VOLTAREN Diclofenac Sodium 25mg Enteric-Coated Tablet 100's
RXDRUG-DR-XY28428-100
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Treatment of: Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and spondylarthritis, painful syndromes of the vertebral column, non-articular rheumatism.
Post-traumatic and post-operative pain, inflammation and swelling, e.g. following dental or orthopaedic surgery.
Painful and/or inflammatory conditions in gynecology, e.g. primary dysmenorrhea or adnexitis.
Voltaren/Voltaren Forte: Inflammatory and degenerative forms of rheumatism: juvenile rheumatoid arthritis.
Acute attacks of gout.
As an adjuvant in severe painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis. In keeping with general therapeutic principles, the underlying disease should be treated with basic therapy, as appropriate. Fever alone is not an indication.
Post-traumatic and post-operative pain, inflammation and swelling, e.g. following dental or orthopaedic surgery.
Painful and/or inflammatory conditions in gynecology, e.g. primary dysmenorrhea or adnexitis.
Voltaren/Voltaren Forte: Inflammatory and degenerative forms of rheumatism: juvenile rheumatoid arthritis.
Acute attacks of gout.
As an adjuvant in severe painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis. In keeping with general therapeutic principles, the underlying disease should be treated with basic therapy, as appropriate. Fever alone is not an indication.
Dosage/Direction for Use
Dosage: As a general recommendation, the dose should be individually adjusted. Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see PRECAUTIONS).
General target population: adults: Voltaren/Voltaren Forte: The recommended initial daily dose is 100 to 150 mg. In milder cases, as well as for long-term therapy, 75 to 100 mg daily is usually sufficient.
The total daily dose should generally be divided into 2 to 3 separate doses. To suppress nocturnal pain and morning stiffness, treatment with tablets during the day can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).
In primary dysmenorrhea, the daily dose should be individually adjusted and is generally 50 to 150 mg. A dose of 50 to 100 mg should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
Voltaren SR: The recommended initial daily dose is 100 mg.
In milder cases, as well as for long-term therapy, 100 mg daily is usually sufficient.
Where the symptoms are most pronounced during the night or in the morning, the tablet should preferably be taken in the evening.
Special populations: Pediatric patients (below 18 years of age): Voltaren/Voltaren Forte: Children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily, divided into 2 to 3 separate doses, depending on the severity of the disorder. For treatment of juvenile rheumatoid arthritis, the daily dose can be raised up to a maximum of 3 mg/kg daily, divided into 2 to 3 separate doses.
The maximum daily dose of 150 mg should not be exceeded.
Because of their dosage strength, diclofenac (Voltaren Forte) 50 mg gastro-resistant tablets are not recommended for use in children and adolescents below 14 years of age; diclofenac (Voltaren) 25 mg gastro-resistant tablets could be used in these patients.
Voltaren SR: Because of their dosage strength, diclofenac (Voltaren SR) prolonged-release tablets 75 mg and 100 mg are not suitable for children and adolescents.
Geriatric patients (aged 65 years or above): No adjustment of the starting dose is generally required for elderly patients. However, caution is indicated on basic medical grounds, especially for frail elderly patients or those with a low body weight (see PRECAUTIONS).
Established cardiovascular disease or significant cardiovascular risk factors: Treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease should be treated with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) only after careful consideration and only at doses ≤100 mg daily if treated for more than 4 weeks (see PRECAUTIONS).
Renal impairment: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is contraindicated in patients with renal failure (GFR <15 mL/min/1.73m2) (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac (Voltaren/Voltaren Forte/Voltaren SR) to patients with renal impairment (see PRECAUTIONS).
Hepatic impairment: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is contraindicated in patients with hepatic failure (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac (Voltaren) to patients with mild to moderate hepatic impairment (see PRECAUTIONS).
Method of administration: Voltaren SR: The tablets should be swallowed whole with liquid, preferably with meals and must not be divided or chewed.
General target population: adults: Voltaren/Voltaren Forte: The recommended initial daily dose is 100 to 150 mg. In milder cases, as well as for long-term therapy, 75 to 100 mg daily is usually sufficient.
