REMETHAN Prolonged-release tablet Ref.[28323] Active ingredients: Diclofenac

Absorption

The same amount of active substance is released and absorbed from prolonged-release tablets as from gastro-resistant tablets. Mean peak plasma concentrations of diclofenac are reached at 4 hours, 0.508 ± 0.185µg/ml (0.5µg/mL 1.6µmol/L) after prolonged-release 100 mg. Prolonged-release tablets are modified release preparations and plasma concentrations of diclofenac of 13ng/mL (40µmol/L) can be recorded at 24 hours after administration. Absorption is unaffected by food.

Bioavailability

The systemic availability of diclofenac from the prolonged-release formulations is on average 82% of that achieved with the same dose of gastro-resistant tablets (possibly due to release rate dependent first-pass metabolism). As a result of the slower release of active substance, peak plasma concentrations are lower than for the equivalent gastro-resistant tablets.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed. Trough levels of diclofenac in the plasma after prolonged-release 100mg daily are around 22ng/ml (70nmol/l).

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and 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 (see section 4.6 Pregnancy and lactation).

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, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of 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.

Characteristics in patients

Elderly

No relevant age-dependent differences in the drug’s absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with 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.

Patients with hepatic disease

In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

None stated.