Diclofenac Darnytsia enteric-coated tablets 25 mg 3 blisters of 10 pcs.

Pharmacodynamics

Diclofenac Darnytsia contains diclofenac sodium – a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic effects. The main mechanism of action of diclofenac is considered to be inhibition of prostaglandin biosynthesis. Prostaglandins play an important role in the genesis of inflammation, pain and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the drug cause a clinical effect, which is characterized by a significant reduction in the severity of such symptoms and complaints as pain at rest and during movement, morning stiffness, joint swelling, as well as improved joint function.

In vitro, diclofenac sodium at concentrations equivalent to those achieved in the treatment of patients does not inhibit the biosynthesis of cartilage proteoglycans.

In post-traumatic and postoperative inflammatory phenomena, diclofenac quickly relieves pain (both at rest and during movement), reduces inflammatory edema and postoperative wound swelling.

Clinical studies have shown a significant analgesic effect of the drug in moderate and severe pain syndrome of non-rheumatic origin. Clinical studies have also shown that diclofenac is able to eliminate pain and reduce the severity of blood loss in primary dysmenorrhea.

Diclofenac also showed a therapeutic effect in migraine attacks.

Pharmacokinetics

Absorption. After oral administration, the active substance, diclofenac, is rapidly and completely absorbed. Food reduces the rate of absorption, but the amount of active substance absorbed does not change.

After a single oral dose of 50 mg diclofenac, Cmax _is reached after approximately 2 hours and is 1.5 μg/ml (5 μmol/l). The amount of active substance absorbed is linearly proportional to the dose.

The passage of the tablet through the stomach is slowed down if the drug is taken during or after a meal (compared to taking it before a meal), but the amount of absorbed diclofenac does not change. Since approximately half of the dose of diclofenac is metabolized during the first passage through the liver (first-pass effect), the AUC after oral or rectal administration is approximately half of the area under the curve for parenteral administration of an equivalent dose. When the dosing interval is observed, accumulation of the drug is not observed.

Plasma drug concentrations achieved in children at equivalent doses (mg/kg body weight) are similar to those observed in adults.

After administration of 75 mg of diclofenac by injection, absorption begins immediately, and mean C _max in plasma, which is about 2.5 μg/ml (8 μmol/l), is reached after 20 minutes. The extent of absorption may be linearly dependent on the dose.

When 75 mg of diclofenac is to be administered by infusion over 2 hours, the mean Cmax _in plasma is about 1.9 μg/ml (5.9 μmol/l). Shorter infusion times result in higher Cmax _in plasma, while longer infusions result in concentrations proportional to the infusion rate after 3-4 hours. After IM injection or administration of gastro-resistant tablets or suppositories, the plasma concentration decreases rapidly after reaching the peak level.

The AUC after IM or IV administration is approximately twice as high as after oral or rectal administration, since approximately half of the active substance is metabolized during the first pass through the liver (first-pass effect) when the drug is administered orally or rectally.

Pharmacokinetic properties do not change after repeated administration. When the recommended dosing intervals are observed, no accumulation of the drug is observed.

Distribution. 99.7% of diclofenac binds to plasma proteins, mainly albumin (99.4%). The possible volume of distribution is 0.12-0.17 l/kg. Diclofenac penetrates into the synovial fluid, where it reaches C _max after 3-6 h. 2 hours after reaching the peak plasma concentration, the levels of the active substance are already higher in the synovial fluid than in the blood plasma, and remain high for up to 12 h.

Biotransformation. The biotransformation of diclofenac occurs partly by glucuronidation of the parent molecule, but mainly by single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites (3′-hydroxy-, 4′-hydroxy-, 5-hydroxy-, 4 ‘, 5 dihydroxy- and 3′-hydroxy-4’-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a lesser extent than diclofenac.

Elimination. The total systemic clearance of diclofenac in plasma is 263 ± 56 ml/min (mean ± standard deviation). The terminal T½ _from plasma is 1-2 hours. 4 metabolites, including 2 active ones, also have short T½ _from plasma. The _T½ of one of the metabolites, 3′-hydroxy-4′-methoxy-diclofenac, is longer; however, this metabolite is virtually inactive.