The total daily dose should generally be divided into 2 to 3 separate doses. To suppress nocturnal pain and morning stiffness, treatment with tablets during the day can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).
In primary dysmenorrhea, the daily dose should be individually adjusted and is generally 50 to 150 mg. A dose of 50 to 100 mg should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
Voltaren SR: The recommended initial daily dose is 100 mg.
In milder cases, as well as for long-term therapy, 100 mg daily is usually sufficient.
Where the symptoms are most pronounced during the night or in the morning, the tablet should preferably be taken in the evening.
Special populations: Pediatric patients (below 18 years of age): Voltaren/Voltaren Forte: Children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily, divided into 2 to 3 separate doses, depending on the severity of the disorder. For treatment of juvenile rheumatoid arthritis, the daily dose can be raised up to a maximum of 3 mg/kg daily, divided into 2 to 3 separate doses.
The maximum daily dose of 150 mg should not be exceeded.
Because of their dosage strength, diclofenac (Voltaren Forte) 50 mg gastro-resistant tablets are not recommended for use in children and adolescents below 14 years of age; diclofenac (Voltaren) 25 mg gastro-resistant tablets could be used in these patients.
Voltaren SR: Because of their dosage strength, diclofenac (Voltaren SR) prolonged-release tablets 75 mg and 100 mg are not suitable for children and adolescents.
Geriatric patients (aged 65 years or above): No adjustment of the starting dose is generally required for elderly patients. However, caution is indicated on basic medical grounds, especially for frail elderly patients or those with a low body weight (see PRECAUTIONS).
Established cardiovascular disease or significant cardiovascular risk factors: Treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease should be treated with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) only after careful consideration and only at doses ≤100 mg daily if treated for more than 4 weeks (see PRECAUTIONS).
Renal impairment: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is contraindicated in patients with renal failure (GFR <15 mL/min/1.73m2) (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac (Voltaren/Voltaren Forte/Voltaren SR) to patients with renal impairment (see PRECAUTIONS).
Hepatic impairment: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is contraindicated in patients with hepatic failure (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac (Voltaren) to patients with mild to moderate hepatic impairment (see PRECAUTIONS).
Method of administration: Voltaren SR: The tablets should be swallowed whole with liquid, preferably with meals and must not be divided or chewed.
Overdosage
Symptoms: There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal hemorrhage, diarrhea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.
Therapeutic Measures: Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.
Special measures such as forced diuresis, dialysis, or hemoperfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein binding and extensive metabolism.
Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life-threatening overdose.
Therapeutic Measures: Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.
Special measures such as forced diuresis, dialysis, or hemoperfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein binding and extensive metabolism.
Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life-threatening overdose.
Administration
Gastro-resistant tab: May be taken with or without food.|SR tab: Should be taken with food: Swallow whole, do not chew/divide.
Contraindications
Known hypersensitivity to the active substance or to any of the other excipients.
Active gastric or intestinal ulcer, bleeding or perforation (see PRECAUTIONS and ADVERSE REACTIONS).
Last trimester of pregnancy (see USE IN PREGNANCY & LACTATION).
Hepatic failure.
Renal failure (GFR <15 mL/min/1.73m2).
Severe cardiac failure (see PRECAUTIONS).
Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is also contraindicated in patients in whom the use of acetylsalicylic acid or other NSAIDs can precipitate asthma, angioedema, urticaria, or acute rhinitis (i.e. NSAID-induced cross reactivity reactions) (see PRECAUTIONS and ADVERSE REACTIONS).
Active gastric or intestinal ulcer, bleeding or perforation (see PRECAUTIONS and ADVERSE REACTIONS).
Last trimester of pregnancy (see USE IN PREGNANCY & LACTATION).
Hepatic failure.
Renal failure (GFR <15 mL/min/1.73m2).
Severe cardiac failure (see PRECAUTIONS).
Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is also contraindicated in patients in whom the use of acetylsalicylic acid or other NSAIDs can precipitate asthma, angioedema, urticaria, or acute rhinitis (i.e. NSAID-induced cross reactivity reactions) (see PRECAUTIONS and ADVERSE REACTIONS).
