MELOX

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve various types of pain, including pain caused by musculoskeletal conditions, osteoarthritis, and rheumatoid arthritis.

With a longer half-life than most other NSAIDS, it is a favorable option for those who require once-daily dosing.

Meloxicam is available in oral, transdermal, and intravenous formulations.

It is a preferential

COX-2 inhibitor, purportedly reducing the risk of adverse gastrointestinal tract effects, however, this is a topic of controversy. 4, 5.

Meloxicam on its own is indicated for: the symptomatic treatment of arthritis and osteoarthritis. 10 the pauciarticular and polyarticular course of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years old or above. 10 the management of moderate-to-severe pain, alone or in combination with non-NSAID analgesics.

Meloxicam, in combination with bupivacaine, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided.

Meloxicam, in combination with Rizatriptan is indicated for the acute treatment of migraine with or without aura in adults.

Off-label uses include the treatment of dental or post-surgical pain.

Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever.

Prostaglandins are substances that contribute to inflammation.

This drug also exerts preferential actions against COX-2 3, which may reduce the possible gastrointestinal effects of this drug.

In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression.

As with other

NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events.

A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS.

Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. 5, 10 In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on diclofenac.

GI events were found to be less severe in the meloxicam-treated patients.

G/H synthase 2 Inhibitor Prostaglandin G/H synthase 1 Inhibitor.

The absolute bioavailability oral capsules after a dose was 89% in one pharmacokinetic study.

Cmax was reached 5–6 hours after administration of a single dose given after the first meal of the day. The Cmax doubled when the drug was administered in the fasting state.

Despite this, meloxicam can be taken without regard to food, unlike many other NSAIDS. 1, 10 Meloxicam formulated for instillation with bupivacaine produced varied systemic measures following a single dose of varying strength.

In patients undergoing bunionectomy, 1.8 mg of meloxicam produced a C max of 26 ± 14 ng/mL, a median T max of 18 h, and an AUC ∞ of 2079 ± 1631 ng*h/mL.

For a 9 mg dose used in herniorrhaphy, the corresponding values were 225 ± 96 ng/mL, 54 h, and the AUC ∞ was not reported.

Lastly, a 12 mg dose used in total knee arthroplasty produced values of 275 ± 134 ng/mL, 36 h, and 25,673 ± 17,666 ng*h/mL.

The volume of distribution of meloxicam is 10-15 L. Because of its high binding to albumin, it is likely to be distributed in highly perfused tissues, such as the liver and kidney.

Meloxicam concentrations in synovial fluid, measured after an oral dose, is estimated at 40% to 50% of the concentrations measured in the plasma.

This drug is known to cross the placenta in humans.

Meloxicam is almost completely metabolized.

CYP2C9 is the main enzyme responsible for the metabolism of meloxicam 1, 6 with minor contributions from CYP3A4.

Meloxicam has 4 major metabolites with no activity determined.

About 60% of the ingested dose is metabolized to 5'-carboxy meloxicam from hepatic cytochrome enzyme oxidation of an intermediate metabolite, 5'-hydroxymethylmeloxicam. 6, 8 Two other metabolites are likely produced via peroxidation. 6, 10 Hover over products below to view reaction partners Meloxicam 5'-hydroxymethyl meloxicam 5'-carboxy meloxicam.

Meloxicam is mainly eliminated through metabolism.

Its metabolites are cleared through renal and fecal elimination.

Less than <0.25% of a dose is eliminated in the urine as unchanged drug.

About 1.6% of the parent drug is excreted in the feces.

The half-life of meloxicam is approximately 20 hours 3, which is considerably longer than most other NSAIDS.

It can therefore be dosed without the need for slow-release formulations.

Meloxicam applied together with bupivacaine for postsurgical analgesia had a median half-life of 33-42 hours, depending on dose and application site.

After an oral dose, the total clearance of meloxicam is 0.42–0.48 L/h. 1, 3 The FDA label indicates a plasma clearance from 7-9 mL/min. No dose changes are required in mild to moderate renal or hepatic impairment.

The use of meloxicam in patients with severe renal or hepatic impairment has not been studied.

