Voltaren®

INSTRUCTIONS for medical use of the medicinal product VOLTAREN® (VOLTAREN®)

Composition:

Active ingredient: sodium diclofenac;

One gastro-resistant tablet contains sodium diclofenac 25 mg or 50 mg;

Excipients:

tablet core 25 mg and 50 mg: silicon dioxide, colloidal anhydrous; microcrystalline cellulose; lactose monohydrate; magnesium stearate; maize starch; povidone K 30; sodium starch glycolate (type A);

tablet coating (sub-coating and colored) 25 mg:

hypromellose (hydroxypropylmethylcellulose); polyoxyl hydrogenated castor oil; iron oxide yellow (E 172); talc; titanium dioxide (E 171);

enteric coating: methacrylic acid copolymer (type A), polyethylene glycol 8000 / macrogol 8000, anti-adherent silicone emulsion SE 2 / simethicone, talc;

tablet coating (sub-coating and colored) 50 mg:

hypromellose (hydroxypropylmethylcellulose); polyoxyl hydrogenated castor oil; iron oxide yellow (E 172); iron oxide red (E 172); talc; titanium dioxide (E 171);

enteric coating: methacrylic acid copolymer (type A), polyethylene glycol 8000 / macrogol 8000, anti-adherent silicone emulsion SE 2 / simethicone, talc.

Medicinal form. Gastro-resistant tablets.

Main physicochemical properties:

25 mg: yellow, round, biconvex tablets with beveled edges; one side of the tablet bears the imprint "CG", the other side "BZ";

50 mg: light brown, round, biconvex tablets with beveled edges; one side of the tablet bears the imprint "CG", the other side "GT".

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

Acetic acid derivatives and related substances. Diclofenac. ATC code M01AB05.

Pharmacological properties.

Pharmacodynamics.

Voltaren® contains diclofenac sodium – a non-steroidal compound exerting pronounced analgesic and anti-inflammatory effects.

It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

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

Pharmacokinetics.

Absorption

Although absorption is complete, the onset of action may be delayed due to passage through the stomach, which may be influenced by food intake, as food delays gastric emptying. Mean peak plasma concentrations of 1.48 ± 0.65 µg/mL (1.5 µg/mL ≡ 5 µmol/L) are reached on average 2 hours after administration of a 50 mg tablet.

Bioavailability

Approximately half of the administered diclofenac is metabolized during the first pass through the liver (first-pass effect); the area under the concentration-time curve (AUC) after oral administration is approximately half of that obtained with an equivalent parenteral dose.

The pharmacokinetic characteristics of the drug do not change with repeated administration. Accumulation does not occur under conditions of recommended dosing.

Plasma concentrations in children receiving equivalent doses (mg/kg body weight) are similar to those observed in adults (for 25 mg tablets only).

Distribution

Binding of diclofenac to plasma proteins is 99.7%, with albumin – 99.4%.

Diclofenac penetrates into synovial fluid, where its maximum concentration is achieved 2–4 hours later than in plasma. The half-life in synovial fluid is 3–6 hours. Two hours after peak plasma concentration is reached, the concentration of diclofenac in synovial fluid remains higher; this phenomenon persists for up to 12 hours.

Diclofenac has been detected in breast milk at a low concentration (100 ng/mL) in one woman. The estimated amount of drug transferred to the infant via breast milk is equivalent to a dose of 0.03 mg/kg/day.

Metabolism.

Diclofenac is partially metabolized by glucuronidation of the unchanged molecule, but mainly by single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which form conjugates with glucuronic acid. Two of these phenolic metabolites are biologically active, but significantly less so than diclofenac.

Elimination

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1–2 hours. The half-life in plasma of four metabolites, including two pharmacologically active ones, is also short and ranges from 1–3 hours. Approximately 60% of the administered dose is excreted in urine as glucuronide conjugate of the intact molecule 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 feces as metabolites.

