Voltaren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VOLTAREN® (VOLTAREN®)

Composition:

Active ingredient: sodium diclofenac – 25 mg, 50 mg or 100 mg;

1 suppository contains sodium diclofenac 25 mg, 50 mg or 100 mg;

Excipient: hard fat.

Pharmaceutical form. Suppositories.

Main physicochemical properties: suppositories are white to yellowish in color, torpedo-shaped, with a smooth or slightly uneven surface.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Diclofenac.

ATC code M01A B05.

Pharmacological Properties

Pharmacodynamics

In 15 clinical studies in which diclofenac was administered rectally for the treatment of postoperative pain in pediatric patients with a mean age of 8 years, the use of rescue analgesics (particularly opioids) was reduced (only for 25 mg suppositories).

Voltaren® contains sodium diclofenac, a non-steroidal compound with pronounced analgesic and anti-inflammatory effects. It acts as an inhibitor of prostaglandin synthetase (cyclooxygenase).

Only for 25 mg suppositories

Experience with diclofenac use in pediatric patients with juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA) in clinical trials is limited. In a randomized, double-blind, 2-week parallel-group study involving children aged 3–15 years with JRA/JIA, the efficacy and safety of diclofenac at a dose of 2–3 mg/kg body weight per day were compared with those of acetylsalicylic acid (ASA) at a dose of 50–100 mg/kg body weight per day and placebo (15 patients in each group). Overall assessment of the data showed improvement in patients (11 out of 15 in the diclofenac group, 6 out of 12 in the aspirin group, and 4 out of 15 in the placebo group), with a statistically significant difference (p < 0.05). The number of painful joints decreased with diclofenac and ASA, but increased with placebo. In another randomized, double-blind, 6-week parallel-group study involving children aged 4–15 years with JRA/JIA, the efficacy of diclofenac (daily dose 2–3 mg/kg body weight, n=22) was comparable to that of indomethacin (daily dose 2–3 mg/kg body weight, n=23).

Pharmacokinetics

Pharmacokinetic data from administration of the drug in 6 children aged 6–16 years with juvenile chronic arthritis who received diclofenac once daily for 2 weeks are limited. After correction for body weight to 75 kg, pharmacokinetic parameters were similar to those in adults (only for 25 mg suppositories).

Absorption. Absorption is rapid, although slower than with enteric-coated tablets. After administration of 50 mg Voltaren® suppositories, peak plasma concentration is reached in approximately 1 hour, but peak concentration per dose unit is about two-thirds of that achieved after administration of enteric-coated tablets (1.95±0.8 μg/mL (1.9 μg/mL ≡ 5.9 μmol/L)).

Bioavailability. As with oral formulations of the drug, the area under the concentration-time curve (AUC) is approximately half of that obtained after parenteral administration. With repeated administration, the pharmacokinetics of the drug do not change. No accumulation of the drug occurs when recommended dosing intervals are observed. Plasma concentrations achieved in children receiving equivalent doses (mg/kg body weight) are similar to those observed in adults (only for 25 mg suppositories).

Distribution. Diclofenac protein binding to plasma proteins is 99.7%, primarily to albumin (99.4%).

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

Diclofenac was detected at low concentrations (100 ng/mL) in breast milk in one patient. The estimated amount of drug transferred to the infant via breast milk corresponds to a dose of 0.03 mg/kg/day.

Metabolism. Diclofenac is partially metabolized by glucuronidation of the unchanged molecule, but primarily by single and multiple hydroxylation and methoxylation, resulting in 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.

Excretion. Total systemic clearance of diclofenac from plasma is 263±56 mL/min (mean ± 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, lasting 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.

Pharmacokinetics in specific patient groups. No effect of patient age on absorption, metabolism, or excretion 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.

