AKIS Solution for injection Ref.[6787] Active ingredients: Diclofenac

Absorption

Intramuscular injection

After administration of AKIS 75 mg/ml Solution for Injection by the i.m. route, absorption is rapid and the mean peak plasma concentration of 2.603 ± 0.959 µg/ml (2.5 ug/ml equals approximately 8 µmol/L) is reached after 34 minutes. The area under the concentration curve AUC_0-t is 250.07 ± 46.89 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol (75mg/3ml) is 2.242 ± 0.566 µg/ml which is reached after 27 minutes and the AUC_0-t is 246.70± 39.74 µg/ml.min. The AUC after i.m. administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.

Subcutaneous injection

After administration of AKIS 75 mg/ml Solution for Injection by the s.c. route, absorption is rapid and the mean peak plasma concentrations of 2.138 ± 0.646 µg/ml (2.5 µg/ml equals approximately 8 µmol/l) is reached in 40 minutes. The AUC_0-t is 261.94 ± 53.29 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol is 2.242 ± 0.566 µg/ml at 27 minutes and the AUC_0-t is 246.70 ± 39.74 µg/ml.min. A subcutaneous dose of 75 mg of AKIS was bioequivalent to an intramuscularly administered dose of Voltarol 75 mg/3 ml in terms of AUC and C_max. The AUC after subcutaneous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.

Dose linearity in terms of AUC has been demonstrated for diclofenac absorbed after subcutaneous administration. C_max was found to be not proportional to dose, with mean C_max values of 1090 ng/ml, 1648.9 ng/ml and 1851.1 ng/ml with the 25 mg, 50 mg and 75 mg dose of AKIS respectively.

Intravenous bolus injection

After administration of AKIS 75mg/mL Solution for Injection by intravenous bolus, absorption sets in immediately, and mean peak plasma concentration of about 16.505 ± 2.829 µg/mL are reached in 3 minutes. In comparative pharmacokinetic studies, were diclofenac was measured in plasma up to 8 hours post-dose, AKIS 75 mg/mL i.v. bolus was found to be bioequivalent to Voltarol 75 mg/3mL ampoule administered as a 30-min i.v. infusion (100 mL) in terms of systemic exposure (AUC0-t: 5193.46 ± 1285 ng/mL.h and 4584.13 ± 1014.20 ng/mL.h, for AKIS and Voltarol, respectively), but with a substantially higher rate of absorption (C_max for Voltarol 75 mg/3mL infusion was 6.117 ± 1.051 µg/mL). Also, diclofenac peak plasma concentration (C_max) following AKIS i.v. bolus injection was found to be comparable to that reported in the literature for a similar diclofenac sodium and hydroxyl-propyl-β-cyclodextrin-containing solution for injection (Dyloject 75mg/2mL, Javelin Pharm. Ltd., UK) given by the same route (C_max: 15.147 ± 2.829 µg/mL). The diclofenac AUC after bolus intravenous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.

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.

Biotransformation

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

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.

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 <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.

No new preclinical safety studies have been performed on sodium diclofenac. The safety profile of the medicinal product is well-established.

The local tolerance study demonstrated that the formulation does not present any significant unexpected local toxicity by either the intramuscular or subcutaneous routes of administration.