Special patient groups

Elderly patients. No influence of patient age on absorption, metabolism, and elimination of the drug has been observed, except for the fact that in five elderly patients, a 15-minute intravenous infusion resulted in a 50% higher plasma concentration of the drug than expected in young healthy volunteers.

Patients with renal impairment. In patients with impaired renal function receiving therapeutic doses, accumulation of unchanged active substance is not expected, based on the drug's kinetics after single administration. In patients with creatinine clearance less than 10 mL/min, calculated steady-state plasma concentrations of hydroxylated metabolites were approximately four times higher than in healthy volunteers. However, ultimately, all metabolites were excreted via bile.

Patients with liver disease. In patients with chronic hepatitis or compensated cirrhosis of the liver, pharmacokinetic parameters and diclofenac metabolism are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

• Inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritides);
• Back pain syndromes;
• Rheumatic diseases of soft tissues outside the joints;
• Acute gout attacks;
• Post-traumatic and postoperative pain syndromes associated with inflammation and edema, e.g., following dental or orthopedic procedures;
• Gynecological conditions associated with pain and inflammation, e.g., primary dysmenorrhea or adnexitis;
• As an adjunctive agent in severe inflammatory conditions of the ear, nose, and throat (ENT) organs accompanied by pain, e.g., pharyngotonsillitis, otitis.

According to general therapeutic principles, the underlying disease should be treated with appropriate basic therapy. Fever alone is not an indication for the use of this medicinal product.

Contraindications.

• Hypersensitivity to the active substance or to any other component of the medicinal product.
• Active peptic ulcer of the stomach or intestine; gastrointestinal hemorrhage or perforation.
• History of gastrointestinal hemorrhage or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active peptic ulceration of the stomach or duodenum / bleeding, or recurrent peptic ulcer / bleeding in history (two or more separate episodes of confirmed ulcer or bleeding).
• Third trimester of pregnancy.
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
• Hepatic failure.
• Renal failure (glomerular filtration rate < 15 ml/min/1.73 m²).
• Congestive heart failure (NYHA II–IV).
• Treatment of perioperative pain in coronary artery bypass grafting (CABG) (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 (TIA).
• Peripheral arterial disease.
• Voltaren®, like other nonsteroidal anti-inflammatory drugs, is contraindicated in patients who have experienced attacks of bronchial asthma, angioedema, urticaria, acute rhinitis, nasal polyps, or other allergic reactions after taking ibuprofen, acetylsalicylic acid, or other NSAIDs.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below have been observed with diclofenac administered as enteric-coated tablets and/or in other pharmaceutical forms.

Inducers of CYP2C9. Caution is required when diclofenac is co-administered with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant decrease in plasma concentration and exposure to diclofenac.

Inhibitors of CYP2C9. Caution is required when diclofenac is co-administered with CYP2C9 inhibitors (e.g., voriconazole). This may lead to a significant increase in maximum plasma concentrations and exposure to diclofenac.

Lithium. Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should be monitored at the start of concomitant therapy and regularly thereafter, particularly when diuretics or ACE inhibitors are used, due to increased risk of nephrotoxicity.

Cyclosporine and tacrolimus. The effect of diclofenac, as with other NSAIDs, on renal prostaglandin synthesis may enhance the nephrotoxicity of cyclosporine and tacrolimus. Therefore, diclofenac should be used at lower doses than those prescribed for patients not receiving cyclosporine or tacrolimus.

Medicinal products causing hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

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

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

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although clinical studies have not shown an effect of diclofenac on anticoagulant activity, there are data indicating an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia occurring in such cases, necessitating dosage adjustments of antidiabetic agents during diclofenac treatment. For this reason, as a precautionary measure, blood glucose levels should be monitored during combination therapy.

There are also isolated reports of metabolic acidosis occurring with concomitant use of diclofenac, particularly in patients with pre-existing renal function impairment.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before or after methotrexate administration, as this may increase methotrexate blood concentration and enhance its toxic effects. Serious toxicity cases have been reported when the interval between methotrexate and NSAID (including diclofenac) administration was within 24 hours. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to the expected increase in phenytoin effects.