About 60% of the dose is excreted in the urine as glucuronide conjugates of the parent molecule and metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The remainder of the dose is excreted as metabolites in the bile.

Pharmacokinetics in different patient groups. No significant differences in absorption, metabolism or excretion of the drug were observed depending on the age of the patients.

In patients with renal insufficiency, accumulation of unchanged active substance is unlikely based on single dose kinetics when the usual dosing regimen is followed. At a creatinine clearance of 10 ml/min, steady-state plasma concentrations of hydroxymetabolites are estimated to be approximately 4 times higher than in healthy subjects. Thus, the metabolites are ultimately excreted in the bile.

In patients with chronic hepatitis or compensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

Tablets. inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis).

Pain syndrome in the spine.

Non-articular rheumatism.

Acute attacks of gout.

Post-traumatic and postoperative pain syndrome accompanied by inflammation and swelling, for example, after dental and orthopedic interventions.

Gynecological diseases accompanied by pain and inflammation, such as primary dysmenorrhea or adnexitis.

As an adjunct in severe inflammatory diseases of the ENT organs, accompanied by pain, for example, in pharyngotonsillitis, otitis. According to general therapeutic principles, the underlying disease should be treated with basic therapy. Fever in itself is not an indication for the use of the drug.

Solution for injection. The drug for intramuscular administration is intended for the treatment of:

inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;

acute attacks of gout;

renal and biliary colic;

pain and swelling after injuries and surgeries;

severe migraine attacks.

The drug, when administered as an intravenous infusion, is intended for the treatment or prevention of postoperative pain.

Tablets. The dosage regimen is set individually, taking into account the indications and severity of the condition. Diclofenac Darnytsia is taken orally, swallow the tablets without chewing, after meals, with sufficient water.

The drug should be used in the lowest effective doses for the shortest period of time, taking into account the treatment objectives of each patient individually.

Adults. The initial dose is usually 100-150 mg/day. With mild symptoms, as well as with long-term therapy, a dose of 75-100 mg/day is sufficient. The daily dose should be divided into 2-3 doses. To avoid night pain or morning stiffness, treatment with the drug can be supplemented by the appointment of rectal suppositories containing diclofenac before bedtime. The daily dose should not exceed 150 mg.

In primary dysmenorrhea, the daily dose should be selected individually, usually it is 50-150 mg. The initial dose may be 50-100 mg, but if necessary it can be increased over several menstrual cycles to a maximum of 200 mg/day. The drug should be started after the first painful symptoms appear and continued for several days depending on the dynamics of symptom regression.

Children. Tablets in a dose of 25 mg can be used in children from 8 years of age (with a body weight of at least 25 kg) to 18 years of age as prescribed by a doctor in a dose of 0.5-2 mg/kg of body weight depending on the severity of symptoms: this dose should be divided into 2-3 doses.

For example, for a child weighing 30 kg, the daily dose may be 15-60 mg. Based on this range, the child may be prescribed 2 tablets of 25 mg 2 times a day.

In the treatment of juvenile rheumatoid arthritis, the daily dose may be increased to 3 mg/kg body weight – the maximum daily dose.

Do not exceed the maximum daily dose of 150 mg.

Elderly patients. Although the pharmacokinetics of the drug are not impaired to any clinically significant extent in elderly patients, NSAIDs should be used with caution in individuals who are generally more susceptible to adverse reactions. The lowest effective dose is recommended, especially in debilitated elderly patients or those with low body weight, and patients should be monitored for gastrointestinal bleeding during treatment with NSAIDs.

Solution for injection. The drug should be used in the lowest recommended doses for the shortest period of time, taking into account the treatment objectives of each patient individually.

The drug Diclofenac Darnytsia, solution for injection, should not be used for more than 2 days. If necessary, treatment can be continued with Diclofenac Darnytsia tablets.

Intramuscular injection. To prevent damage to nerves or other tissues at the injection site, the following rules must be followed.