Special Precautions
Gastrointestinal effects: Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs, including diclofenac, and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac (Voltaren/Voltaren Forte/Voltaren SR), the treatment should be discontinued.
As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see ADVERSE REACTIONS). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation and in the elderly.
To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.
Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other drugs likely to increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see INTERACTIONS).
Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see ADVERSE REACTIONS).
NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using Voltaren/Voltaren Forte/Voltaren SR after gastro-intestinal surgery.
Cardiovascular effects: Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks.
Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.
Voltaren SR: Treatment with diclofenac (Voltaren SR) is generally not recommended in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) should be treated with diclofenac (Voltaren SR) only after careful consideration and only at doses ≤100 mg daily when treatment continues for more than 4 weeks.
Hematologic effects: During prolonged treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR), as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, diclofenac (Voltaren/Voltaren Forte/Voltaren SR) may temporarily inhibit platelet aggregation. Patients with defects of hemostasis should be carefully monitored.
Respiratory effects (pre-existing asthma): In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesics-asthma), Quincke's edema or urticaria are more frequent than in other patients. Therefore, special caution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.
Hepatobiliary effects: Close medical surveillance is required when prescribing diclofenac (Voltaren/Voltaren Forte/Voltaren SR) to patients with impaired hepatic function, as their condition may be exacerbated.
As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) (e.g. in the form of tablets or suppositories), regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), diclofenac (Voltaren/Voltaren Forte/Voltaren SR) should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is called for when using diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in patients with hepatic porphyria, since it may trigger an attack.
Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (Voltaren/Voltaren Forte/Voltaren SR) (see ADVERSE REACTIONS). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug.
Renal effects: As fluid retention and edema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion of any cause, e.g. before or after major surgery (see CONTRAINDICATIONS). Monitoring of renal function is recommended as a precautionary measure when using diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Interactions with NSAIDs: The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to undesirable effects (see INTERACTIONS).
Masking signs of infections: Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Use in the Elderly: Caution is indicated in the elderly on basic medical grounds, especially in frail elderly patients or those with a low body weight.
As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see ADVERSE REACTIONS). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation and in the elderly.
To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.
Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other drugs likely to increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see INTERACTIONS).
Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see ADVERSE REACTIONS).
NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using Voltaren/Voltaren Forte/Voltaren SR after gastro-intestinal surgery.
Cardiovascular effects: Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks.
Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.
Voltaren SR: Treatment with diclofenac (Voltaren SR) is generally not recommended in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) should be treated with diclofenac (Voltaren SR) only after careful consideration and only at doses ≤100 mg daily when treatment continues for more than 4 weeks.
Hematologic effects: During prolonged treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR), as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, diclofenac (Voltaren/Voltaren Forte/Voltaren SR) may temporarily inhibit platelet aggregation. Patients with defects of hemostasis should be carefully monitored.
Respiratory effects (pre-existing asthma): In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesics-asthma), Quincke's edema or urticaria are more frequent than in other patients. Therefore, special caution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.
Hepatobiliary effects: Close medical surveillance is required when prescribing diclofenac (Voltaren/Voltaren Forte/Voltaren SR) to patients with impaired hepatic function, as their condition may be exacerbated.
As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) (e.g. in the form of tablets or suppositories), regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), diclofenac (Voltaren/Voltaren Forte/Voltaren SR) should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is called for when using diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in patients with hepatic porphyria, since it may trigger an attack.
Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (Voltaren/Voltaren Forte/Voltaren SR) (see ADVERSE REACTIONS). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug.
Renal effects: As fluid retention and edema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion of any cause, e.g. before or after major surgery (see CONTRAINDICATIONS). Monitoring of renal function is recommended as a precautionary measure when using diclofenac (Voltaren/Voltaren Forte/Voltaren SR) in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Interactions with NSAIDs: The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to undesirable effects (see INTERACTIONS).
Masking signs of infections: Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Use in the Elderly: Caution is indicated in the elderly on basic medical grounds, especially in frail elderly patients or those with a low body weight.