In patients with impaired renal function receiving therapeutic doses, accumulation of the unchanged active substance is not expected, based on pharmacokinetics 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 hepatic impairment. 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 rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, including spondyloarthritis;
• Spinal pain syndromes;
• Rheumatic diseases of extra-articular soft tissues;
• Post-traumatic and postoperative pain syndromes accompanied by inflammation and swelling, particularly after dental and orthopedic surgeries;
• Gynecological conditions associated with pain and inflammation, e.g. primary dysmenorrhea and adnexitis;
• Migraine attacks;
• Acute gout attacks;
• As an adjunctive agent in severe inflammatory ENT disorders accompanied by pain, e.g. pharyngotonsillitis, otitis.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• History of gastrointestinal bleeding or perforation related to previous treatment with NSAIDs;
• Active peptic ulceration of the stomach or duodenum / bleeding, or recurrent peptic ulcer / bleeding in history (two or more distinct 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) surgery (or use of cardiopulmonary bypass);
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
• Cerebrovascular disorders in patients with history of stroke or transient ischemic attacks;
• Peripheral arterial disease;
• Voltaren®, like other non-steroidal anti-inflammatory drugs (NSAIDs), is contraindicated in patients in whom administration of acetylsalicylic acid or other NSAIDs induces attacks of bronchial asthma, urticaria, angioedema, acute rhinitis, or nasal polyps;
• Proctitis.

Interaction with other medicinal products and other forms of interaction.

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

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

Digoxin. Diclofenac may increase digoxin plasma 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 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. Adequate hydration should be ensured, and renal function should be monitored after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent patient monitoring is recommended.

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, data indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are required. Like other non-steroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

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 have been some reports of both hypoglycemia and hyperglycemia requiring dosage adjustments of antidiabetic agents during diclofenac treatment. For this reason, blood glucose monitoring is recommended during combination therapy.

There have also been isolated reports of metabolic acidosis when used concomitantly with diclofenac, particularly in patients with pre-existing renal 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 plasma concentrations and enhance its toxicity. Serious toxicity has been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors; therefore, diclofenac should be administered at lower doses in patients receiving tacrolimus compared to those not receiving tacrolimus.

Quinolone antibacterial agents. There are isolated reports of seizures 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 quinolone use in patients already receiving NSAIDs.

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

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, diclofenac should be administered at least one hour before or 4–6 hours after cholestyramine/colestipol administration.

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

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

CYP2C9 inhibitors. Caution is required when co-prescribing diclofenac with CYP2C9 inhibitors (e.g. voriconazole), as this may lead to a significant increase in diclofenac’s maximum plasma concentration and exposure.

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

Special precautions for use.

• General

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during use of non-steroidal anti-inflammatory drugs (NSAIDs), regardless of whether they are COX-2 selective, even in the absence of warning symptoms or history of predisposition. To minimize adverse effects, the lowest effective dose should be used for the shortest possible duration.

Placebo-controlled studies have indicated an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. Whether this risk is directly correlated with COX-1/COX-2 selectivity of individual NSAIDs remains unknown.

Concomitant use of 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.

As there are currently no comparative clinical data on long-term treatment with maximum doses of diclofenac, the possibility of such increased risk cannot be excluded. Until such data become available, a careful benefit-risk assessment should be performed before using diclofenac in patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Because of this risk, the lowest effective dose should be used for the shortest possible duration.

Caution is required when administering to patients over 65 years of age. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

In rare cases, 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 signs and symptoms of infection.

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, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported. These events may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events generally 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, patients with symptoms indicating gastrointestinal (GI) disturbances require medical supervision and special caution. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac, and in patients with a history of peptic ulcer, especially with complications such as bleeding or perforation, and in elderly patients.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly 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 drugs capable of 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., acetylsalicylic acid), or selective serotonin reuptake inhibitors.

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 administered 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.

This occurred very frequently in clinical trials of diclofenac (approximately in 15% of patients), but rarely was associated with clinical symptoms. Most of these cases involved borderline elevations. Moderate increases (≥ 3 to < 8 times the upper limit of normal) were observed frequently (in 2.5% of cases), while significant increases (≥ 8 times the upper limit of normal) occurred in about 1%. In the aforementioned clinical trials, 0.5% of patients experienced elevated liver enzyme levels associated with clinically evident liver injury. After discontinuation of the drug, liver enzyme levels returned to baseline.

