May 29, 2017
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Ofirmev

"The the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) will review the risks and benefits of modified- and prolonged-release paracetamol (acetaminophen) tablets, the agency said today.

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CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

Acetaminophen has been shown to have analgesic and antipyretic activities in animal and human studies.

Single doses of OFIRMEV up to 3000 mg and repeated doses of 1000 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.

Pharmacokinetics

Distribution

The pharmacokinetics of OFIRMEV have been studied in patients and healthy subjects up to 60 years old. The pharmacokinetic profile of OFIRMEV has been demonstrated to be dose proportional in adults following administration of single doses of 500, 650, and 1000 mg.

The maximum concentration (Cmax) occurs at the end of the 15 minute intravenous infusion of OFIRMEV. Compared to the same dose of oral acetaminophen, the Cmax following administration of OFIRMEV is up to 70% higher, while overall exposure (area under the concentration time curve [AUC]) is very similar.

Pharmacokinetic parameters of OFIRMEV (AUC, Cmax, terminal elimination half-life [T½], 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 1000 mg in adults are summarized in Table 5.

Table 5. OFIRMEV Pharmacokinetic Parameters

Sub populations Mean (SD)
AUC0-6h(μg × h/mL) Cmax (μg/mL) T½ (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 1000 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.

Metabolism And Excretion

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 mercapturic acid conjugates.

Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as unconjugated (free) acetaminophen and more than 90% of the administered dose is excreted within 24 hours.

Clinical Studies

Adult Acute Pain

The efficacy of OFIRMEV in the treatment of acute pain in adults was evaluated in two randomized, double-blind, placebo-controlled clinical trials in patients with postoperative pain.

Pain Study 1 evaluated the analgesic efficacy of repeated doses of OFIRMEV 1000 mg vs. placebo every 6 hours for 24 hours in 101 patients with moderate to severe pain following total hip or knee replacement. OFIRMEV was statistically superior to placebo for reduction in pain intensity over 24 hours. There was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated.

Pain Study 2 evaluated the analgesic efficacy of repeated doses of OFIRMEV 1000 mg every 6 hours or 650 mg every 4 hours for 24 hours versus placebo in the treatment of 244 patients with moderate to severe postoperative pain after abdominal laparoscopic surgery. Patients receiving OFIRMEV experienced a statistically significant greater reduction in pain intensity over 24 hours compared to placebo.

Adult Fever

The efficacy of OFIRMEV 1000 mg in the treatment of adult fever was evaluated in one randomized, double-blind, placebo-controlled clinical trial. The study was a 6-hour, single-dose, endotoxin-induced fever study in 60 healthy adult males. A statistically significant antipyretic effect of OFIRMEV was demonstrated through 6 hours in comparison to placebo. The mean temperature over time is shown in Figure 1.

Mean Temperature (°C) Over Time - Illustration

Figure 1: Mean Temperature (°C) Over Time

Pediatric Acute Pain And Fever

OFIRMEV was studied in pediatric patients in three active-controlled trials and three open-label safety and pharmacokinetic trials [see Use In Specific Populations].

Last reviewed on RxList: 2/13/2017
This monograph has been modified to include the generic and brand name in many instances.

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