Dicloberl® 50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOBERL® 50 (DICLOBERL 50)

Composition:

Active substance: diclofenac sodium;

1 suppository contains 50 mg of sodium diclofenac;

Excipients: propyl gallate, ethanol 96%, maize starch, hard fat.

Dosage form. Suppositories.

Main physicochemical properties: torpedo-shaped suppositories of almost white to yellowish color with a concave base.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances.

ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

Dicloberl® 50 contains diclofenac sodium – a non-steroidal compound exerting pronounced analgesic and anti-inflammatory effects. It is a prostaglandin synthetase (cyclooxygenase) inhibitor.

Pharmacokinetics.

Absorption. Absorption is rapid, but slower than with enteric-coated tablets. After administration of Dicloberl® suppositories at a dose of 50 mg, maximum plasma concentration (Cmax) is reached approximately within 1 hour, but the maximum 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 dosage forms of the drug, the area under the concentration-time curve (AUC) is approximately half of that obtained after parenteral administration. After repeated administration, the pharmacokinetics of the drug do not change. No accumulation of the drug is observed when the recommended dosage regimen is followed.

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

Diclofenac penetrates into synovial fluid, where its Cmax is reached 2–4 hours later than in plasma. The apparent half-life from synovial fluid is 3–6 hours. Two hours after achieving Cmax in plasma, the concentration of diclofenac 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 lactating woman. 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 hydroxylations and methoxylations, 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 to 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 significant effect of patient age on absorption, metabolism, and elimination of the drug has been observed, except for one finding: 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 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 hepatic impairment. In patients with chronic hepatitis or compensated cirrhosis of the liver, pharmacokinetic parameters and metabolism of diclofenac 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 soft tissues around joints;
• 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 diseases 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 basic therapy agents. Fever alone is not an indication for the use of this drug.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition";
• Dicloberyl® 50, like other nonsteroidal anti-inflammatory drugs (NSAIDs), is contraindicated in patients who have experienced attacks of bronchial asthma, urticaria, angioedema, acute rhinitis, or nasal polyps in response to acetylsalicylic acid or other NSAIDs;
• Unspecified disorders of blood coagulation;
• Active peptic ulcer disease/bleeding or recurrent peptic ulcer/bleeding in history (two or more separate episodes of diagnosed ulcer or bleeding);
• History of gastrointestinal bleeding or perforation associated with previous NSAID therapy;
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis);
• Acute gastric or intestinal ulcer, bleeding, or perforation;
• Cerebrovascular or other active bleeding;
• Severe impairment of liver or kidney function, hepatic failure, renal failure (glomerular filtration rate <15 mL/min/1.73 m²) (see section "Special precautions");
• Treatment of perioperative pain in coronary artery bypass grafting (or use of cardiopulmonary bypass apparatus);
• Congestive heart failure (NYHA II-IV); ischemic heart disease in patients with angina pectoris or history of myocardial infarction; peripheral arterial disease and/or cerebrovascular disease in patients with history of stroke or transient ischemic attacks;
• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");
• Proctitis.

Interaction with other medicinal products and other types of interactions.

Other NSAIDs, including salicylates

Concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects. Therefore, simultaneous use of diclofenac with other NSAIDs is not recommended (see section "Special precautions").

Digoxin, phenytoin, lithium

Concomitant use of Dicloberyl® with digoxin, phenytoin, or lithium may increase the blood concentration of these drugs. Serum lithium levels should be monitored. Monitoring of serum digoxin and phenytoin levels is recommended.

Diuretics, β-blockers, ACE inhibitors, and angiotensin II antagonists

NSAIDs may reduce the efficacy of diuretics and antihypertensive drugs (e.g., β-blockers, ACE inhibitors, and angiotensin II antagonists); therefore, blood pressure should be monitored periodically. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Thus, such combinations should be used with caution, especially in elderly patients.

Patients should receive adequate hydration. Monitoring of renal function is also recommended after initiation of concomitant therapy and periodically thereafter, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia

Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is required.

Concomitant use of Dicloberyl® with potassium-sparing diuretics may lead to hyperkalemia. Therefore, frequent monitoring of potassium levels is recommended during concomitant therapy.

Corticosteroids

Increase the risk of gastrointestinal ulcers or bleeding (see section "Special precautions").

Selective serotonin reuptake inhibitors (SSRIs)

Increase the risk of gastrointestinal ulcers and bleeding (see section "Special precautions").

