Mechanism of action
The activation of descending serotonergic inhibitory pathways in the CNS is thought to be responsible for the analgesic effects. It's also possible that interactions with other nociceptive systems are involved. The hypothalamic heat-regulating center is inhibited, resulting in antipyresis.
Dosage Forms:
Capsule, Oral: 500 mg, 325 mg
Elixir, Oral: 160 mg/5 mL
Gel, Oral: 160 mg/5 mL
Liquid, Oral: 500 mg/15 mL
Suppository: 120 mg, 325 mg, 650 mg
Pharmacokinetics
Onset of action:
Oral: <1 hour
IV: Analgesia: 5 to 10 minutes; Antipyretic: Within 30 minutes
Peak effect: IV: Analgesic: 1 hour
Duration:
IV, Oral: Analgesia: 4 to 6 hours
IV: Antipyretic: ≥6 hours
Distribution:
~1 L/kg at therapeutic doses
Protein binding:
10% to 25% at therapeutic concentrations; 8% to 43% at toxic concentrations
Metabolism:
At therapeutic doses, primarily hepatic metabolism to sulfate and glucuronide conjugates, with a small amount metabolized by CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is rapidly conjugated with glutathione and inactivated to nontoxic cysteine and mercapturic acid conjugates. Glutathione conjugation becomes insufficient to meet metabolic demand at toxic doses (as low as 4 g daily), resulting in an increase in NAPQI concentrations, which may cause hepatic cell necrosis. First-pass metabolism affects oral administration.
Half-life elimination: Prolonged following toxic doses
Neonates: 7 hours (range: 4 to 10 hours)
Infants: ~4 hours (range: 1 to 7 hours)
Children: 3 hours (range: 2 to 5 hours)
Adolescents: ~3 hours (range: 2 to 4 hours)
Adults: ~2 hours (range: 2 to 3 hours); maybe slightly prolonged in severe renal insufficiency (CrCl<30 mL/minute): 2 to 5.3 hours
Time to peak, serum: Oral: Immediate release:
10 to 60 minutes (maybe delayed in acute overdoses); IV: 15 minutes
Excretion:
Urine (<5% unchanged; 60% to 80% as glucuronide metabolites; 20% to 30% as sulphate metabolites; ~8% cysteine and mercapturic acid metabolites)
Adverse Reactions
Oral, Rectal: Frequency not defined:
Otic: Hearing loss
Dermatologic: Skin erythema, skin blisters, skin rash Dermatologic: Skin erythema, skin
IV:
>10%: Gastrointestinal: Nausea (34% in adults, 5% in neonates, infants, children, and adolescents), vomiting (15% in adults, 5% in neonates, infants, children, and adolescents).
1% to 10%:
Hypertension, hypotension, and peripheral edema are all symptoms of cardiovascular disease (adults)
Pruritus (5% of newborns, infants, children, and adolescents) Dermatologic
Hypoalbuminemia (neonates, infants, children, and adolescents), hypokalemia, hypomagnesemia (neonates, infants, children, and adolescents), hypophosphatemia are all endocrine and metabolic disorders (neonates, infants, children, and adolescents)
Constipation (neonates, infants, children, and adolescents: 5%), diarrhea (neonates, infants, children, and adolescents: 5%). (neonates, infants, children, and adolescents)
Oliguria is a genitourinary condition (neonates, infants, children, and adolescents)
Oncologic & hematologic: Anemia
Serum aspartate aminotransferase levels are higher in the liver (Watkins 2006)
Local: Infusion site pain, injection site pain
Nervous system: agitation (infants, children, and adolescents), anxiety (adults), fatigue (adults), headache, insomnia (adults: 7%), and trismus (neonates, infants, children, and adolescents) (adults)
Muscle spasm (1%), neuromuscular & skeletal:
Respiratory problems include abnormal breath sounds (in adults), atelectasis (in neonates, infants, children, and adolescents), dyspnea (in adults), pleural effusion (in neonates, infants, children, and adolescents), pulmonary edema (in neonates, infants, children, and adolescents), stridor (in adults), and wheezing.
Warnings/Precautions
Concerns about diseases:
• G6PD deficiency: Use caution in people who have been diagnosed with G6PD deficiency.
• Hepatic impairment: In patients with hepatic impairment or active liver disease, use with caution; use of the IV formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease.
• Hypovolemia: In patients with severe hypovolemia, use the IV formulation with caution (eg, due to dehydration or blood loss).
Specific Dosage Form Issues:
• Aspartame: Some products contain aspartame, which is metabolized to phenylalanine and should be avoided (or used with caution) by phenylketonuria patients.
•Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium benzoate/benzoic acid; benzoic acid (benzoate) is a benzyl alcohol metabolite.
Dietary Suggestions
Phenylalanine and/or sodium may be present in some products.
Storage/Stability
Injection: Refrigerate or freeze intact vials and bags at 20°C to 25°C (68°F to 77°F). Some products require light protection.
Oral formulations should be stored at 20°C to 25°C (68°F to 77°F); excessive heat (40°C [104°F]) should be avoided. High humidity should be avoided (chewable tablets).
Suppositories: Do not freeze; store at 2°C to 27°C (25°F to 80°F).