The usual dose is 75 mg (1 ampoule) per day, which should be administered by deep injection into the upper outer sector of the gluteus maximus muscle. In severe cases, the daily dose can be increased to 2 injections of 75 mg, between which an interval of several hours should be maintained (1 injection in each buttock). Alternatively, 75 mg can be combined with other dosage forms of Diclofenac Darnytsia (e.g. tablets) up to a total maximum total daily dose of 150 mg.

In the setting of migraine attacks, clinical experience is limited to cases with the initial use of 1 ampoule of 75 mg, the dose should be administered immediately after the use of diclofenac-containing suppositories of 100 mg on the same day (if necessary). The total daily dose should not exceed 175 mg on the first day.

There are no data available on the use of the drug for the treatment of migraine attacks lasting more than 1 day.

In / in infusion. Diclofenac Darnytsia, solution for injection, should not be administered as a bolus injection.

Immediately before starting the infusion of Diclofenac Darnytsia, depending on its required duration, 1 ampoule of the drug should be diluted in 100-500 ml of 0.9% sodium chloride solution or 5% glucose solution, buffered with sodium bicarbonate solution for injection (0.5 ml of 8.4% solution or 1 ml of 4.2% or the corresponding volume of another concentration), which was taken from a freshly opened container. Only clear solutions can be used. If there are crystals or sediment in the solution, it cannot be used for infusion.

Two alternative dosing regimens for Diclofenac Darnytsia, solution for injection, are recommended.

For the treatment of moderate to severe postoperative pain, 75 mg should be administered continuously over 30 minutes to 2 hours. If necessary, treatment can be repeated after 4-6 hours, but the dose should not exceed 150 mg/day.

For the prevention of postoperative pain, a loading dose of 25-50 mg should be administered 15 minutes to 1 hour after surgery, followed by a continuous infusion of approximately 5 mg/h up to a maximum daily dose of 150 mg.

Elderly patients. Although the pharmacokinetics of the drug are not impaired to any clinically significant extent in elderly patients, NSAIDs should be used with caution in such individuals, who are generally more prone to developing adverse reactions. In particular, it is recommended that the lowest effective dose be used in debilitated elderly patients or those with low body weight (see Precautions); patients should also be monitored for gastrointestinal bleeding during treatment with NSAIDs.

The recommended maximum daily dose of Diclofenac Darnytsia is 150 mg.

Tablets. Hypersensitivity to the active substance or any other component of the drug.

Diclofenac Darnytsia, like other nonsteroidal anti-inflammatory drugs, is contraindicated in patients who experience attacks of bronchial asthma, urticaria or acute rhinitis, nasal polyps, and other allergic symptoms in response to the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Third trimester of pregnancy.

Acute stomach or intestinal ulcer; gastrointestinal bleeding or perforation.

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

Severe liver failure (Child-Pugh class C, cirrhosis or ascites).

Severe renal failure (creatinine clearance 30 ml/min).

Congestive heart failure (NYHA II-IV).

CHD in patients with angina pectoris, previous myocardial infarction.

Cerebrovascular disease in patients who have had a stroke or have episodes of transient ischemic attacks.

Peripheral artery disease.

Treatment of postoperative pain after coronary artery bypass graft surgery (or use of a cardiopulmonary bypass machine).

History of gastrointestinal bleeding or perforation related to previous NSAID treatment.

Active peptic ulcer/bleeding or history of recurrent peptic ulcer/bleeding (two or more separate episodes of established ulceration or bleeding).

Solution for injection. Known hypersensitivity to the active substance, metabisulfite or any other component of the drug.

Like other non-steroidal anti-inflammatory drugs, diclofenac is also contraindicated in patients in whom the use of ibuprofen, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs provokes an attack of asthma, angioedema, urticaria or acute rhinitis.

History of gastrointestinal bleeding or perforation related to previous NSAID treatment.

Active peptic ulcer/bleeding or history of recurrent peptic ulcer/bleeding (two or more separate episodes of established ulceration or bleeding).