Methotrexate

Diclofenac may inhibit methotrexate clearance in renal tubules, leading to elevated methotrexate levels. Caution should be exercised when using Dicloberyl® within 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 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

Nonsteroidal anti-inflammatory drugs such as sodium diclofenac may enhance the nephrotoxicity of cyclosporine due to effects on renal prostaglandins. Therefore, diclofenac should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus

When NSAIDs are used with tacrolimus, there may be an increased risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors. Therefore, diclofenac should be used at lower doses than in patients not receiving tacrolimus.

Anticoagulants and antithrombotic agents

Caution is recommended because concomitant use may enhance the effects of antithrombotic agents or anticoagulants such as warfarin (see section "Special precautions"). Caution is advised because concomitant use may increase the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, there are individual reports of increased hemorrhage risk in patients taking diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended. Like other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Probenecid

Medicinal products containing probenecid may inhibit the elimination of diclofenac.

Antidiabetic medicinal products

Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without affecting their therapeutic effect. However, there are some reports of individual cases of both hypoglycemia and hyperglycemia requiring adjustment of antidiabetic agent dosage 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 impairment.

Antibacterial quinolones

There are isolated reports of seizures possibly associated with concomitant use of quinolone derivatives and NSAIDs. This may occur in patients with or without prior history of epilepsy or seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Cholestyramine and colestipol

These agents may cause delayed or reduced absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

Cardiac glycosides

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

Mifepristone

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

Strong CYP2C9 inhibitors

Caution is recommended when co-prescribing diclofenac with strong CYP2C9 inhibitors (e.g., sulfaphenazole and voriconazole), which may lead to a significant increase in plasma Cmax and exposure to diclofenac due to inhibition of diclofenac metabolism.

CYP2C9 inducers

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

Special precautions for use.

General

Concomitant use of Dicloberl® with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effects and because of potential additive adverse effects.

To minimize adverse effects, treatment should be initiated at the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and gastrointestinal and cardiovascular risks).

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

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

As there are currently no comparative clinical trial data on long-term treatment using the maximum dose of diclofenac, the possibility of such an 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 for the shortest possible duration should be used.

Elderly patients

Caution is required in elderly patients. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding, ulceration, or perforation. These gastrointestinal reactions are generally more serious in elderly patients and may be fatal (see section "Dosage and administration").

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

Due to its pharmacodynamic properties, Dicloberl® as well as other NSAIDs may mask signs and symptoms of infection.

Gastrointestinal bleeding, ulcers, and perforation

Gastrointestinal (GI) bleeding, ulceration, or perforation, which may be fatal, have been reported with the use of all NSAIDs at any time during treatment, with or without warning symptoms or serious GI events in medical history.

The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses in patients with a history of peptic ulcer, especially if complicated by hemorrhage or perforation (see section "Contraindications"), and in elderly patients. Such patients should initiate and maintain treatment with the lowest available doses.

For these patients, as well as for those requiring concomitant use of low-dose aspirin-containing medications, consideration should be given to using combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) (see below and section "Interaction with other medicinal products and other forms of interaction"). Patients with a history of GI toxicity, particularly elderly patients, should be informed about any unusual abdominal symptoms (especially GI bleeding), particularly at the beginning of treatment. Caution is also required in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antithrombotic agents (e.g., aspirin) (see section "Interaction with other medicinal products and other forms of interaction"). If GI bleeding or ulceration occurs in patients receiving Dicloberl®, the drug should be discontinued.

NSAIDs, including diclofenac, should be used with caution and under close medical supervision in patients with symptoms suggesting possible GI disorders, history of gastric or intestinal ulcer, bleeding or perforation, or history of GI diseases (e.g., ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated (see section "Adverse reactions").

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

Effects on the cardiovascular system

Dicloberl® is generally not recommended in 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 the duration of therapy exceeds 4 weeks. Since cardiovascular risks of diclofenac may increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac use for symptom relief and response to therapy should be periodically reviewed.

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 the use of NSAIDs, including diclofenac.

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

The need for symptom relief and response to therapy should be periodically evaluated, especially if therapy lasts longer than 4 weeks.

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

Skin reactions

Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell’s syndrome), have been rarely reported in association with NSAID use (see section "Adverse reactions").

The highest risk of these reactions occurs early in the course of therapy, with most cases appearing within the first month of treatment. Dicloberl® 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, 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.

Effects on the liver

Close medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen. As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. If Dicloberl® is used long-term or repeatedly, regular monitoring of liver function is recommended as a precaution. Dicloberl® should be discontinued immediately if clinical signs of liver dysfunction occur. Hepatitis may occur without prodromal symptoms during treatment with Dicloberl®. Caution is required when diclofenac is used in patients with hepatic porphyria, due to the risk of provoking an attack.

