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Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, acetic acid derivatives and related substances. ATC code: M01A B05.
Pharmacology: Mechanism of action: Voltaren/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 to be 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 elicit a clinical response characterised 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 rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
Voltaren: In clinical trials Voltaren 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 dysmenorrhoea, Voltaren is capable of relieving the pain and reducing the extent of bleeding.
Suppository: Voltaren also has beneficial effects on the symptoms of migraine attacks.
Voltaren SR: Voltaren 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. Voltaren 75 mg prolonged-release tablets also allow the maximum daily dose of 150 mg to be given in a balanced b.i.d. schedule.
Pharmacokinetics: Absorption: 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.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Voltaren: The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Enteric-coated tablet: Diclofenac is completely absorbed from the gastro-resistant 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.
Suppository: Diclofenac shows a rapid onset of absorption from suppositories, although the rate of absorption is slower than from gastro-resistant tablets administered orally. After the administration of 50 mg suppositories, peak plasma concentrations are attained on average within 1 hour, but maximum concentrations per dose unit are about two thirds of those reached after administration of gastro-resistant tablets.
Voltaren SR: Judged by urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from Voltaren prolonged-release tablets as from gastro-resistant tablets. However, the systemic availability of diclofenac from Voltaren prolonged-release tablets is on average about 82% of that achieved with the same dose of Voltaren 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 Voltaren 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 micro mol/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 Voltaren 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 Voltaren prolonged-release tablets 100 mg (75 mg).
Trough concentrations are around 22 ng/mL or 25 ng/mL (70 nmol/L or 80 nmol/L) during treatment with Voltaren prolonged-release tablets 100 mg once daily or 75 mg twice daily.
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.
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 size of the dose.
Special populations: Geriatric patients: 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: Diclofenac did not influence fertility of parent animals (rats). Except for minimal fetal effects at maternally toxic doses, the pre, peri- and postnatal development of the offspring was not affected (Voltaren suppository).
No mutagenic effects could be demonstrated in various in vitro and in vivo experiments, and no carcinogenic potential was detected in long term studies in rats and mice.
For more information, see Use in Pregnancy & Lactation.
