Gland Pharma

ACETAMINOPHEN

acetaminophen

LOE Approaching

RECTAL · SUPPOSITORY

12.1 Mechanism of Action The precise mechanism of the analgesic and antipyretic properties of acetaminophen is not established but is thought to primarily involve central actions. 12.2 Pharmacodynamics Acetaminophen has been shown to have analgesic and antipyretic activities in animal and human studies. Single doses of acetaminophen up to 3,000 mg and repeated doses of 1,000 mg every 6 hours for 48 hours have not been shown to cause a significant effect on platelet aggregation. Acetaminophen does not have any immediate or delayed effects on small-vessel hemostasis. Clinical studies of both healthy subjects and patients with hemophilia showed no significant changes in bleeding time after receiving multiple doses of oral acetaminophen. 12.3 Pharmacokinetics Distribution The pharmacokinetics of Acetaminophen Injection have been studied in patients and healthy subjects up to 60 years old. The pharmacokinetic profile of Acetaminophen Injection has been demonstrated to be dose proportional in adults following administration of single doses of 500, 650, and 1,000 mg. The maximum concentration (C max ) occurs at the end of the 15-minute intravenous infusion of Acetaminophen Injection. Compared to the same dose of oral acetaminophen, the C max following administration of Acetaminophen Injection is up to 70% higher, while overall exposure (area under the concentration time curve [AUC]) is very similar. Pharmacokinetic parameters of Acetaminophen Injection (AUC, C max , terminal elimination half-life [T ½ ], systemic clearance [CL], and volume of distribution at steady state [Vss]) following administration of a single intravenous dose of 15 mg/kg in children and adolescents and 1,000 mg in adults are summarized in . Table 5. Acetaminophen Injection Pharmacokinetic Parameters Subpopulations Mean (SD) AUC 0-6h (mcg×h/mL) C max (mcg /mL) T ½ (h) CL (L/h/kg) Vss (L/kg) Children 38 (8) 29 (7) 3.0 (1.5) 0.34 (0.10) 1.2 (0.3) Adolescents 41 (7) 31 (9) 2.9 (0.7) 0.29 (0.08) 1.1 (0.3) Adults 43 (11) 28 (21) 2.4 (0.6) 0.27 (0.08) 0.8 (0.2) The concentrations of acetaminophen observed in neonates greater than 32 weeks gestational age at birth treated with 12.5 mg/kg dose are similar to infants, children and adolescents treated with a 15 mg/kg dose, and similar to adults treated with a 1,000 mg dose. At therapeutic levels, binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%). Acetaminophen appears to be widely distributed throughout most body tissues except fat. Elimination Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI). With therapeutic doses, NAPQI undergoes rapid conjugation with glutathione and is then further metabolized to form cysteine and merc

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