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

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

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

Special precautions for use.

• General

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

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

Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. As there are currently no comparative clinical trial data on long-term use of diclofenac at maximum doses, a similar risk cannot be excluded. A direct correlation between this risk and the selectivity of individual NSAIDs for COX-1/COX-2 has not been established. In the absence of such data, a careful risk-benefit assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Due to this risk, the lowest effective dose should be used for the shortest possible duration of treatment.

NSAID effects on the kidneys include fluid retention with edema and/or arterial hypertension. Diclofenac should be used with caution in patients with cardiac dysfunction or other conditions predisposing to fluid retention. This is also recommended for patients receiving concomitant diuretics or ACE inhibitors, or those prone to hypovolemia.

Consequences are generally more serious in elderly patients. Caution should be exercised when prescribing the drug to elderly individuals. Special caution is required for patients over 65 years of age. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

If gastrointestinal bleeding or ulcers occur in patients taking Voltaren®, the use of this drug should be discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, even without prior exposure to diclofenac.

Due to its pharmacodynamic properties, Voltaren®, like other NSAIDs, may mask symptoms of infection.

Voltaren® enteric-coated tablets contain lactose. Patients with rare hereditary lactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not use Voltaren® enteric-coated tablets.

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

• Gastrointestinal effects

When using all NSAIDs, both COX-2 selective and non-selective, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported. These events can be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, medical monitoring and special caution are required for patients with symptoms indicating gastrointestinal (GI) disorders when diclofenac is prescribed. The risk of GI bleeding, ulceration, or perforation increases with higher doses of NSAIDs, particularly diclofenac.

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 such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant low-dose acetylsalicylic acid (ASA/aspirin or other agents increasing GI adverse 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 elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

The use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic insufficiency. Careful medical monitoring and caution are recommended when using Voltaren® after gastrointestinal surgery.

• Hepatic effects

Careful medical monitoring is required when Voltaren® is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, one or more liver enzymes may increase during diclofenac therapy. Such enzyme elevations are usually reversible upon discontinuation of the drug.

This elevation was very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but rarely accompanied by clinical symptoms. Most of these cases involved borderline increases. Moderate increases (≥ 3 to < 8 times the upper limit of normal) occurred frequently (in 2.5% of cases), while marked increases (≥ 8 times the upper limit of normal) occurred in approximately 1% of cases. Clinically evident liver injury occurred in 0.5% of cases in the aforementioned clinical trials.

During long-term treatment with Voltaren®, regular monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function abnormalities persist or worsen, if clinical symptoms suggest progressive liver disease, or if other signs occur (e.g., eosinophilia, rash), Voltaren® should be discontinued.

In addition to elevated liver enzymes, rare reports of severe hepatic reactions have been reported, including jaundice, fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which have been fatal.

Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when Voltaren® is used in patients with hepatic porphyria, due to the potential to provoke an attack.

• Renal effects

NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension have been frequently (1–10%) reported during NSAID therapy, particularly with diclofenac, special attention should be given to patients with cardiac or renal dysfunction, history of arterial hypertension, elderly patients, patients receiving concomitant diuretics or drugs significantly affecting renal function, and patients with significant extracellular fluid volume depletion from any cause (e.g., before or after major surgery). In such cases, monitoring of renal function is recommended as a precaution. Discontinuation of therapy usually results in return to the pre-treatment state.

• Skin effects

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

• Systemic lupus erythematosus (SLE) and mixed connective tissue disorders

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

• Cardiovascular and cerebrovascular effects

Voltaren® therapy is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily for treatment courses longer than 4 weeks. Since cardiovascular risks associated with diclofenac may increase with higher doses and longer treatment duration, the drug should be used for the shortest possible time and at the lowest effective dose. The need for diclofenac and the patient's response to therapy should be periodically reviewed, especially if treatment lasts longer than 4 weeks.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and advice, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

Voltaren® should be used with caution in patients taking concomitant diuretics or ACE inhibitors, or those at increased risk of hypovolemia.