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

In addition to elevated liver enzyme levels, isolated reports of severe hepatic reactions have been received, including jaundice, fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which were fatal.

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

• Renal effects

Due to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of NSAIDs, including diclofenac, often (1–10%) leads to fluid retention, edema, and hypertension.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant reduction in extracellular fluid volume for any reason, such as before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually results in return to the pre-treatment state.

• Skin effects

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have very rarely been reported in association with NSAIDs, including Voltaren®. The highest risk of these reactions occurs early in the course of treatment: reactions typically appear within the first month of therapy. Voltaren® should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

• Systemic lupus erythematosus and mixed connective tissue diseases

Patients with systemic lupus erythematosus and mixed connective tissue diseases may have an increased risk of developing aseptic meningitis.

• Cardiovascular and cerebrovascular effects

Voltaren® is generally not recommended for patients with established cardiovascular disease (e.g., heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled 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 if treatment duration exceeds 4 weeks. Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for continued diclofenac use for symptom relief and response to therapy should be reviewed periodically.

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

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

The need for symptom relief and response to therapy should be reviewed periodically, especially if treatment duration exceeds 4 weeks.

Patients should be informed of the need to monitor for symptoms of serious arterial thromboembolic events (e.g., chest pain, dyspnea, weakness, slurred speech), which may occur without warning. If such an event occurs, patients should seek immediate medical attention.

• Hematological effects

With prolonged use of this drug, as with other NSAIDs, monitoring of all blood parameters is recommended.

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

• Asthma history

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

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

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre- and post-implantation loss and embryonic/fetal death. Furthermore, 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

During the first and second trimesters of pregnancy, Voltaren® should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus. If Voltaren® is used by a woman trying to conceive or by a pregnant woman 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 / ductus arteriosus constriction

NSAID use from week 20 of gestation may lead to impaired fetal renal function, causing oligohydramnios and, in some cases, renal dysfunction in the newborn. These adverse effects are observed on average after several days or weeks of treatment, although in rare cases oligohydramnios developed within 48 hours of starting NSAID therapy. 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 dysfunction required invasive procedures such as exchange transfusion or dialysis.

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

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

Third trimester

During the third trimester of pregnancy, use of Voltaren® is contraindicated.

All prostaglandin synthesis inhibitors may:

• expose the fetus to risks:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • impaired renal function, which may progress to renal failure with oligohydramnios;
• expose the mother and child to risks:
  • possible prolongation of bleeding time – an effect of platelet aggregation inhibition, 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 breast milk in small amounts. Therefore, Voltaren® suppositories should not be used in women during breastfeeding to avoid undesirable effects on the infant. If treatment is essential, the infant should be switched to artificial feeding.

Female fertility.

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

Regarding animals, based on available data, impaired fertility in males cannot be excluded. The significance of these data for humans is unclear.

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 treatment with Voltaren® should not drive or operate machinery.

Method of Administration and Dosage.

The drug should be used at the lowest effective dose for the shortest duration necessary, taking into account the individual treatment goals for each patient.

To minimize adverse effects, the lowest effective dose should be used for the shortest possible duration.

Do not take orally; for rectal use only.

Suppositories should be inserted into the rectum as deeply as possible, preferably after bowel evacuation.

The initial dose is usually 100–150 mg per day. In cases of mild symptoms or during long-term therapy, a dose of 75–100 mg/day is sufficient.

The daily dose should be divided into 2–3 administrations. To prevent nocturnal pain or morning stiffness, administer Voltaren® as rectal suppositories before bedtime (daily dose must not exceed 150 mg).

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

Treatment should begin after the onset of the first painful symptoms and continued for several days, depending on the symptomatic improvement.