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The oral

LD50 in rats is 98 mg/kg.

Signs and symptoms of overdose with meloxicam may include shallow breathing, seizure, decreased urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, and black tarry stools.

In the case of an overdose, offer supportive treatment and attempt to remove gastrointestinal contents.

Cholestyramine has been shown to enhance the elimination of meloxicam.

Meloxicam is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs.

Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients In the setting of coronary artery bypass graft (CABG) surgery Known hypersensitivity to meloxicam or any components of the drug product History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs In the setting of CABG surgery.

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals OA and RA: Starting dose: 7.5 mg once daily Dose may be increased to 15 mg once daily JRA: 7.5 mg once daily in children ≥60 kg Meloxicam Tablets are not interchangeable with approved formulations of oral meloxicam even if the total milligram strength is the same 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of meloxicam tablets and other treatment options before deciding to use meloxicam tablets.

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with meloxicam tablets, adjust the dose to suit an individual patient's needs.

In adults, the maximum recommended daily oral dose of meloxicam tablets is 15 mg regardless of formulation.

In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended.

Meloxicam tablets may be taken without regard to timing of meals. 2.2 Osteoarthritis For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam tablets is 7.5 mg once daily.

Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.3 Rheumatoid Arthritis For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam tablets is 7.5 mg once daily.

Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of meloxicam is 7.5 mg once daily in children who weigh ≥60 kg. There was no additional benefit demonstrated by increasing the dose above 7.5 mg in clinical trials.

Meloxicam tablets should not be used in children who weigh <60 kg. 2.5 Renal Impairment The use of meloxicam in subjects with severe renal impairment is not recommended.

In patients on hemodialysis, the maximum dosage of meloxicam is 7.5 mg per day. 2.6 Non-Interchangeability with Other Formulations of Meloxicam Meloxicam Tablets have not shown equivalent systemic exposure to other approved formulations of oral meloxicam.

Therefore, Meloxicam Tablets are not interchangeable with other formulations of oral meloxicam product even if the total milligram strength is the same.

Do not substitute similar dose strengths of Meloxicam Tablets with other formulations of oral meloxicam product.

USP are available as light yellow coloured, round, biconvex tablets, plain on one side and debossed with '7.5' on other side containing meloxicam 7.5 mg or as light yellow coloured, oval shaped, biconvex tablets, plain on one side and debossed with '15' on other side containing meloxicam 15 mg. Meloxicam Tablets USP, 7.5 mg are available as follows: Bottles of 100 NDC 68180-501-01 Bottles of 1000 NDC 68180-501-03 Meloxicam Tablets USP, 15 mg are available as follows: Bottles of 100 NDC 68180-502-01 Bottles of 1000 NDC 68180-502-03 Storage Store at 20° to 25°C (68° to 77°F) .

Keep meloxicam tablets

USP in a dry place.

Dispense tablets in a tight container.

Keep this and all medications out of the reach of children.

Risk Summary Use of

NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

Because of these risks, limit dose and duration of meloxicam use between about and 30 weeks of gestation, and avoid meloxicam use at about 30 weeks of gestation and later in pregnancy.

Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65.

• and 6.5-times the maximum recommended human dose (MRHD) of meloxicam.

Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD.

In pre.

• and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam.

No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD.

Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.

In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre.

• and post-implantation loss.

Prostaglandins also have been shown to have an important role in fetal kidney development.

In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

If meloxicam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios.

If oligohydramnios occurs, discontinue meloxicam and follow up according to clinical practice.

There are no studies on the effects of meloxicam during labor or delivery.

In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug.

There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible.

Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications.

These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use.

Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full.

• term infant exposed to NSAIDs through maternal use is uncertain.

Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of meloxicam based on BSA comparison).

Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison).

The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).

In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65-and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis.

Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison).

Females and Males of Reproductive Potential Infertility Females: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation.

Small studies in women treated with

NSAIDs have also shown a reversible delay in ovulation.

Consider withdrawal of

NSAIDs, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility.

The safety and effectiveness of meloxicam in pediatric JRA patients from to 17 years of age has been evaluated in three clinical trials.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions.

If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.