Dolox retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOLOX RETARD (DOLOX RETARD)

Composition:

Active ingredient: diclofenac;

1 tablet contains 100 mg of sodium diclofenac;

Excipients: lactose monohydrate; microcrystalline cellulose; hypromellose; maize starch; magnesium stearate; colloidal anhydrous silicon dioxide; talc; Opadry White 04B580000 (hypromellose, titanium dioxide (E 171), polyethylene glycol, talc); Yellow West FCF coloring agent (E 110).

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties: round, biconvex, orange-colored film-coated tablets.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AB05.

Pharmacological Properties

Pharmacodynamics

Diclofenac, the active ingredient in DOLOX RETARD, exerts antipyretic, analgesic, and anti-inflammatory effects. Its primary mechanism of action is inhibition of prostaglandin synthesis through suppression of the enzyme prostaglandin synthetase. By blocking prostaglandin synthesis, diclofenac significantly reduces the symptoms of inflammation; interferes with the effects of prostaglandins on the hypothalamic component of the thermoregulation process, resulting in decreased body temperature; and reduces pain in primary dysmenorrhea.

DOLOX RETARD demonstrates pronounced analgesic activity in cases of moderate to severe non-rheumatic pain.

Pharmacokinetics

Diclofenac is completely absorbed in the intestine. Analysis of unchanged diclofenac and its hydroxylated metabolites excreted in urine shows that the amount of released and absorbed diclofenac is equivalent to that observed after administration of an equivalent dose of enteric-coated diclofenac tablets (without delayed release).

However, the systemic bioavailability of diclofenac (released from DOLOX RETARD) averages 82% of that observed after oral administration of an enteric-coated diclofenac tablet (without delayed release) at the same dose. Due to the slow release of the active substance from DOLOX RETARD, peak plasma concentrations are lower than those achieved after administration of enteric-coated tablets. Maximum concentrations of 0.5 μg/mL or 0.4 μg/mL (1.6 or 1.25 μmol/L) are reached on average 4–5 hours after ingestion of a 100 mg tablet.

Food intake does not clinically affect the absorption or systemic bioavailability of DOLOX RETARD.

Since approximately half of diclofenac undergoes first-pass metabolism in the liver (first-pass effect), the area under the concentration-time curve (AUC) after administration of the delayed-release tablet is nearly half that observed after parenteral administration of an equivalent dose. After repeated dosing of DOLOX RETARD, pharmacokinetic parameters remain unchanged. No accumulation occurs when the recommended dosing intervals are maintained. Diclofenac is 99.7% bound to plasma proteins, primarily to albumin (99.4%). The volume of distribution is 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where its maximum concentration occurs 2–4 hours later than in plasma. The estimated half-life in synovial fluid is 3–6 hours. Four to six hours after peak plasma concentrations are achieved, the concentration of the active substance in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

Biotransformation of diclofenac occurs mainly via single and multiple hydroxylations and methoxylation, leading to the formation of several phenolic metabolites, most of which are conjugated with glucuronic acid. Two of these phenolic metabolites are pharmacologically active, but to a much lesser extent than diclofenac.

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD).

Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates of the intact active substance and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of the administered dose is excreted in bile and feces as metabolites.

In patients with severe renal impairment (creatinine clearance less than 10 mL/min), biliary excretion of metabolites increases in relative proportion; therefore, no increase in their blood concentrations is observed.

No significant changes in diclofenac pharmacokinetics have been observed in elderly individuals or in patients with chronic hepatitis or chronic compensated cirrhosis of the liver.

Clinical characteristics.

Indications.

Inflammatory and degenerative forms of rheumatism (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, pain syndrome of various localizations, periarticular rheumatism); post-traumatic and postoperative pain, inflammation and edema; painful and/or inflammatory conditions in gynecology (e.g., primary dysmenorrhea or adnexitis).

Contraindications.

• Hypersensitivity to the active substance or to any other component of the medicinal product;
• Active gastric or intestinal ulcer; gastrointestinal hemorrhage or perforation; history of gastrointestinal hemorrhage or perforation following use of nonsteroidal anti-inflammatory drugs (NSAIDs); history of acute or recurrent gastric or intestinal ulcer;
• DOLOX RETARD, like other NSAIDs, is contraindicated in patients in whom administration of acetylsalicylic acid or other NSAIDs induces attacks of bronchial asthma, urticaria, or acute rhinitis;
• Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis);
• Severe hepatic insufficiency (Child-Pugh class C, cirrhosis or ascites);
• Severe renal insufficiency (creatinine clearance <30 mL/min);
• Congestive heart failure (NYHA II-IV);
• Treatment of perioperative pain in 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;
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

The following interactions may occur during the use of DOLOX RETARD.

