INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DYCLOBERLâ100 (DICLOBERL 100)

Composition:

Active substance: diclofenac sodium;

1 suppository contains sodium diclofenac 100 mg;

Excipient: hard fat.

Pharmaceutical form. Suppositories.

Main physicochemical properties: torpedo-shaped ivory-colored suppositories.

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

ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

Dicloberl® 100 contains diclofenac sodium – a non-steroidal compound exerting pronounced analgesic and anti-inflammatory effects. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

Pharmacokinetics.

Absorption. Absorption is rapid, but slower compared to enteric-coated tablets. After administration of Dicloberl® suppositories in a dose of 50 mg, maximum plasma concentration (Cmax) is reached approximately within 1 hour; however, Cmax per dose unit is about two-thirds of the concentration 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. With repeated administration, the pharmacokinetics of the drug do not change. No accumulation of the drug occurs under conditions of recommended dosing.

Distribution. Diclofenac binding to plasma proteins is 99.7%, mainly 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 reaching Cmax, the concentration of diclofenac in synovial fluid remains higher than in plasma, and 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 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.

Excretion. 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 effect of patient age on absorption, metabolism, and 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 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 concentrations of hydroxylated metabolites in plasma were approximately four times higher than in healthy volunteers. However, ultimately, all metabolites were excreted via bile.

Patients with hepatic impairment. Pharmacokinetic parameters and metabolism of diclofenac in patients with chronic hepatitis or compensated cirrhosis are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, including spondyloarthritis;
Spinal pain syndromes;
Rheumatic diseases of soft tissues surrounding joints;
Post-traumatic and postoperative pain syndromes associated with inflammation and edema, including after dental and orthopedic surgeries;
Gynecological conditions accompanied by pain and inflammation, e.g., primary dysmenorrhea and adnexitis;
Migraine attacks;
Acute gout attacks;
As an adjunctive agent in severe inflammatory conditions of the ear, nose, and throat (ENT) organs associated with pain, e.g., pharyngotonsillitis, otitis.

According to general therapeutic principles, the underlying disease should be treated with disease-modifying 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";
Diclobene® 100, like other nonsteroidal anti-inflammatory drugs (NSAIDs), is contraindicated in patients who experience 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 ulceration/hemorrhage or recurrent peptic ulceration/hemorrhage in history (two or more separate episodes of diagnosed ulcer or bleeding);
Gastrointestinal bleeding or perforation in history related to 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 hemorrhages;
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 (CABG) (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.

Diclobene® 100 is not intended for use in children and adolescents under 18 years of age.

Interaction with other medicinal products and other forms of interaction.

Other NSAIDs, including salicylates

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

Digoxin, phenytoin, lithium

Concomitant use of Diclobene® 100 with digoxin, phenytoin, or lithium may increase the blood concentration of these medicinal products. 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 agents (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 potentially reversible acute renal failure. Therefore, such combinations should be used with caution, especially in elderly patients.

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

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

Concomitant use of Diclobene® 100 and potassium-sparing diuretics may lead to hyperkalemia. Therefore, frequent monitoring of serum 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 the renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is advised when using Diclobene® 100 within 24 hours before or after methotrexate administration, as this may increase methotrexate plasma concentrations and enhance its toxicity. Cases of severe toxicity 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 agents such as sodium diclofenac may enhance the nephrotoxicity of cyclosporine through effects on renal prostaglandins. Therefore, diclofenac should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus

Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated through renal anti-prostaglandin effects of NSAIDs and calcineurin inhibition. Therefore, diclofenac should be administered at lower doses than in patients not receiving tacrolimus.

Anticoagulants and antithrombotic agents

Caution is recommended, as concomitant use may potentiate 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 have not shown 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 nonsteroidal anti-inflammatory drugs, high-dose diclofenac may transiently 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 concomitantly with oral antidiabetic agents without affecting their therapeutic efficacy. However, there are isolated reports of both hypoglycemia and hyperglycemia requiring dosage adjustment of antidiabetic agents during diclofenac treatment. Therefore, as a precaution, blood glucose levels should be monitored during combination therapy. There are also isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Quinolone antibiotics

There are isolated reports of seizures possibly associated with concomitant use of quinolone derivatives and NSAIDs. This may occur in patients with or without a 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 delay or reduce the 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.

Potent CYP2C9 inhibitors

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

CYP2C9 inducers

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

Special precautions for use.

General

Concomitant use of Dicloberl® 100 with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to the 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 directly correlates 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 the lack of evidence for synergistic effects and because of potential additive adverse effects.

