactions appear, dexibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Effects on the immune system.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur. NSAIDs may induce bronchospasm in patients with a history of bronchial asthma.

Dexibuprofen should be used with caution in patients with systemic lupus erythematosus and mixed connective tissue disorders due to an increased risk of adverse reactions affecting the nervous system and kidneys, including aseptic meningitis.

Masking symptoms of underlying infections.

Dexibuprofen may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the course of illness. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief during infection, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Effects on female fertility.

Limited data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect fertility and are not recommended for women attempting to conceive. Dexibuprofen should be discontinued in women experiencing difficulties conceiving or undergoing infertility investigations.

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre- and post-implantation embryonic and fetal mortality, as well as increased incidence of various developmental abnormalities, including cardiovascular defects.

From the 20th week of pregnancy, use of dexibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after second-trimester treatment, most of which resolved after stopping treatment. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to dexibuprofen for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitor may result in fetal effects such as cardiopulmonary toxicity (premature constriction/closure of the fetal ductus arteriosus with pulmonary hypertension) and impaired kidney function, which may progress to renal failure with oligohydramnios. Maternal effects may include inhibition of uterine contractility, leading to prolonged labor and increased risk of bleeding in both mother and child, even with very low doses.

Dexibuprofen should be avoided during the first and second trimesters of pregnancy unless the expected benefit to the patient outweighs the potential risk to the fetus. If use during the first or second trimester is necessary, the lowest effective dose should be used for the shortest possible duration. From the beginning of the 6th month of pregnancy (24th week), use of dexibuprofen is contraindicated.

Breastfeeding.

Dexibuprofen passes into breast milk in very low concentrations. Use during breastfeeding is possible only at low doses and for a short duration.

Fertility.

NSAIDs may affect fertility and are not recommended for women attempting to conceive (see section "Special precautions for use").

Ability to influence reaction speed when driving or operating machinery.

When used according to recommended dosage and treatment duration, the medicinal product does not affect reaction speed when driving or operating machinery. However, if dizziness, increased fatigue, somnolence, disorientation, or visual disturbances occur, driving or operating machinery should be avoided.

Dosage and Administration

The dosage regimen should be individually determined by a physician, taking into account the severity of pain. Adults should be administered 1–2 tablets (200–400 mg of dexibuprofen) three times daily after meals. The recommended initial dose is 200 mg of dexibuprofen. The recommended daily dose is 600–900 mg of dexibuprofen, divided into three doses. The maximum daily dose is 1200 mg, and the maximum single dose is 400 mg.

For dysmenorrhea, the maximum single dose is 300 mg and the maximum daily dose is 900 mg. It is advisable to take the medication during meals.

The drug is intended for symptomatic relief of pain. However, if symptoms persist for more than 3 days, are accompanied by high fever, headache, or other manifestations, further diagnostic evaluation and adjustment of the treatment regimen are required.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Instructions").

Patients with hepatic or renal impairment.

Patients with moderate hepatic or renal impairment should start treatment with reduced doses. Dexibuprofen is contraindicated in patients with severe hepatic or renal dysfunction.

Elderly patients.

Elderly patients should start therapy with lower doses. The dose may be increased to the recommended daily dose only after good tolerability of the drug has been established.

Children.

The drug is not intended for use in pediatric practice.

Overdose.

Dexibuprofen is characterized by low acute toxicity. In most cases, overdose is asymptomatic. The risk of developing symptoms arises when doses exceed 80–100 mg/kg of ibuprofen (equivalent to 40–50 mg/kg of dexibuprofen).

Symptoms: abdominal pain, nausea, vomiting, lethargy, drowsiness, headache, nystagmus, tinnitus, ataxia; in rare cases – gastrointestinal bleeding, arterial hypotension, hypothermia, metabolic acidosis, seizures, renal dysfunction, coma, adult respiratory distress syndrome, transient apnea attacks.

Treatment: symptomatic therapy; there is no specific antidote. In case of overdose, activated charcoal should be administered and gastric lavage performed (only within the first hour after ingestion). Forced diuresis, hemodialysis, and hemoperfusion are ineffective due to the high degree of plasma protein binding of dexibuprofen.

Adverse Reactions

Infections and infestations: Exacerbation of inflammatory infectious processes (necrotizing fasciitis).

Cardiac disorders: Kounis syndrome (frequency not known).

Immune system disorders: Angioedema, anaphylactic reactions, rhinitis, generalized hypersensitivity reactions including bronchospasm, bronchial asthma, tachycardia, arterial hypotension, shock, fever with rash, abdominal pain, headache, nausea, vomiting. Most cases of aseptic meningitis were observed in patients with risk factors such as various forms of autoimmune diseases.

Blood and lymphatic system disorders: Prolonged blood clotting time, thrombocytopenia, leukopenia, granulocytopenia, pancytopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Psychiatric disorders: Anxiety, psychotic reactions, depression, irritability, hallucinations.

Nervous system disorders: Somnolence, headache, vertigo, dizziness, insomnia, restlessness, disorientation, confusion, excitement, aseptic meningitis.

Eye disorders: Visual disturbances (including diplopia), reversible toxic amblyopia.

Ear and labyrinth disorders: Tinnitus, hearing disturbances.

Gastrointestinal disorders: Dyspepsia, abdominal pain, diarrhea, nausea, vomiting, gastrointestinal ulcers and bleeding, gastritis, ulcerative stomatitis, melena, gastrointestinal perforations, flatulence, constipation, esophagitis, esophageal strictures, exacerbation of diverticulitis, ulcerative colitis, Crohn's disease, non-specific hemorrhagic colitis.

In cases of gastrointestinal bleeding, development of anemia and hematemesis is possible.

Renal and urinary disorders: Interstitial nephritis, nephrotic syndrome, and renal failure cannot be excluded based on the experience with NSAIDs.

Hepatobiliary disorders: Liver function abnormalities, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: Rash, urticaria, pruritus, purpura (including allergic purpura), erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, systemic lupus erythematosus and other collagenoses, alopecia, photosensitivity reactions, Stevens-Johnson syndrome, Lyell's syndrome, allergic vasculitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis.

General disorders: Increased fatigue, excessive sweating.

With the use of NSAIDs, edema, development of heart failure, increased blood pressure, and fluid retention have also been reported, particularly in patients with hypertension or renal impairment.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen (especially at high doses of 2400 mg per day) and long-term treatment may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special warnings and precautions for use").

Reporting of adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address and location of operations.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.