With long-term treatment with Dicloberl® 50, regular monitoring of liver function is recommended as a precaution. If liver function abnormalities persist or worsen, and if clinical symptoms may be related to progressive liver disease or other manifestations (e.g., eosinophilia, skin rash) are observed, Dicloberl® 50 should be discontinued.

In addition to elevated liver enzymes, isolated reports of severe hepatic reactions have been received, including jaundice, fulminant hepatitis, hepatic necrosis, and liver failure.

The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is required when Dicloberl® 50 is used in patients with hepatic porphyria, due to the risk of provoking an attack.

Effects on the kidneys

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

Since fluid retention and edema have been reported with NSAID treatment, including diclofenac, special attention should be paid to patients with impaired renal function, 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, e.g., before or after major surgery (see section "Contraindications"). In such cases, monitoring of renal function is recommended as a precaution during diclofenac use. Discontinuation of therapy usually leads to return to the pre-treatment state.

Effects on hematological parameters

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.

History of asthma

Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., 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-induced asthma), Quincke’s edema, or urticaria. Therefore, special precautions (readiness for emergency treatment) are recommended for such patients. This also applies to patients with allergic reactions (e.g., pruritus or urticaria) to other substances.

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

Other information

Dicloberl® should be used only after careful benefit-risk assessment:

• in patients with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• in systemic lupus erythematosus (SLE) and mixed connective tissue disease (see section "Adverse reactions").

Physicians should carefully monitor such patients (emergency preparedness):

• patients with asthma, hay fever, nasal polyps, or chronic obstructive pulmonary diseases or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms), as they have an increased risk of allergic reactions. This may manifest as asthma attacks (so-called analgesic-induced asthma), Quincke’s edema, or urticaria;
• patients with allergic reactions to other substances, e.g., skin reactions, pruritus, or urticaria, as they also have an increased risk of hypersensitivity reactions when using Dicloberl®.

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been rarely observed. Therapy should be discontinued at the first signs of hypersensitivity reactions after administration of Dicloberl®. According to symptoms, specialized personnel should initiate necessary medical interventions.

Hypersensitivity reactions may also develop into Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms may include chest pain occurring during an allergic reaction to diclofenac.

Diclofenac may temporarily inhibit platelet aggregation; therefore, patients with coagulation disorders should be closely monitored.

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

If signs of infection or worsening condition occur during Dicloberl® use, patients are advised to seek immediate medical attention. The need for anti-infective/antibiotic therapy should be determined.

With prolonged use of Dicloberl®, renal function and blood parameters should be regularly monitored.

Prolonged use of analgesics may lead to headache, which should not be treated by increasing the drug dose.

Generally, habitual use of analgesics, especially combinations of several analgesic active substances, may lead to chronic kidney damage with risk of renal failure (analgesic nephropathy).

When alcohol is consumed concomitantly, adverse reactions related to the active substance, especially those affecting the gastrointestinal tract or central nervous system, may be intensified with NSAID use.

For female fertility, see section "Use during pregnancy or breastfeeding."

Use during pregnancy or breastfeeding.

Pregnancy

From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, there are reports of fetal arterial duct constriction after NSAID treatment in the second trimester of pregnancy, which in most cases resolved after discontinuation of therapy. Therefore, unless absolutely necessary, diclofenac should not be used in the first or second trimester of pregnancy. In the first and second trimesters, Dicloberl® 50 may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only at the lowest effective dose; treatment duration should be as short as possible. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable if diclofenac exposure occurred for several days starting from the 20th gestational week. Diclofenac use should be discontinued if oligohydramnios or arterial duct constriction is detected. Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the fetal arterial duct).

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

The risk may increase with dose and duration of treatment.

Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular defects, has been observed. If Dicloberl® 50 is used by a woman planning pregnancy or in the first trimester of pregnancy, the dose should be as low as possible and treatment duration as short as possible.

Diclofenac should not be used during the first and second trimesters of pregnancy unless there is unequivocal necessity.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above);

and in the mother at the end of pregnancy and in the newborn:

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

Therefore, Dicloberl® 50 is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, Dicloberl® 50 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, Dicloberl® 50 may negatively affect female fertility and therefore is not recommended for women attempting to conceive. For women with infertility problems or undergoing infertility investigations, discontinuation of Dicloberl® 50 should be considered. Regarding animal data, impaired fertility in males cannot be excluded. The relevance of these data to humans is unclear.

