ACET Suppository Ref.[27536] Active ingredients: Paracetamol

Therapeutic classification: Analgesic / Antipyretic

Acetaminophen is the major metabolite of phenacetin and acetanilid. Animal and clinical studies have shown acetaminophen to have antipyretic and analgesic activity equal to that of acetylsalicylic acid. Acetaminophen lacks anti-inflammatory effects.

Unlike the salicylates, acetaminophen does not interfere with tubular secretion of uric acid nor does it affect acid-base balance if taken in therapeutic doses. Acetaminophen does not interfere with hemostasis and, in particular does not inhibit platelet aggregation. Allergic reactions are rare and thus the drug is useful in patients who cannot tolerate salicylates and those with an allergic diathesis, including bronchial asthmatics.

The rate of acetaminophen absorption from the gastrointestinal tract following oral administration is a function of stomach emptying rate and is generally rapid and complete with peak plasma concentrations of free drug being achieved in ½ to 2 hours following administration.

With doses up to 650 mg the peak plasma concentrations are from 5 to 20 mcg/mL. The time to reach peak effect is 1 to 3 hours and the duration of action is 3 to 4 hours. The plasma half-life of unchanged drug is about 2 hrs with approximately 85% of a 1 gm oral dose being recovered in the urine in 24 hrs. Approximately 3% is excreted unchanged with the balance being eliminated principally as the glucoronide and sulfate conjugates.

A small portion of the administered acetaminophen is converted by hepatic microsomal enzymes to reactive metabolite. At therapeutic doses this minor metabolite is rapidly inactivated by conjugation with glutathione and eliminated by renal excretion. However, where hepatic glutathione has been depleted, covalent binding of the reactive metabolite to liver-cell macromolecules occurs and hepatic cell necrosis ensues.

It has been shown that glutathione precursors such as N-acetylcysteine, cysteine, cysteamine and methionine can decrease experimental acetaminophen induced hepatic necrosis when administered promptly after a toxic dose of acetaminophen. Rectal absorption of acetaminophen, as with most rectally administered drugs, is more erratic than absorption following oral administration. Absorption rate is generally slower.

A double-blind, single dose, randomized, cross-over study was conducted on healthy adults (average weight 75.2 kg) to evaluate and compare the rate and extent of absorption and comparative bioavailability between ACET 120 (120 mg) suppository (test product), and ABENOL 120 mg suppository, a Canadian marketed formulation (reference product). Comparative bioavailability between formulations was evaluated on statistical comparison of areas under the plasma concentrations versus time curves (AUC’s), peak concentrations (C_max) and time to reach peak concentrations (T_max).

The summary of the results obtained are as follows:

Results of Comparative Pharmacokinetic Study of Unchanged Acetaminophen in Blood Following Administration of 120 mg Suppositories:

AUC_CUM = Cumulative area under the plasma concentration time curve calculated
from 0 to time of last quantifiable concentration.
MRT = Mean Residence Time

From this study, no statistical difference could be detected between the two formulations for all the pharmacokinetic parameters under study; the relative bioavailability was 106.4%.

A similar double-blind, single dose, randomized, cross-over study was conducted on healthy adults (average weight 74.3 kg) to evaluate and compare the rate and extent of absorption and comparative bioavailability between ACET 650 (650 mg) suppository (test product) and ABENOL 650 mg suppository, a Canadian marketed formulation (reference product). Comparative bioavailability between formulations was evaluated on statistical comparison of areas under the plasma concentrations versus time curves (AUCs), peak concentrations (C_max) and time to reach peak concentrations (T_max).

The summary of the results obtained are as follows:

Results of Comparative Pharmacokinetic Study of Unchanged Acetaminophen in Blood Following Administration of 650 mg Suppositories:

AUC_CUM = Cumulative area under the plasma concentration time curve calculated from 0 to time of last quantifiable concentration.
MRT = Mean Residence Time

Peak blood levels of free acetaminophen are not reached until 3 hours following rectal administration of ACET Suppositories and the peak concentration in the blood is approximately 50% of that observed following an equivalent oral dose (10-20 mcg/mL).

The percentage of a rectal dose of acetaminophen absorbed also varies, giving wide variances in the bioavailability. In view of these observations, higher rectal doses or more frequent administration may be required to achieve and/or maintain blood concentrations of acetaminophen comparable to those obtained following oral administration. No adverse reactions were reported and all physical, medical and laboratory evaluations were judged to be clinically normal.