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

Liver failure.

Kidney failure.

Congestive heart failure (NYHA II-IV).

CHD (angina pectoris, previous myocardial infarction).

Cerebrovascular disease in patients who have had a stroke or have episodes of transient ischemic attacks.

Peripheral artery disease.

Treatment of perioperative pain during coronary artery bypass grafting (or the use of a cardiopulmonary bypass machine).

High risk of developing postoperative bleeding, blood clotting disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular bleeding.

Third trimester of pregnancy.

In this dosage form, the drug is contraindicated in children.

Intravenous infusions are contraindicated in:

concomitant use of NSAIDs or anticoagulants (including low-dose heparin);

history of hemorrhagic diathesis or confirmed/suspected cerebrovascular bleeding;

surgical interventions with a high risk of bleeding;

History of asthma;

moderate or severe renal failure (plasma creatinine level 160 mmol/l);

hypovolemia or dehydration of various origins.

The frequency category of adverse reactions, starting with the most frequent, is defined as follows: very common (1/10); common (≥1/100, 1/10); uncommon (≥1/1000, 1/100); rare (≥1/10,000, 1/1000); very rare (1/10,000); frequency unknown (cannot be estimated from the available data).

The following are undesirable effects, including those reported with short-term or long-term use of the drug.

From the blood and lymphatic system: very rarely – thrombocytopenia, leukopenia, anemia (including hemolytic anemia and aplastic anemia), agranulocytosis.

On the part of the immune system: rarely – hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock); very rarely – angioedema (including facial edema).

On the part of the psyche: very rarely – disorientation, depression, insomnia, irritability, nightmares, mental disorders.

From the nervous system: often – headache, dizziness; rarely – drowsiness, fatigue; very rarely – paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbance, stroke; frequency unknown – confusion, hallucinations, sensory disturbances, general malaise.

On the part of the organ of vision: very rarely – visual impairment, blurred vision, diplopia; frequency unknown – optic neuritis.

From the side of the organs of hearing and vestibular apparatus: often – vertigo; very rarely – tinnitus, hearing impairment.

From the cardiovascular system: very rarely – palpitations, chest pain, heart failure, myocardial infarction, hypertension, arterial hypotension, vasculitis.

From the respiratory system, thoracic organs and mediastinum: rarely – asthma (including dyspnea); very rarely – bronchospasm, pneumonitis.

Gastrointestinal: often – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rarely – gastritis, gastrointestinal bleeding (vomiting with blood, melena, diarrhea with blood), gastric and intestinal ulcers, accompanied by bleeding or perforation (sometimes fatal, especially in elderly patients); very rarely – colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, diaphragmatic stenosis of the intestine, pancreatitis.

From the liver and biliary tract: often – increased transaminase levels, rarely – hepatitis, jaundice, impaired liver function; very rarely – transient hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: often – rash; rarely – urticaria; very rarely – bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, hair loss, photosensitivity reaction, purpura, including allergic, itching.

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

General disorders: rarely – edema.

From the reproductive system and mammary gland function: very rarely – impotence.

Diclofenac, especially in high doses (150 mg/day) and with prolonged use, may lead to an increased risk of arterial thromboembolic complications (e.g. myocardial infarction or stroke).

General disorders and administration site conditions: malaise, injection site reaction, pain, induration, swelling, injection site necrosis, injection site abscess.

General precautions for the use of systemic NSAIDs.

To reduce the risk of gastrointestinal ulceration, bleeding or perforation, which can occur at any time during treatment with NSAIDs, regardless of their selectivity for COX-2 and even in the absence of warning symptoms or predisposing factors in history, the minimum effective dose should be used for the shortest possible period.

Patients with gastrointestinal disorders, liver dysfunction, or a history of suspected gastric or intestinal ulcers should use this medicine only if absolutely indicated and under close supervision.

An increased risk of thrombotic cardiovascular and cerebrovascular events has been reported with certain selective COX-2 inhibitors. It is currently unclear whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs.