Use In Pregnancy & Lactation
Women of child-bearing potential: There are no data to suggest any recommendations for women of child-bearing potential.
Pregnancy: There are insufficient data on the use of diclofenac in pregnant women. Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Voltaren/Voltaren Forte/Voltaren SR should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia, fetal renal impairment with subsequent oligohydramnios and/or premature closure of the ductus arteriosus (see CONTRAINDICATIONS and PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Breast-feeding: Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, it should not be administered during breast-feeding in order to avoid undesirable effects in the infant.
Fertility: As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of treatment should be considered.
Pregnancy: There are insufficient data on the use of diclofenac in pregnant women. Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Voltaren/Voltaren Forte/Voltaren SR should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia, fetal renal impairment with subsequent oligohydramnios and/or premature closure of the ductus arteriosus (see CONTRAINDICATIONS and PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Breast-feeding: Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, it should not be administered during breast-feeding in order to avoid undesirable effects in the infant.
Fertility: As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of treatment should be considered.
Adverse Reactions
Tabulated summary of adverse drug reactions: Adverse drug reactions from clinical trials and/or spontaneous or literature cases (see table) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (>1/10); common (>1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000).
The following undesirable effects include those reported with the enteric coated/prolonged-released tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use. (See table.)
The following undesirable effects include those reported with the enteric coated/prolonged-released tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use. (See table.)
Description of selected adverse drug reactions: Arteriothrombotic events: Meta-analysis and pharmacoepidemiological data point towards a small increased risk of arteriothrombotic events (for example myocardial infarction) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (see PRECAUTIONS).
Visual effects: Visual disturbances such as visual impairment, blurred vision or diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.
Visual effects: Visual disturbances such as visual impairment, blurred vision or diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.
Drug Interactions
The following interactions include those observed with diclofenac (Voltaren/Voltaren Forte/Voltaren SR) enteric-coated/prolonged-released tablets and/or other pharmaceutical forms of diclofenac.
Observed interactions to be considered: CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac.
Lithium: If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.
Digoxin: If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity (see PRECAUTIONS).
Ciclosporin and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin and tacrolimus due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin or tacrolimus.
Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently (see PRECAUTIONS).
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Anticipated interactions to be considered: Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see PRECAUTIONS).
Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see PRECAUTIONS). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of hemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see PRECAUTIONS).
Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycemic and hyperglycemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.
There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with metformin, especially in patients with pre-existing renal impairment.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Methotrexate: Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.
CYP2C9 inducers: Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.
Observed interactions to be considered: CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac.
Lithium: If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.
Digoxin: If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity (see PRECAUTIONS).
Ciclosporin and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin and tacrolimus due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin or tacrolimus.
Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently (see PRECAUTIONS).
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Anticipated interactions to be considered: Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see PRECAUTIONS).
Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see PRECAUTIONS). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of hemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see PRECAUTIONS).
Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycemic and hyperglycemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.
There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with metformin, especially in patients with pre-existing renal impairment.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Methotrexate: Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.
CYP2C9 inducers: Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.
Caution For Usage
Instructions for Use and Handling: No special requirements.
Incompatibilities: Not applicable.
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic Group: Analgesic, Non-Steroidal Anti-Inflammatory Drug (NSAID).
Pharmacology: Mechanism of action: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) contains diclofenac sodium, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered fundamental to its mechanism of action. Prostaglandins play an important role in causing inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.
Pharmacodynamics: In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac (Voltaren/Voltaren Forte/Voltaren SR) elicit a clinical response characterized by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In post-traumatic and post-operative inflammatory conditions, diclofenac (Voltaren/Voltaren Forte/Voltaren SR) rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound edema.
Voltaren/Voltaren Forte: In clinical trials diclofenac has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. Clinical studies have also revealed that, in primary dysmenorrhea, diclofenac is capable of relieving the pain and reducing the extent of bleeding.