Since comparable clinical trial data on long-term treatment with the maximum dose of diclofenac are currently lacking, 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 occlusive disease, or significant risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Due to this risk, the lowest effective dose should be used for the shortest possible duration.

Elderly patients

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

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

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, Dicloberl®, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal bleeding, ulcers, and perforations

Gastrointestinal (GI) bleeding, ulcers, or perforations, which may be fatal, have been reported during treatment with all NSAIDs at any time, with or without warning symptoms or a history of serious GI events.

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 therapy at the lowest available doses.

For these patients, as well as those requiring concomitant use of low-dose aspirin-containing medications, consideration should be given to combined 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 advised to report 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 antiplatelet 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® 100, 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 disturbances, a history of peptic ulcer, gastrointestinal bleeding or perforation, or a history of GI disorders (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 insufficiency. Close medical supervision and caution are recommended when diclofenac is used after gastrointestinal surgery.

Cardiovascular effects

Dicloberl® 100 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 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 periodically reassessed.

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 diclofenac use, particularly 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 periodically reassessed, especially if the duration of therapy exceeds 4 weeks.

Patients should be informed about the necessity 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.

Skin reactions

Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell’s syndrome), have very rarely been 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® 100 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 individual 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.

Hepatic effects

Close medical supervision is required when diclofenac is prescribed to patients with hepatic impairment, as their condition may worsen. As with other NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. If Dicloberl® 100 is used long-term or repeatedly, periodic monitoring of liver function is recommended as a precaution. Dicloberl® 100 should be discontinued immediately if clinical signs of liver dysfunction occur. Hepatitis may occur without prodromal symptoms during diclofenac use. Caution is necessary when diclofenac is used in patients with hepatic porphyria due to the potential to provoke an attack. With long-term treatment with Dicloberl®, regular monitoring of liver function is recommended as a precaution. If liver function abnormalities persist or worsen and clinical symptoms may be related to progressive liver disease or other manifestations occur (e.g., eosinophilia, skin rash), Dicloberl® 100 should be discontinued.

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

Conditions such as hepatitis may progress without prodromal symptoms. Caution is required when Dicloberl® 100 is used in 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, frequently (1–10%) leads to edema and hypertension.

Since fluid retention and edema have been reported with NSAID treatment, including diclofenac, particular attention should be paid to patients with renal impairment, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery (see section "Contraindications"). In such cases, monitoring of renal function is recommended as a precaution when using diclofenac. Discontinuation of therapy usually results in return to the pre-treatment state.

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. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be carefully monitored.

History of asthma

Patients with asthma, seasonal allergic rhinitis, nasal mucosal swelling (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 intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for these 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 administered to patients with bronchial asthma or a history of bronchial asthma.

Other information

Dicloberl® 100 should be used only after careful benefit-risk assessment:

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

Physicians should particularly closely monitor the following patients (preparedness for emergency situations):

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, which 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® 100.

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed rarely. Treatment should be discontinued at the first signs of hypersensitivity reactions after administration of Dicloberl® 100. Specialized personnel should initiate appropriate medical interventions according to symptoms.

Hypersensitivity reactions may also progress to 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 under close supervision.

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® 100 use, patients are advised to seek immediate medical attention. The need for anti-infective/antibiotic therapy should be determined.

With prolonged use of Dicloberl® 100, renal function and blood parameters should be regularly checked.

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

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

Concomitant alcohol consumption may enhance adverse reactions related to the active substance, particularly those affecting the gastrointestinal tract or the central nervous system, during NSAID use.

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

Use during pregnancy or breastfeeding.

Pregnancy

From the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible after discontinuation. Additionally, reports of arterial duct constriction after second-trimester treatment, which mostly resolved after treatment cessation, have been documented. Therefore, unless absolutely necessary, diclofenac should not be used during the first or second trimester of pregnancy. Dicloberl® 100 may be prescribed during the first and second trimesters 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 arterial duct in the fetus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy progression and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and risk of cardiac defects 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%. 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 incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

Diclofenac should not be used during the first and second trimesters of pregnancy unless clearly necessary. If a woman using diclofenac attempts to become pregnant or is already pregnant during the first or second trimester, the dose should be kept as low as possible and treatment duration as short as possible.