Diclofenac should only be prescribed to patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking) after careful clinical evaluation. Since the cardiovascular risks of diclofenac may increase with increasing dose and duration of treatment, it should be used for the shortest possible period of time and at the lowest effective dose. The patient’s need for diclofenac should be periodically reassessed to assess symptom relief and response to therapy. Use with caution in patients over 65 years of age.

The effect of NSAIDs on the kidneys leads to fluid retention and edema and/or hypertension, so diclofenac should be used with caution in patients with cardiac disorders or other conditions predisposing to fluid retention. Use with caution in patients who are concomitantly taking diuretics or ACE inhibitors or who are at increased risk of developing hypovolemia.

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with NSAIDs, including diclofenac, and may occur during treatment, with or without warning symptoms or a history of severe gastrointestinal disorders. In elderly patients, such complications are usually more severe. If gastrointestinal bleeding or ulceration occurs in patients receiving Diclofenac Darnytsia, the drug should be discontinued.

Very rarely, severe skin reactions (in some cases fatal), including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with the use of NSAIDs. Patients are at greatest risk of developing such reactions at the start of treatment, with the onset of these reactions usually occurring within the first month of treatment. Diclofenac Darnytsia should be discontinued at the first sign of rash, mucosal lesions or any other sign of hypersensitivity.

Systemic lupus erythematosus and mixed connective tissue diseases: Patients with systemic lupus erythematosus and mixed connective tissue diseases may be at increased risk of developing aseptic meningitis.

As with all analgesics, prolonged use of a drug for the treatment of headache may result in improvement or worsening of the condition (medication overuse headache). If headache is due to overuse of analgesics, the dose should not be increased; in such cases, treatment should be discontinued. Medication overuse headache should be suspected in patients with frequent or daily attacks of headache that occur despite (or because of) regular use of analgesics.

As with other non-steroidal anti-inflammatory drugs, allergic reactions (including anaphylactic/anaphylactoid reactions) may rarely occur, even without prior use of diclofenac. Like other non-steroidal anti-inflammatory drugs, Diclofenac Darnytsia, due to its pharmacodynamic properties, may mask the signs and symptoms of infection.

reservation

General: Diclofenac Darnytsia and other nonsteroidal anti-inflammatory drugs of systemic action, including selective COX-2 inhibitors, should not be used simultaneously, as there is no evidence of the benefits of synergistic action, as well as due to the occurrence of additional side effects.

The drug should be used with caution in elderly patients. In particular, it is recommended to prescribe the minimum effective dose in physically weak elderly patients or those with insufficient body weight.

History of asthma. Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (e.g. nasal polyps), COPD or chronic respiratory tract infections (especially with manifestations similar to symptoms of allergic rhinitis) when taking NSAIDs more often than other patients, develop side effects such as exacerbation of asthma (so-called analgesic intolerance or analgesic asthma), angioedema, urticaria. In this regard, such patients require special measures (readiness to provide emergency care). The above also applies to patients with allergic manifestations (e.g. rash, itching, urticaria) when using other drugs.

Effects on the digestive tract. As with other NSAIDs, close medical supervision and special caution are necessary when prescribing the drug to patients with symptoms suggestive of gastrointestinal disorders or a history of ulcer, bleeding or perforation of the stomach or intestines. The risk of gastrointestinal bleeding increases with increasing dose of NSAIDs, as well as in patients with a history of ulcer, especially if complicated (bleeding or perforation), and in elderly patients. To reduce the risk of gastrointestinal toxicity in such patients, treatment should be initiated and maintained at the lowest effective dose. For such patients, as well as for patients who require concomitant use of drugs containing acetylsalicylic acid or other drugs that increase the risk of adverse effects on the digestive tract, combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered. Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding). Use with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding (systemic corticosteroids, anticoagulants, antithrombotic agents, or selective serotonin reuptake inhibitors).

Hepatic effects: Patients with hepatic impairment should be monitored closely as their condition may worsen.