Voltaren SR: Diclofenac (Voltaren SR) 75 mg and 100 mg prolonged-release tablets are particularly suitable for patients in whom a daily dose of 75 mg or 100 mg is appropriate to the clinical picture. The possibility of prescribing the medicinal product in a single daily dose considerably simplifies long-term treatment and helps to avoid the possibility of dosage errors. Diclofenac (Voltaren SR) 75 mg prolonged-release tablets also allow the maximum daily dose of 150 mg to be given in a balanced b.i.d. schedule.
Clinical Studies: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is a well-established product.
Pharmacokinetics: Absorption: Voltaren/Voltaren Forte: Diclofenac is completely absorbed from the enteric coated tablets after their passage through the stomach. Although absorption is rapid, its onset may be delayed due to the gastro-resistant coating of the tablet.
Mean peak plasma concentrations of 1.5 micrograms/mL (5 micromol/L) are attained on average 2 hours after ingestion of one tablet of 50 mg.
The passage of a tablet through the stomach is slower when ingested with or after a meal than when it is taken before a meal, but the amount of diclofenac absorbed remains the same.
Since about half of diclofenac is metabolised during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Voltaren SR: Judged by urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from diclofenac (Voltaren SR) prolonged-release tablets as from gastro-resistant tablets. However, the systemic availability of diclofenac from prolonged-release tablets is on average about 82% of that achieved with the same dose of diclofenac (Voltaren SR) administered in the form of gastro-resistant tablets (possibly due to release-rate dependent "first-pass" metabolism). As a result of a slower release of the active substance from diclofenac (Voltaren SR) prolonged-release tablets, peak concentrations attained are lower than those observed following the administration of gastro-resistant tablets.
Mean peak concentrations of 0.5 micrograms/mL or 0.4 micrograms/mL (1.6 or 1.25 micromol/L) are reached on average 4 hours after ingestion of a prolonged-release tablet of 100 mg or 75 mg.
Food has no clinically relevant influence on the absorption and systemic availability of diclofenac (Voltaren SR) prolonged-release tablets.
On the other hand, mean plasma concentrations of 13 ng/mL (40 nmol/L) can be recorded at 24 hours (16 hours) after administration of diclofenac (Voltaren SR) prolonged-release tablets 100 mg (75 mg).
Since about half of diclofenac is metabolized during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
Trough concentrations are around 22 ng/mL or 25 ng/mL (70 nmol/L or 80 nmol/L) during treatment with diclofenac (Voltaren SR) prolonged-release tablets 100 mg once daily or 75 mg twice daily.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Distribution: 99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Biotransformation/metabolism: Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-,4'-hydroxy-,5-hydroxy-,4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent 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 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life. However, this metabolite is virtually inactive.
About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.
Linearity/non-linearity: The amount absorbed is linearly related to the dose strength.
Special populations: Geriatric patient: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed. However, in a few elderly patients a 15-minute intravenous infusion resulted in 50% higher plasma concentrations than expected from the data on young healthy subjects.
Renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects.
However, the metabolites are ultimately cleared through the bile.
Hepatic impairment: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
Toxicology: Non-Clinical Safety Data: Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity, and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses. In standard preclinical animal studies, there was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. Except for minimal fetal effects at maternally toxic doses, the prenatal, perinatal and postnatal development of the offspring was not affected.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat, and led to premature closure of the ductus arteriosus in the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as constriction of the ductus arteriosus in utero are pharmacologic consequences of this class of prostaglandin synthesis inhibitors (see CONTRAINDICATIONS and USE IN PREGNANCY & LACTATION).
Pharmacology: Mechanism of action: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) contains diclofenac sodium, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered fundamental to its mechanism of action. Prostaglandins play an important role in causing inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.
Pharmacodynamics: In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac (Voltaren/Voltaren Forte/Voltaren SR) elicit a clinical response characterized by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In post-traumatic and post-operative inflammatory conditions, diclofenac (Voltaren/Voltaren Forte/Voltaren SR) rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound edema.
Voltaren/Voltaren Forte: In clinical trials diclofenac has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. Clinical studies have also revealed that, in primary dysmenorrhea, diclofenac is capable of relieving the pain and reducing the extent of bleeding.
