Meloxicam 20 mg, Paracetamol 150 mg Liquid injectables

The precise mechanism of the analgesic and antipyretic properties of acetaminophen is not established but is thought to primarily involve central actions.

Distribution — The pharmacokinetics of acetaminophen have been studied in patients and healthy subjects up to 60 years old. The pharmacokinetic profile of acetaminophen 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. Compared to the same dose of oral acetaminophen, the C maxfollowing administration of acetaminophen is up to 70% higher, while overall exposure (area under the concentration time curve [AUC]) is very similar.

Pharmacokinetic parameters of acetaminophen (AUC, C max, terminal elimination half-life [T½], systemic clearance [CL], and volume of distribution at steady state [V ss]) 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.

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.

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.

Meloxicam has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivoeffects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption — Following intravenous administration of meloxicam injection to healthy volunteers, plasma concentrations of 30 mg meloxicam injection exceed that of 15 mg oral meloxicam for the first 24 hours. The single-dose pharmacokinetics of meloxicam following intravenous administration of QAMZOVA are presented in Table 4.

Following multiple dosing, QAMZOVA is predicted to have slightly higher than 2-fold accumulation without a change in the terminal elimination half-life.

Meloxicam injection exhibits linear pharmacokinetics over intravenous doses ranging from 15 mg to 180 mg.

Distribution — Following administration of meloxicam injection, the apparent volume of distribution during the terminal elimination phase (Vz) of meloxicam is 9.63 L.

Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.

Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.

Metabolism — Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitrostudies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivopharmacological activity.

Excretion — Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.

The mean elimination half-life (t 1/2) for QAMZOVA 30 mg is approximately 21 hours.

Specific Populations — Based on population pharmacokinetics analyses, age, sex and race do not have a clinically meaningful effect on the PK of meloxicam injection.

Hepatic Impairment: The pharmacokinetics of QAMZOVA have not been investigated in patients with hepatic impairment. However, following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied. Monitor for adverse events when used in patients with severe hepatic impairment [ see Warnings and Precautions ( 5.3), Use in Specific Populations ( 8.6) ].