As with other non-steroidal anti-inflammatory drugs, an increase in the level of one or more liver enzymes is possible. This has been observed very commonly with diclofenac, but has very rarely been accompanied by the manifestation of clinical symptoms. In most cases, an increase to borderline levels was observed. The increase in liver enzymes has been accompanied by clinical manifestations of liver damage. This increase was usually reversible after discontinuation of the drug.

It should be noted that Diclofenac Darnytsia is recommended only for short-term treatment (no more than 2 weeks). In case of long-term use of diclofenac, regular monitoring of liver function is a precautionary measure. The use of this medicinal product should be discontinued if liver function is impaired or worsened, if clinical signs or symptoms suggestive of liver disease develop, or other symptoms occur, such as eosinophilia, rash. Hepatitis may occur without prodromal symptoms.

In addition to elevated liver enzymes, severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis and hepatic failure, which in some cases were fatal, have been reported rarely.

Diclofenac should be used with caution in patients with hepatic porphyria due to the possibility of provoking an attack.

Effects on the kidneys. Prolonged use of high doses of NSAIDs often leads to edema and hypertension.

Particular caution should be exercised in patients with cardiac or renal impairment, a history of hypertension, the elderly, patients who are concomitantly taking diuretics or drugs that significantly affect renal function, and patients with significant volume depletion, e.g. before/after surgery. When prescribing Diclofenac Darnytsia in such cases, renal function should be monitored. After discontinuation of therapy, the patient’s condition usually returns to normal.

Effect on hematological parameters. Diclofenac Darnytsia is recommended only for short-term treatment. When prescribing this drug for a long period, it is recommended (as for other NSAIDs) to regularly monitor the blood picture.

Like other nonsteroidal anti-inflammatory drugs, diclofenac may temporarily inhibit platelet aggregation, therefore, patients with impaired hemostasis should be carefully monitored.

Diclofenac Darnytsia contains lactose, therefore it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

You should not drink alcohol during treatment.

Use during pregnancy and lactation. The use of diclofenac in pregnant women has not been studied. Animal studies do not indicate any direct or indirect toxic effects with respect to pregnancy, embryonic development, fetal development, parturition and/or postnatal development.

In the I and II trimesters of pregnancy, Diclofenac Darnytsia, enteric-coated tablets, should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only in the minimum effective dose. As with other nonsteroidal anti-inflammatory drugs, the drug is contraindicated in the last trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the ductus arteriosus in the fetus).

Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryo/foetal development. Epidemiological studies have shown an increased risk of miscarriage and/or cardiac malformations and gastroschisis following exposure to a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular malformations was increased from less than 1% to approximately 1.5%.

It is possible that the risk increases with dose and duration of treatment. In animals, administration of a prostaglandin synthesis inhibitor has been shown to increase pre- and post-implantation loss and embryo/fetal lethality.

In addition, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various malformations, including those of the cardiovascular system, was recorded. If the drug is used by a woman attempting to conceive, or in the first trimester of pregnancy, the dose of the drug should be as low as possible and the duration of treatment as short as possible.

In the third trimester of pregnancy, all prostaglandin synthesis inhibitors can affect the fetus in the following ways:

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

For the mother and newborn, as well as at the end of pregnancy:

• possible prolongation of bleeding time, antiplatelet effect, which can develop even when taken in very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Diclofenac Darnytsia is contraindicated in the third trimester of pregnancy.

As with other non-steroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. Therefore, Diclofenac Darnytsia, enteric-coated tablets, should not be used during breastfeeding. If treatment is absolutely necessary, breastfeeding should be discontinued.

Like other nonsteroidal anti-inflammatory drugs, Diclofenac Darnytsia, enteric-coated tablets, may adversely affect female fertility and is therefore not recommended for use in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, discontinuation of Diclofenac Darnytsia, enteric-coated tablets should be considered.

Children. Diclofenac Darnytsia, enteric-coated tablets, at a dose of 25 mg can be used in children over 8 years of age (with a body weight of at least 25 kg). Diclofenac Darnytsia in the form of a solution for injection is contraindicated for use in children.