Litium. Concomitant use of DOLOX RETARD may increase plasma lithium concentrations. Monitoring of plasma lithium levels is recommended.

Digoxin. DOLOX RETARD may increase plasma digoxin concentrations when used concomitantly. Monitoring of plasma digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of DOLOX RETARD may attenuate the antihypertensive effect of diuretics or antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Patients should maintain adequate fluid intake, and renal function should be periodically monitored before and after initiation of concomitant therapy, particularly when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

Anticoagulants and antithrombotic agents (alteplase, streptokinase, urokinase). Concomitant use is recommended with caution, as it may increase the risk of bleeding. Close monitoring of patients receiving diclofenac and anticoagulants is recommended, and dose adjustment of anticoagulants may be necessary. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may reversibly inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors and corticosteroids. Concomitant use of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Concomitant use of two or more NSAIDs should be avoided. Concomitant use of diclofenac and corticosteroids may increase the frequency of adverse reactions.

Antidiabetic agents. Clinical studies have shown that DOLOX RETARD can be used in combination with oral antidiabetic agents without altering their therapeutic effect. However, isolated reports exist of both hypoglycemia and hyperglycemia occurring in such cases, requiring dose adjustments of antidiabetic drugs during DOLOX RETARD therapy. For this reason, monitoring of blood glucose levels is recommended as a precautionary measure during combination therapy.

Methotrexate. Diclofenac may inhibit tubular renal clearance of methotrexate, thereby increasing methotrexate levels. NSAIDs, including diclofenac, should be used with caution when administered less than 24 hours before methotrexate treatment, as methotrexate blood levels may rise and its toxicity may be enhanced. Cases of severe toxicity have been reported when methotrexate and NSAIDs, including diclofenac, were administered less than 24 hours apart. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Diclofenac, like other NSAIDs, may enhance the nephrotoxicity of cyclosporine by affecting renal prostaglandins. Therefore, the drug should be administered at lower doses than in patients not receiving cyclosporine.

Concomitant use of diclofenac with tacrolimus increases the risk of nephrotoxicity. This may be mediated through inhibition of renal prostaglandins by both NSAIDs and calcineurin inhibitors.

Agents that induce drug-metabolizing enzymes, such as rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), and others, may theoretically reduce plasma concentrations of diclofenac.

There have been isolated reports of seizures in patients receiving concomitant quinolone derivatives and DOLOX RETARD. This may occur both in patients with epilepsy or history of seizures and in those without such history. Therefore, quinolone antibiotics should be used with caution in patients already receiving NSAIDs.

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after administration of cholestyramine/colestipol.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

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

Strong CYP2C9 inhibitors. Diclofenac should be prescribed with caution concomitantly with strong CYP2C9 inhibitors (e.g., sulfaphenazole, voriconazole), which may lead to a significant increase in maximum plasma concentration and exposure of diclofenac due to inhibition of its metabolism.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use of NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.

Agents whose use may lead to hyperkalemia.

Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels, which should be monitored.

Medicinal products that increase photosensitivity may enhance the photosensitizing effect of diclofenac to ultraviolet radiation.

Special precautions for use.

General

Concomitant use of DOLOX RETARD with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to the lack of any synergistic effect and the potential for additive adverse effects.

Treatment should be prescribed with caution in patients over 65 years of age according to recommendations for this patient group. In particular, the use of the lowest effective dose is recommended in frail elderly patients or patients with low body weight.

As with other nonsteroidal anti-inflammatory drugs, including diclofenac, allergic reactions, including anaphylactic/anaphylactoid reactions, may rarely occur even without prior exposure to the drug.

Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Like other NSAIDs, diclofenac, due to its pharmacodynamic properties, may mask signs and symptoms of infection.

DOLOX RETARD contains lactose. This medicinal product is contraindicated in patients with rare hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Gastrointestinal effects

Gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal, have been reported with the use of nonsteroidal anti-inflammatory drugs, including diclofenac, and may occur at any time during treatment, with or without warning symptoms or history of serious gastrointestinal events. In elderly patients, such complications usually have more serious consequences. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac therapy, the drug should be discontinued.

As with all NSAIDs, including diclofenac, careful medical supervision and special caution are required when prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or suspected ulcer, bleeding, or perforation of the stomach or intestine in history. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation.

