Voltaren/Voltaren SR Mechanism of Action

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic product, non-steroid, acetic acid derivative and related substance. ATC code: M01AB05.
Pharmacology: Pharmacodynamics: Mechanism of action: Voltaren contains the sodium salt of diclofenac, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis has been demonstrated experimentally and is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain, and fever.
In vitro, diclofenac sodium does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
Pharmacokinetics: Distribution: Diclofenac is 99.7% bound to serum proteins, mainly albumin (99.4%). The apparent volume of distribution has been calculated at 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 elimination half-life from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma values, 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: Biotransformation of diclofenac is partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation. This results in several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are subsequently converted to glucuronide conjugates. Two of these phenolic metabolites are pharmacologically active, but to a much lesser extent than diclofenac itself.
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. The virtually inactive metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer plasma half-life.
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 via the bile in the faeces.
Linearity/non-linearity: The amount absorbed is in linear proportion to the size of the dose.
Pharmacokinetics in special populations: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed.
Renal impairment: In patients with renal impairment, the drug's single-dose pharmacokinetics do not suggest any accumulation of unchanged active substance with the usual dosage schedule. In patients with a creatinine clearance of <10 mL/min, theoretical steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared via the bile.
Hepatic impairment: In patients with hepatic impairment (chronic hepatitis or non-decompensated cirrhosis), the pharmacokinetics and metabolism of diclofenac are the same as in patients without liver disease.
Toxicology: Preclinical 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.
Voltaren EC tablet: Pharmacology: Pharmacodynamics: Pharmacodynamic effects: In rheumatic diseases, the anti-inflammatory and analgesic properties of Voltaren 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, Voltaren rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
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.
Pharmacokinetics: Absorption: 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.
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.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Toxicology: Preclinical safety data: 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. The prenatal, perinatal and postnatal development of the offspring was not affected.
Voltaren SR-FC tablet: Pharmacology: Pharmacodynamics: Clinical efficacy: In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterised by improved function and marked relief of signs and symptoms such as pain at rest, pain on movement, morning stiffness and swelling of the joints. In post-traumatic and post-operative inflammatory conditions, Voltaren rapidly relieves both spontaneous pain and pain on movement, and reduces inflammatory swelling and wound oedema.
In clinical trials, the product has also been shown to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. It can relieve the pain, and also reduce bleeding, in primary dysmenorrhoea.
Pharmacokinetics: Absorption: Judged on the basis of the urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from Voltaren prolonged-release coated tablets as from the gastro-resistant coated tablets. However, on average the systemic bioavailability of diclofenac from Voltaren prolonged-release coated tablet is approximately 82% of that attained with the same dose of Voltaren administered in the form of gastro-resistant coated tablets (possibly due to release-rate-dependent first-pass metabolism). Owing to the slower release of the active substance from Voltaren prolonged-release coated tablets, peak plasma concentrations are lower than with the gastro-resistant coated tablets.
Mean peak plasma concentrations of 0.5 μg/ml and 0.4 μg/ml are attained on average 4 hours after administration, respectively, of 100 mg or 75 mg prolonged-release coated tablets. Ingestion with food has no notable effect on the absorption and systemic bioavailability of Voltaren prolonged-release coated tablets.
On the other hand, mean plasma concentrations of 13 ng/ml are recorded 24 hours (16 hours) after ingestion of 100 mg (75 mg).
Ingestion of 100 mg once daily or 75 mg twice daily produces trough plasma levels of approximately 22 ng/ml and 25 ng/ml, respectively.
Distribution: A low concentration of diclofenac (100 ng/ml) was detected in the breast milk of one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Toxicology: Preclinical safety data: The increased incidence of lymphomas (thymus) in mice, and subcutaneous fibromas, fibroadenomas (mammary gland) or C-cell adenomas (thyroid gland) in rats were all within the historical control range of the laboratory for the animal strain used, and are considered to have occurred by chance.
In all toxicity studies carried out in rats, hypertrophy of mesenteric lymph nodes or lymphadenitis with reactive hyperplasia were observed. These changes were accompanied by neutrophilia that was also observed in studies in monkeys. These are presumably secondary reactions to the ulcers observed in the gastrointestinal tract. In a two-year study, a dose-dependent increase in thrombotic vascular occlusions in the heart was observed in rats treated with diclofenac.
Reproductive toxicity: Additional studies indicate that, with repeated oral doses in rats (>1 mg/kg body weight), diclofenac causes effects that influence fertility (lower testosterone level, and decreased epididymal and testicular weight in association with histopathological changes). Similar effects were also observed in the F1 generation following doses of ≥1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of 2 mg/kg diclofenac sodium led to an increased spermatid count. Further studies describe a decreased mating frequency in female rats following a repeated dose of ≥0.5 mg/kg diclofenac. For this reason, an influence on both male and female fertility cannot be ruled out.
Diclofenac crosses the placental barrier in rodents. Administration of NSAIDs (including diclofenac) inhibited ovulation in rabbits and implantation and placentation in rats, and led to premature closure of the ductus arteriosus in pregnant rats. 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 closure of the ductus arteriosus in utero are pharmacological effects of this class of prostaglandin synthetase inhibitors (see Contraindications and Use in Pregnancy & Lactation).
In a study in mice, teratogenicity (cleft palate) was observed at the maternally toxic dose of 4 mg/kg. In rats and rabbits, doses up to the maternally toxic level did not lead to teratogenic effects. Delayed ossification and reduced fetal weight in a study in rabbits were the only changes observed in these investigations.
At maternally toxic doses, the perinatal and post-natal development of the offspring were impaired (fertility, see as previously mentioned, also birth weight and delayed post-natal growth).
Voltaren suppository: Pharmacology: Pharmacodynamics: Pharmacodynamic effects: In rheumatic diseases, the anti-inflammatory and analgesic properties of Voltaren 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, Voltaren rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
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.
Voltaren also has beneficial effects on the symptoms of migraine attacks.
Pharmacokinetics: Absorption: 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.
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.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Toxicology: Preclinical safety data: 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. The prenatal, perinatal and postnatal development of the offspring was not affected.