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

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful risk-benefit assessment and at a dose not exceeding 100 mg daily for no more than 4 weeks.

Patients should be informed about the possibility of serious thrombotic events (chest pain, dyspnea, weakness, speech disturbances) at any time during treatment. In such cases, immediate medical attention should be sought.

• Hematological effects

With prolonged use of diclofenac, as with other NSAIDs, monitoring of blood counts with differential leukocyte count is recommended.

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

• Asthma history

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

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

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. This risk is believed to be proportional to the dose and duration of treatment. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. In animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

First/second trimester

Voltaren® may be prescribed during the first and second trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus. If Voltaren® is used by a woman planning pregnancy or during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible.

Oligohydramnios/renal dysfunction in newborns/constriction of the arterial duct

NSAID use from the 20th week of pregnancy may lead to impaired fetal renal function, causing oligohydramnios, and in some cases, neonatal renal failure. These adverse effects are typically observed after several days or weeks of treatment, although oligohydramnios has developed as early as 48 hours after starting NSAID therapy in rare cases. Oligohydramnios often, but not always, resolves after discontinuation of NSAID treatment. Complications of prolonged oligohydramnios may include, for example, limb contractures and pulmonary hypoplasia. In some post-marketing clinical observations, neonatal renal failure required invasive procedures such as exchange transfusion or dialysis.

Additionally, constriction of the arterial duct has been reported after second-trimester treatment, which resolves in most cases after discontinuation of therapy.

If treatment with Voltaren® lasts longer than 48 hours, ultrasound monitoring of amniotic fluid and fetal heart should be considered. If oligohydramnios or arterial duct constriction occurs, Voltaren® should be discontinued and appropriate treatment initiated according to clinical practice.

Third trimester

Voltaren® is contraindicated during the third trimester of pregnancy.

All prostaglandin synthesis inhibitors may:

• expose the fetus to risks:
  • cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
  • renal dysfunction, which may progress to renal failure with oligohydramnios;
• expose the mother and child to risks:
  • possible prolongation of bleeding time – due to inhibition of platelet aggregation, which may occur even with very low doses;
  • inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding

Like other NSAIDs, diclofenac is excreted in small amounts in breast milk. Therefore, Voltaren® is contraindicated in women during breastfeeding to avoid undesirable effects on the infant.

If treatment is necessary, breastfeeding should be discontinued.

Female fertility

Like other NSAIDs, Voltaren® may negatively affect female fertility and is therefore not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of Voltaren® should be considered.

Based on relevant animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

The medicinal product should be used at the lowest effective doses for the shortest duration necessary, taking into account the treatment objective for each individual patient.

Adults

The tablets should preferably be taken before meals, swallowed whole with liquid; they must not be divided or chewed.

The usual initial dose is 100–150 mg per day. For mild symptoms or long-term therapy, a daily dose of 75–100 mg is sufficient. The daily dose should be divided into 2–3 administrations. To prevent nocturnal pain or morning stiffness, therapy with gastro-resistant Voltaren® tablets may be supplemented with rectal suppositories of Voltaren® administered before bedtime. The maximum daily dose must not exceed 150 mg.

For primary dysmenorrhea, the daily dose should be individually adjusted and usually ranges from 50–150 mg. The initial dose may be 50–100 mg, but if necessary, it can be increased over several menstrual cycles up to the maximum daily dose of 150 mg.

The recommended maximum daily dose of Voltaren® is 150 mg.

Children aged 1–14 years

Voltaren®, gastro-resistant tablets of 50 mg, are not recommended for children due to the high content of active substance. Tablets of 25 mg may be administered to children from the age of 1 year, under medical supervision, at a daily dose of 0.5–2 mg/kg body weight depending on symptom severity; this dose should be divided into 2–3 administrations.

If the required dose cannot be achieved with tablets, other diclofenac formulations with appropriate dosing should be used for children.