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

To reduce the risk of gastrointestinal toxicity in patients with a history of peptic ulcer, especially with bleeding or perforation, and in elderly patients, treatment should be initiated with the lowest effective dose, and this dose should be maintained.

Concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for patients who require concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other medicinal products that may increase gastrointestinal risk.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, require monitoring for unusual abdominal symptoms (especially gastrointestinal bleeding).

Caution should be exercised in patients receiving concomitant therapy with drugs that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid.

Careful medical monitoring and caution are required in patients with ulcerative colitis or Crohn’s disease, as these conditions may worsen.

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

Hepatobiliary effects

Careful medical monitoring is required if DOLOX RETARD 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. Regular monitoring of liver function is recommended during long-term diclofenac therapy as a precautionary measure.

If changes in liver function tests persist or worsen, clinical signs or symptoms of liver disease appear, or other manifestations occur (e.g., eosinophilia, rash), DOLOX RETARD should be discontinued.

Hepatitis without prodromal symptoms may develop during diclofenac therapy.

Diclofenac should be used with caution in patients with hepatic porphyria, as it may provoke an acute attack.

Renal effects

Since fluid retention and edema have been observed during the use of NSAIDs, including diclofenac, particular caution is required in patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that may significantly affect renal function, and patients with significant reduction in extracellular fluid volume for any reason, e.g., before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure during diclofenac therapy. After discontinuation of treatment, the condition of patients usually returns to the pre-treatment state.

Skin effects

Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely during the use of NSAIDs, including DOLOX RETARD. The highest risk of these reactions occurs at the beginning of therapy, and these reactions usually develop within the first month of treatment. DOLOX RETARD should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus and mixed connective tissue disorders

An increased risk of aseptic meningitis may occur in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

Cardiovascular and cerebrovascular effects

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with increasing dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be reviewed periodically.

Appropriate medical monitoring and counseling are required for patients with hypertension and/or mild to moderate congestive heart failure in history, as fluid retention and edema have been observed during NSAID use, including diclofenac.

Results of clinical studies and epidemiological data suggest that the use of diclofenac, especially at high doses (150 mg per day) and during long-term treatment, may be associated with a small increased risk of arterial thrombosis (e.g., myocardial infarction or stroke).

DOLOX RETARD is not recommended for patients with existing cardiovascular diseases (congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If necessary, DOLOX RETARD may be used in patients with existing cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, and smoking) only after careful consideration and only at daily doses ≤ 100 mg if treatment lasts longer than 4 weeks.

Patients requiring symptomatic treatment should be examined periodically, especially if treatment lasts longer than 4 weeks.

Patients should be informed about signs and symptoms of serious arterial thrombotic events (e.g., chest pain, shortness of breath, weakness, slurred speech) that may occur without warning.

Hematological effects

During long-term diclofenac therapy, as with other NSAIDs, periodic blood tests to determine the count of blood cells are recommended.

DOLOX RETARD may reversibly inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological abnormalities require careful monitoring.

During long-term diclofenac therapy, as with other NSAIDs, periodic blood tests to determine the count of blood cells are recommended.

Respiratory effects (in patients with asthma)

In patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially if associated with symptoms resembling allergic rhinitis), reactions to NSAIDs resembling asthma exacerbations (so-called aspirin-induced asthma with analgesic intolerance), Quincke's edema, and urticaria occur more frequently than in other patients. Therefore, special precautions (readiness for emergency intervention) are recommended for these patients. This also applies to patients who have allergic reactions to other substances, e.g., rash, pruritus, or urticaria.

Use during pregnancy or breastfeeding.

Starting from the 20th week of pregnancy, the use of DOLOX RETARD may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after the start of treatment and is usually reversible upon discontinuation of therapy. DOLOX RETARD should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If DOLOX RETARD is used by women trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios may be appropriate after exposure to DOLOX RETARD for several days starting from the 20th week of pregnancy. DOLOX RETARD should be discontinued if oligohydramnios is detected.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or cardiac defects and gastroschisis after the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular defects increased from less than 1% to approximately 1.5%.

The risk is considered to increase with higher doses and longer duration of therapy.

The drug is contraindicated during the last three months of pregnancy because it may affect the fetus as follows:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios.

The following effects may occur in the mother and newborn, which may also occur towards the end of pregnancy:

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

Therefore, DOLOX RETARD is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to prevent adverse reactions in infants, this drug is contraindicated during breastfeeding.