Ability to influence reaction speed when driving vehicles or operating machinery.

Since undesirable effects on the central nervous system such as fatigue and dizziness may occur with the use of Dicloberl® at high doses, the ability to react and the ability to participate actively in road traffic and operate machinery may be impaired in individual cases. This applies particularly when the drug is used in combination with alcohol. Patients experiencing such effects should refrain from driving or operating machinery.

Dosage and Administration

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Do not take orally; for rectal use only.

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

The usual initial dose is 100–150 mg daily. For mild symptoms and during long-term therapy, a daily dose of 75–100 mg is sufficient.

Divide the daily dose into 2–3 administrations. To prevent nocturnal pain or morning stiffness, administer Diclobene® 50 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 to 150 mg daily. The initial dose may be 50–100 mg daily, but if necessary, it can be increased over several menstrual cycles up to the maximum dose of 150 mg daily. Treatment should begin after the onset of the first painful symptoms and continue for several days, depending on symptom improvement.

For the treatment of migraine attacks, initiate therapy with a dose of 100 mg at the first signs of an attack. If necessary, additional suppositories (100 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).

For the treatment of juvenile rheumatoid arthritis, the daily dose may be up to 3 mg/kg, which is the maximum daily dose and must not exceed 150 mg daily. Children aged 14 years and older may be prescribed 50 mg suppositories.

Elderly Patients

Although the pharmacokinetics of Diclobene® 50 is not significantly impaired in elderly patients to a clinically relevant extent, NSAIDs should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. In particular, lower 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

Diclobene® 50 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 renal impairment; therefore, dose adjustment recommendations cannot be provided. Diclobene® 50 should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Hepatic Function Impairment

Diclobene® 50 is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

No specific studies have been conducted in patients with hepatic impairment; therefore, dose adjustment recommendations cannot be provided. Diclobene® 50 should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Diclobene® 50 should not be administered to children under 14 years of age due to the high content of the active substance. The medicinal product may be used in children over 14 years of age.

Overdose

a) Symptoms of overdose

There is no typical clinical picture specific to diclofenac overdose. Central nervous system disturbances such as headache, dizziness, vertigo, excitation, coma, drowsiness, tinnitus, and loss of consciousness (including myoclonic seizures in children), as well as abdominal pain, diarrhea, nausea, and vomiting, may occur as symptoms of overdose. Additionally, gastrointestinal bleeding, hepatic and renal dysfunction, acute renal failure, and liver damage are possible in cases of severe intoxication. Hypotension, respiratory depression, and cyanosis may also occur.

b) Management of overdose

There is no specific antidote.

Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. In cases of complications such as hypotension, renal failure, seizures, gastrointestinal disturbances, or respiratory depression, supportive care and symptomatic treatment should be administered.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be beneficial in eliminating NSAIDs, including diclofenac, due to their high protein binding and active metabolism. Activated charcoal should be considered within one hour of ingestion of a potentially toxic amount. In addition, gastric lavage should be considered in adults within one hour of ingestion of a potentially toxic amount. Intravenous diazepam should be administered for frequent or prolonged seizures. Other measures may be indicated based on the patient's clinical condition.

Side effects

The following frequency definition was used in assessing side effects:

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.

It should be noted that the adverse reactions listed below are dose-dependent and variable.

The most commonly observed adverse reactions are gastrointestinal in nature.

Peptic ulcer, perforation, or gastrointestinal (GI) bleeding, sometimes fatal, especially in elderly patients, may occur (see section "Special instructions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, gastritis, ulcerative stomatitis, and exacerbation of ulcerative colitis and Crohn's disease have been reported following administration of the drug (see section "Special instructions").

The risk of GI bleeding is particularly dependent on dose and duration of treatment.

Edema, arterial hypertension, and heart failure have been reported with NSAID use.

Clinical trials and epidemiological data consistently indicate an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) associated with diclofenac use, especially at high doses (150 mg daily) and during prolonged treatment (see sections "Contraindications" and "Special instructions").

Infections and infestations

Very rarely, exacerbation of infection-related inflammation (e.g., development of necrotizing fasciitis) has been described in association with systemic NSAID use. This may be related to the mechanism of action of NSAIDs.

If signs of infection occur or the patient's condition worsens during treatment with Diclobene®, immediate medical consultation is recommended. Anti-infective/antibiotic therapy should be considered.

Very rarely, symptoms of aseptic meningitis, including neck stiffness, headache, nausea, vomiting, fever, or altered consciousness, have been observed during diclofenac use. Patients with autoimmune disorders (e.g., SLE, mixed connective tissue disease) may be predisposed.