For the treatment of migraine attacks, therapy should start at a dose of 100 mg at the first signs of an attack. If necessary, a second suppository (50 mg of diclofenac) may be administered on the same day. If needed, treatment may continue in the following days (daily dose must not exceed 150 mg, divided into 2–3 doses).

Children (aged 1–14 years) with juvenile chronic arthritis: 1–3 mg/kg/day in divided doses (only suppositories of 25 mg).

Children (aged 6–14 years) with acute postoperative pain: 1–2 mg/kg/day in divided doses. The duration of treatment for acute postoperative pain should be limited to a maximum of 4 days (only suppositories of 25 mg).

For example, in a child weighing 30 kg, the daily dose may range from 30 to 60 mg. Given this range, the child may be given one 25 mg suppository twice daily.

Due to the higher concentration of the active substance in Voltaren®, 50 mg suppositories are not recommended for children and adolescents under 14 years of age. Voltaren® 100 mg suppositories are not suitable for use in children and adolescents due to the high content of active ingredient.

Elderly patients: 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, as they are generally more susceptible to adverse reactions. Specifically, the lowest effective doses are recommended for frail elderly patients or those with low body weight. Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Renal function impairment

Voltaren® is contraindicated in patients with renal insufficiency (GFR <15 mL/min/1.73 m²; see section "Contraindications").

No specific studies have been conducted in patients with impaired renal function; therefore, dosage adjustment recommendations cannot be provided. Voltaren® should be used with caution in patients with renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic function impairment

Voltaren® is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

No specific studies have been conducted in patients with impaired liver function; therefore, dosage adjustment recommendations cannot be provided. Voltaren® should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Voltaren® is not administered to children under 1 year of age. For children aged 1–14 years with juvenile chronic arthritis, only 25 mg suppositories should be used. For children aged 6–14 years with acute postoperative pain, only 25 mg suppositories should be used. Due to the higher concentration of the active substance, 50 mg suppositories of Voltaren® are not recommended for children and adolescents under 14 years of age. Voltaren® 100 mg suppositories are not used in children and adolescents due to the high content of active ingredient.

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, agitation, coma, somnolence, tinnitus, or convulsions. Acute renal failure and hepatic injury are possible in cases of severe intoxication.

Treatment. Symptomatic therapy should be administered as needed. Supportive measures and symptomatic treatment should be provided for complications 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, from the body due to their high protein binding and extensive metabolism. Activated charcoal should be considered within one hour of ingestion of a potentially toxic dose. In addition, gastric lavage should be considered in adults within one hour of ingestion of a potentially toxic dose. Intravenous diazepam should be administered for frequent or prolonged convulsions. Other interventions may be indicated based on the patient's clinical condition.

Adverse Reactions

The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, anaemia (haemolytic anaemia, 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 – disorientation, 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, 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 and vascular disorders: common – arterial hypertension; uncommon* – palpitations, chest pain, heart failure, myocardial infarction, arterial hypotension; very rare – vasculitis; frequency not known – Kounis syndrome.

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

Gastrointestinal disorders: common – nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia, decreased appetite; 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, proctitis; 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, haemorrhoidal flare-up.

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, Schönlein–Henoch purpura, pruritus.

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 and administration site conditions: common – irritation at the site of administration; rare – swelling.

*Frequency data are based on long-term use at high doses (150 mg/day).

Reproductive system and breast disorders: very rare – impotence.

Clinical studies and epidemiological data suggest 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 daily) and with prolonged use.

Visual disturbances.

Visual disturbances such as impaired vision, worsening of vision, and diplopia are class effects of NSAIDs and are usually reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which may disrupt retinal blood flow regulation and contribute to the development of visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging.

Suppositories 25 mg and 50 mg: 5 suppositories per strip; 2 strips per cardboard box.

Suppositories 100 mg: 5 suppositories per strip; 1 strip per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Delpharm Huningue S.A.S./Delpharm Huningue S.A.S.

Manufacturer's address and place of business.

26 rue de la Chapelle, 68330 Huningue, France /
26 rue de la Chapelle, 68330 Huningue, France.