Female fertility

Like other NSAIDs, diclofenac may affect female fertility and therefore is not recommended for women planning pregnancy. Consideration should be given to discontinuing diclofenac in women who are unable to conceive and in women undergoing infertility investigations.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or fatigue during therapy with DOLOX RETARD should not drive or operate complex machinery.

Method of administration and dosage.

The dose should be individually adjusted, starting with the lowest effective dose, and should be taken for the shortest possible duration.

The recommended initial dose of the drug for adults is 100 mg once daily (1 tablet of DOLOX RETARD).

Adults: 1 tablet (100 mg) of DOLOX RETARD per day.

If disease symptoms are most pronounced at night or in the morning, DOLOX RETARD should be taken in the evening. Tablets should be swallowed whole, without chewing, with sufficient fluid, preferably during food intake.

To minimize adverse effects, the drug should be used at the lowest effective doses for the shortest duration possible, taking into account the treatment goals for each individual patient.

Elderly patients: Clinically significant changes in pharmacokinetics have not been observed when DOLOX RETARD is administered to elderly patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in elderly patients, as they are more prone to adverse reactions. The use of the lowest effective dose is recommended in elderly patients or those with low body weight, as well as in patients requiring close monitoring for possible gastrointestinal bleeding during NSAID therapy.

Patients with renal impairment: Specific studies in patients with renal impairment have not been conducted, and no dosage recommendations are available. DOLOX RETARD should be prescribed with caution to patients with moderate or severe renal impairment.

Patients with hepatic impairment: Specific studies in patients with hepatic impairment have not been conducted, and no dosage recommendations are available. DOLOX RETARD should be prescribed with caution to patients with moderate or severe hepatic impairment.

Children. DOLOX RETARD should not be used for the treatment of children due to the high content of active substance in the tablet.

Overdose.

There is no typical clinical picture characteristic of DOLOX RETARD overdose. In case of overdose, symptoms such as headache, nausea, epigastric pain, vomiting, gastrointestinal bleeding, diarrhea, dizziness, disorientation, drowsiness, coma, excitement, tinnitus, or convulsions may occur. In cases of severe poisoning, acute renal failure and liver damage are possible.

Treatment of acute NSAID poisoning consists of supportive and symptomatic therapy. Symptomatic and supportive measures are indicated for complications such as arterial hypotension, renal failure, convulsive syndrome, gastrointestinal disturbances, and respiratory depression. Specific therapeutic interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be beneficial in eliminating DOLOX RETARD, since the active substances of the drug are highly protein-bound and undergo extensive metabolism. Activated charcoal may be administered after ingestion of potentially toxic doses, and gastric decontamination (induced emesis, gastric lavage) may be performed after ingestion of potentially life-threatening doses.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, hemolytic anemia, aplastic anemia, agranulocytosis.

Immune system disorders: hypersensitivity, anaphylactic and anaphylactoid reactions (including bronchospasm, hypotension, and shock), angioedema (including facial swelling).

Psychiatric disorders: confusion, depression, insomnia, nightmares, irritability, psychotic disorders.

Nervous system disorders: headache, dizziness, increased fatigue, somnolence, sensory disturbances including paresthesia, memory disorders, convulsions, anxiety, tremor, psychiatric disorders, aseptic meningitis, taste disturbances, cerebral circulation disorders, confusion, hallucinations.

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

Ear and labyrinth disorders: vertigo, tinnitus, hearing impairment.

Cardiovascular disorders: palpitations, chest pain, heart failure, arrhythmia, tachycardia, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis, Kounis syndrome.

Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding (hematemesis, melena, bloody diarrhea), gastric and intestinal ulcers with or without bleeding or perforation, colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, development of diaphragm-like intestinal strictures, pancreatitis.

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

Skin and subcutaneous tissue disorders: rash, urticaria, bullous eruption, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura (including allergic purpura), pruritus.

Renal and urinary disorders: acute renal failure, hematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, renal papillary necrosis, renal medullary necrosis, fluid retention.

General disorders: edema, malaise.

Reproductive system and breast disorders: impotence.

Shelf life. 3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 1, 2, or 10 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Uniq Pharmaceuticals Laboratories (a division of J. B. Chemicals and Pharmaceuticals Ltd.).

Manufacturer's address and location of business operations. Plot No. 215-219, G.I.D.C. Industrial Area, Panoli - 394 116, Bharuch District, India.