Elderly patients (aged 65 years and older)

Although the pharmacokinetics of Voltaren® are not significantly altered in elderly patients to a clinically relevant extent, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in this population, who are generally more susceptible to adverse reactions. In particular, the lowest effective doses are recommended for frail elderly patients or those with low body weight. Additionally, patients should be monitored for gastrointestinal bleeding during NSAID therapy.

Cardiovascular diseases or significant risk factors

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and, if used for more than 4 weeks, at maximum daily doses of up to 100 mg (see "Special precautions for use"). Since cardiovascular risks associated with diclofenac may increase with higher doses and longer treatment duration, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac and the patient's response to therapy should be reviewed regularly.

Patients with renal impairment

Voltaren® is contraindicated in patients with renal failure (glomerular filtration rate < 15 mL/min/1.73 m²).

No specific studies have been conducted in patients with renal impairment, and no dosage adjustment recommendations are available. Voltaren® should be used with caution in patients with impaired renal function.

Patients with hepatic impairment

Voltaren® is contraindicated in patients with hepatic failure.

No specific studies have been conducted in patients with hepatic impairment, and no dosage adjustment recommendations are available. Voltaren® should be used with caution in patients with moderate to severe hepatic impairment.

Children

Voltaren®, gastro-resistant 50 mg tablets, are not recommended for children due to the high content of active substance.

Overdose

Symptoms

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

Treatment

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

Side effects.

The frequency category of adverse reactions 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 not known (cannot be estimated from the available data).

The undesirable effects listed below include events reported during short-term or long-term use of the medicinal product.

Blood and lymphatic system disorders: very rare – thrombocytopenia, leucopenia, anaemia, including haemolytic anaemia and aplastic anaemia, agranulocytosis.

Immune system disorders: rare – hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock); very rare – angioneurotic oedema (including facial swelling).

Psychiatric disorders: very rare – confusion, depression, insomnia, irritability, nightmares, psychotic disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence, fatigue; very rare – paraesthesia, memory impairment, convulsions, restlessness, tremor, aseptic meningitis, taste disturbances, stroke; frequency not known – confusion, hallucinations, sensory disturbances, general malaise.

Eye disorders: very rare – visual disturbances, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing disturbances.

Cardiac disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction, arterial hypotension; frequency not known – Kounis syndrome.

Vascular disorders: common – arterial hypertension; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnoea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal haemorrhage, haematemesis, melaena, haemorrhagic diarrhoea, gastric and intestinal ulcers with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis; very rare – colitis (including haemorrhagic colitis, ischaemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal dysfunction, diaphragm-like intestinal stricture, pancreatitis.

Voltaren® may cause chronic inflammatory conditions with pseudomembranes and strictures in the distal gastrointestinal tract (small intestine and large intestine).

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver disorders; very rare – fulminant hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: common – rash; rare – urticaria; very rare – blistering rash, eczema, erythema, erythema multiforme, Stevens–Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura (including allergic purpura), pruritus; frequency not known – drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders: common – fluid retention, oedema; very rare – acute kidney injury (acute renal failure), haematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, renal papillary necrosis.

General disorders: rare – oedema.

Reproductive system and breast disorders: very rare – impotence.

Clinical trial data and epidemiological evidence indicate an increased risk of thrombotic complications (e.g. myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and during prolonged treatment.

Visual disturbances.

Visual disturbances such as impaired vision, worsening of vision, and diplopia are class effects of NSAIDs and are generally reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which, due to impaired regulation of retinal blood flow, may alter the regulation of intraocular arterial pressure and lead to changes in visual acuity. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to exclude other possible causes.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30°C. Protect from moisture. Keep out of reach of children.

Packaging.

25 mg tablets: 10 tablets in a blister; 3 blisters in a cardboard box.

50 mg tablets: 10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Novartis Sağlık, Gıda ve Tarım Ürünleri San. ve Tic. A.Ş.

Manufacturer's address and place of business.

Yenisehir Mahallesi, Ihlara Vadi Sokak No 2, Pendik, Istanbul, TR 34912, Turkey.