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);
renal dysfunction, which may progress to renal failure with oligohydramnios (see above);

and the mother and newborn, especially at the end of pregnancy:

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

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

Breastfeeding period

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, diclofenac should not be used in women who are 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® 100 may negatively affect female fertility; therefore, it is not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of Dicloberl® 100 should be considered. Regarding animal data, impairment of fertility in males cannot be excluded. The significance of these data for humans is unclear.

Ability to influence reaction speed when driving or operating machinery

Since undesirable effects on the central nervous system, such as fatigue and dizziness, may occur with high-dose use of Dicloberl® 100, reaction ability and the ability to actively participate in road traffic and operate machinery may be impaired in individual cases. This is particularly relevant when the drug is used concomitantly 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 administer 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 per day. For mild symptoms and during long-term therapy, a daily dose of 75–100 mg is usually sufficient.

The daily dose should be divided into 2–3 administrations. To prevent nocturnal pain or morning stiffness, administer Diclobene® 100 as rectal suppositories at bedtime (daily dose must not exceed 150 mg).

For primary dysmenorrhea, the daily dose should be individually adjusted, usually ranging from 50–150 mg per day. The initial dose may be 50–100 mg per day; if necessary, it may be increased over several menstrual cycles up to the maximum dose of 150 mg per day. Treatment should begin after the onset of the first painful symptoms and continued for several days, depending on symptom improvement.

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

Elderly Patients

Although the pharmacokinetics of Diclobene® 100 are 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 Impairment

The use of Diclobene® 100 is contraindicated in patients with renal insufficiency (GFR <15 mL/min/1.73 m²; see section "Contraindications").

Specific studies in patients with renal impairment have not been conducted; therefore, dose adjustment recommendations cannot be provided. Diclobene® 100 should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

The use of Diclobene® 100 is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

Specific studies in patients with hepatic impairment have not been conducted; therefore, dose adjustment recommendations cannot be provided. Diclobene® 100 should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Diclobene® 100 suppositories are not recommended for use in children and adolescents under 18 years of age. For further information on use in children and adolescents, see section "Contraindications".

Overdose

a) Symptoms of overdose

There is no typical clinical picture characteristic of diclofenac overdose. Central nervous system disturbances such as headache, dizziness, vertigo, excitement, 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 may occur, as well as impaired liver and kidney function. 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, consists essentially of supportive measures and symptomatic treatment. In cases of complications such as hypotension, renal failure, seizures, gastrointestinal disturbances, or respiratory depression, appropriate supportive care and symptomatic treatment should be initiated.

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 dose. In addition, gastric lavage should be considered in adults within one hour of ingestion of a potentially toxic dose. In cases of frequent or prolonged seizures, intravenous diazepam should be administered. Other measures may be indicated depending on the patient's clinical condition.

Side effects

The following frequency classification was used to assess adverse reactions:

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 available data.

The adverse reactions listed below are dose-dependent and variable.

Gastrointestinal adverse reactions are the most commonly observed.

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

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

Edema, arterial hypertension, and heart failure have been reported in association 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 precautions").

Infections and infestations

Very rarely, exacerbation of infection-related inflammation (e.g., development of necrotizing fasciitis) has been described in connection 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® 100, immediate medical consultation is recommended. Anti-infective or antibiotic therapy should be considered if indicated.

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

Blood and lymphatic system disorders

Very rare: hematological 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® 100.

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—treatment with Diclobene® 100 must be discontinued immediately and urgent medical attention sought.

Very rare: allergic vasculitis and pneumonia.

Psychiatric disorders

Very rare: psychotic disorders, depression, anxiety, insomnia, nightmares, disorientation, irritability.

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, mild GI bleeding (which in rare cases may lead to anemia), dyspepsia, bloating, abdominal pain, anorexia, decreased appetite, and GI ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients).

Painful defecation and bloody mucus discharge may occur frequently with suppository use.

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, ischemic 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 that if severe upper abdominal pain, melena, or hematemesis occur, they must discontinue the medication immediately and seek urgent medical attention.

Hepatobiliary disorders

Common: elevated transaminase levels, jaundice.
Uncommon: liver injury, particularly during long-term therapy, hepatitis with or without jaundice (very rarely progressing 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: bullous eruptions, exanthema, eczema, erythema, multiform erythema, photosensitivity reactions, purpura (including allergic purpura), bullous skin eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, hair loss, photosensitivity reactions, purpura (including 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 injury (interstitial nephritis, papillary necrosis), which may be associated with acute renal failure, proteinuria, and/or hematuria. Nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use 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 operations.

Glienicker Weg 125, 12489 Berlin, Germany.