Voltaren SR: Diclofenac (Voltaren SR) 75 mg and 100 mg prolonged-release tablets are particularly suitable for patients in whom a daily dose of 75 mg or 100 mg is appropriate to the clinical picture. The possibility of prescribing the medicinal product in a single daily dose considerably simplifies long-term treatment and helps to avoid the possibility of dosage errors. Diclofenac (Voltaren SR) 75 mg prolonged-release tablets also allow the maximum daily dose of 150 mg to be given in a balanced b.i.d. schedule.
Clinical Studies: Diclofenac (Voltaren/Voltaren Forte/Voltaren SR) is a well-established product.
Pharmacokinetics: Absorption: Voltaren/Voltaren Forte: Diclofenac is completely absorbed from the enteric coated tablets after their passage through the stomach. Although absorption is rapid, its onset may be delayed due to the gastro-resistant coating of the tablet.
Mean peak plasma concentrations of 1.5 micrograms/mL (5 micromol/L) are attained on average 2 hours after ingestion of one tablet of 50 mg.
The passage of a tablet through the stomach is slower when ingested with or after a meal than when it is taken before a meal, but the amount of diclofenac absorbed remains the same.
Since about half of diclofenac is metabolised during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Voltaren SR: Judged by urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from diclofenac (Voltaren SR) prolonged-release tablets as from gastro-resistant tablets. However, the systemic availability of diclofenac from prolonged-release tablets is on average about 82% of that achieved with the same dose of diclofenac (Voltaren SR) administered in the form of gastro-resistant tablets (possibly due to release-rate dependent "first-pass" metabolism). As a result of a slower release of the active substance from diclofenac (Voltaren SR) prolonged-release tablets, peak concentrations attained are lower than those observed following the administration of gastro-resistant tablets.
Mean peak concentrations of 0.5 micrograms/mL or 0.4 micrograms/mL (1.6 or 1.25 micromol/L) are reached on average 4 hours after ingestion of a prolonged-release tablet of 100 mg or 75 mg.
Food has no clinically relevant influence on the absorption and systemic availability of diclofenac (Voltaren SR) prolonged-release tablets.
On the other hand, mean plasma concentrations of 13 ng/mL (40 nmol/L) can be recorded at 24 hours (16 hours) after administration of diclofenac (Voltaren SR) prolonged-release tablets 100 mg (75 mg).
Since about half of diclofenac is metabolized during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
Trough concentrations are around 22 ng/mL or 25 ng/mL (70 nmol/L or 80 nmol/L) during treatment with diclofenac (Voltaren SR) prolonged-release tablets 100 mg once daily or 75 mg twice daily.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Distribution: 99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Biotransformation/metabolism: Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-,4'-hydroxy-,5-hydroxy-,4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent 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 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life. However, this metabolite is virtually inactive.
About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.
Linearity/non-linearity: The amount absorbed is linearly related to the dose strength.
Special populations: Geriatric patient: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed. However, in a few elderly patients a 15-minute intravenous infusion resulted in 50% higher plasma concentrations than expected from the data on young healthy subjects.
Renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects.
However, the metabolites are ultimately cleared through the bile.
Hepatic impairment: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
Toxicology: Non-Clinical Safety Data: Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity, and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses. In standard preclinical animal studies, there was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. Except for minimal fetal effects at maternally toxic doses, the prenatal, perinatal and postnatal development of the offspring was not affected.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat, and led to premature closure of the ductus arteriosus in the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as constriction of the ductus arteriosus in utero are pharmacologic consequences of this class of prostaglandin synthesis inhibitors (see CONTRAINDICATIONS and USE IN PREGNANCY & LACTATION).
MedsGo Class
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Features
Brand
Voltaren
Full Details
Dosage Strength
25mg
Drug Ingredients
- Diclofenac
Drug Packaging
Enteric-Coated Tablet 100's
Generic Name
Diclofenac Sodium
Dosage Form
Enteric-Coated Tablet
Registration Number
DR-XY28428
Drug Classification
Prescription Drug (RX)
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