Ability to influence the speed of reactions when driving vehicles or using other mechanisms. Patients who experience visual disturbances, dizziness, vertigo, drowsiness or other central nervous system disorders during treatment with the drug should refrain from driving vehicles or operating other mechanisms.

The following types of interactions have been observed with the use of diclofenac in the form of a solution for injection and / or other dosage forms.

Lithium: Concomitant use of diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin: Diclofenac may increase plasma concentrations of digoxin when used concomitantly. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensives: As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensives (e.g. β-blockers, ACE inhibitors) may result in a reduction in their antihypertensive effect. Therefore, such a combination should be used with caution and patients, especially the elderly, should be closely monitored for blood pressure.

Patients should be adequately hydrated and monitoring of renal function is recommended after initiation of concomitant therapy and regularly thereafter, especially for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

Drugs known to cause hyperkalemia. Concomitant treatment with potassium drugs may be associated with an increase in serum potassium levels, which requires constant monitoring of patients.

Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the incidence of gastrointestinal side effects.

Anticoagulants and antithrombotic agents: Caution is advised as concomitant administration may increase the risk of bleeding. Although clinical studies have not shown an effect of diclofenac on the activity of anticoagulants, there is some evidence of an increased risk of bleeding in patients receiving diclofenac and these drugs concomitantly, and close monitoring of such patients is recommended.

Like other nonsteroidal anti-inflammatory drugs, diclofenac in high doses can temporarily inhibit platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.

Antidiabetic drugs. Diclofenac can be used together with oral antidiabetic drugs without affecting their clinical effect. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring a change in the dose of antidiabetic drugs during treatment with diclofenac. Such conditions require monitoring of blood glucose levels, which is a precautionary measure during concomitant therapy.

Colestipol and cholestyramine. These drugs may delay or reduce the absorption of diclofenac. Therefore, it is recommended to take diclofenac at least 1 hour before or 4-6 hours after taking colestipol/cholestyramine.

Medicinal products that induce drug-metabolizing enzymes. Enzyme-inducing medicinal products, such as rifampicin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum), are theoretically capable of reducing the plasma concentration of diclofenac.

Methotrexate: Caution is advised when administering NSAIDs less than 24 hours before or after treatment with methotrexate, as increased blood concentrations and toxicity of this substance may occur.

Cyclosporine and tacrolimus. Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine through its effects on renal prostaglandins. This risk is increased in patients treated with tacrolimus. Therefore, it should be used in lower doses than in patients not receiving cyclosporine.

Quinolone antibiotics: There have been isolated reports of convulsions, which may be associated with the concomitant use of quinolones and nonsteroidal anti-inflammatory drugs.

Potent CYP 2C9 inhibitors: Caution should be exercised when administering diclofenac and CYP 2C9 inhibitors (such as sulfinpyrazone and voriconazole) concomitantly, as this may result in a significant increase in peak plasma concentrations and effects of diclofenac due to inhibition of diclofenac metabolism.

Phenytoin: When using phenytoin simultaneously with diclofenac, it is recommended to monitor the concentration of phenytoin in the blood plasma due to a possible increase in the effect of phenytoin.

Cardiac glycosides. Concomitant use of cardiac glycosides and nonsteroidal anti-inflammatory drugs may exacerbate heart failure, reduce glomerular filtration rate, 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.

Symptoms. There is no typical clinical picture of the consequences of diclofenac overdose. Overdose can cause symptoms such as headache, vomiting, epigastric pain and gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, drowsiness, tinnitus or convulsions. In case of severe poisoning, acute respiratory distress syndrome and liver damage are possible.

Treatment. Treatment of acute poisoning consists primarily of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment are necessary to address complications such as hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression.

Special measures such as forced diuresis, dialysis or hemoperfusion cannot guarantee the removal of NSAIDs due to their high binding to plasma proteins and intensive metabolism. Activated charcoal may be used after ingestion of potentially toxic doses, and gastric decontamination (e.g., induction of vomiting, gastric lavage) after ingestion of potentially life-threatening doses.

At a temperature not exceeding 25°C. Do not freeze the solution for injection.