Blood and lymphatic system disorders

Very rare: hematopoietic disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis), hemolytic and aplastic anemia. Initial symptoms may include fever, sore throat, oral ulcers, influenza-like symptoms, severe lethargy, epistaxis, and skin bleeding. Blood counts should be monitored regularly during long-term therapy.

Immune system disorders

Common: hypersensitivity reactions such as skin rash and pruritus.

Uncommon: urticaria.

Patients should be informed that if such reactions occur, they should immediately consult a physician and discontinue further use of Diclobene®.

Rare: hypersensitivity, anaphylactic and anaphylactoid reactions (including bronchospasm, respiratory arrest, tachycardia, arterial hypotension, and shock).

Very rare: angioedema (including facial swelling).

If any of these symptoms occur, even for the first time, Diclobene® must not be continued, and immediate medical attention is required.

Very rare: allergic vasculitis and pneumonia.

Nervous system disorders

Common: central nervous system disturbances such as headache, dizziness, vertigo, excitement, irritability, or somnolence.

Rare: somnolence, fatigue.

Very rare: paresthesia, taste disturbances, memory impairment, restlessness, disorientation, seizures, tremor, cerebrovascular disorders, aseptic meningitis, 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 disorders

Common: arterial hypertension.

Uncommon: palpitations, chest pain, heart failure, myocardial infarction, arterial hypotension.

Very rare: vasculitis.

Frequency not known: Kounis syndrome.

Vascular disorders

Very rare: hypertension.

Respiratory, thoracic and mediastinal disorders

Rare: asthma (including dyspnea).

Very rare: pneumonitis.

Gastrointestinal disorders

Common: gastrointestinal complaints such as nausea, vomiting, diarrhea, as well as mild gastrointestinal bleeding, which in rare cases may lead to anemia, dyspepsia, flatulence, abdominal pain, anorexia, decreased appetite, and gastrointestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients). With suppository use, bloody mucus discharge and painful defecation may frequently occur.

Uncommon: hematemesis, melena, or hemorrhagic diarrhea.

Rare: gastritis, gastrointestinal hemorrhages, gastric and intestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis, proctitis.

Very rare: stomatitis (including ulcerative stomatitis), glossitis, esophageal lesions, lower abdominal complaints such as colitis (including hemorrhagic colitis or exacerbation of ulcerative colitis or Crohn's disease), constipation, pancreatitis, diaphragm-like intestinal stricture, hemorrhoid exacerbation.

Frequency not known: ischemic colitis.

Patients should be informed of the necessity to discontinue the drug and seek immediate medical attention if severe upper abdominal pain, melena, or hematemesis occur.

Hepatobiliary disorders

Common: increased transaminase levels, jaundice.

Uncommon: liver damage, particularly during long-term therapy, hepatitis with or without jaundice (very rarely progresses rapidly, even without prodromal symptoms).

Rare: liver disorders.

Very rare: fulminant hepatitis, hepatonecrosis, liver failure.

Liver function tests should be monitored regularly during prolonged treatment.

Skin and subcutaneous tissue disorders

Common: rash.

Rare: urticaria.

Uncommon: hair loss.

Very rare: blister-like rash, exanthema, eczema, erythema, photosensitivity reactions, purpura (including allergic purpura), bullous eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reactions, purpura, including allergic purpura, Schönlein-Henoch purpura, pruritus.

Renal and urinary disorders

Common: fluid retention.

Uncommon: edema formation, particularly in patients with arterial hypertension or renal impairment.

Very rare: renal tissue damage (interstitial nephritis, papillary necrosis), which may be accompanied by acute renal failure, proteinuria and/or hematuria. Nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

Therefore, renal function should be monitored regularly.

General disorders and administration site conditions

Common: irritation at the site of administration.

Rare: edema.

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 diclofenac use, particularly at high therapeutic doses (150 mg daily) and during prolonged treatment.

Visual disturbances

Visual disturbances such as blurred vision, impaired 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 and related compound synthesis, which may disrupt retinal blood flow regulation and contribute to visual disturbances. If such symptoms occur during diclofenac treatment, an ophthalmological examination should be performed to exclude other possible causes.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions is highly important during the post-marketing phase of the medicinal product. This allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep the medicinal product out of the reach of children.

Packaging.

5 suppositories in a blister; 1 or 2 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and location of its business operations.

Glienicker Weg 125, 12489 Berlin, Germany.