Meloxicam tablet

Boxed warning section

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

See full prescribing information for complete boxed warning .

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1)
  • Meloxicam tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4, 5.1)
  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2)

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WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Thrombotic Events

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1)].
  • Meloxicam tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4) and Warnings and Precautions ( 5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2)].

Recent major changes

Boxed Warning 5/2016

Indications and Usage, Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course ( 1.3) 6/2016

Dosage and Administration, General Dosing Instructions ( 2.1) 6/2016

Dosage and Administration, Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course ( 2.4) 6/2016

Warnings and Precautions, Cardiovascular Thrombotic Events ( 5.1) 5/2016

Warnings and Precautions, Heart Failure and Edema ( 5.5) 5/2016

1 indications and usage

Meloxicam tablets are a non-steroidal anti-inflammatory drug indicated for:

  • Osteoarthritis (OA) ( 1.1)
  • Rheumatoid Arthritis (RA) ( 1.2)
  • Juvenile Rheumatoid Arthritis (JRA) in patients who weigh 60 kg ( 1.3)

2 dosage and administration

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1)

Starting dose: 7.5 mg once daily

Dose may be increased to 15 mg once daily

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 ( 2.6)

3 dosage forms and strengths

  • Meloxicam Tablets USP: 7.5 mg and 15 mg ( 3)

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Meloxicam Tablets USP:

  • 7.5 mg: Light yellow, round flat beveled edged, tablet with U & L debossed on one side and 7.5 debossed centrally on the other side
  • 15 mg: Light yellow, capsule shaped, biconvex, tablet with U & L debossed on one side and 15 debossed centrally on the other side

4 contraindications

  • Known hypersensitivity to meloxicam or any components of the drug product ( 4)
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4)
  • In the setting of CABG surgery ( 4)

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Meloxicam tablets are contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [ see Warnings and Precautions ( 5.7, 5.9)]
  • 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 [ see Warnings and Precautions ( 5.7, 5.8)]
  • In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1)]

5 warnings and precautions

  • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3)
  • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4, 7)
  • Heart Failure and Edema: Avoid use of Meloxicam in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5)
  • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of Meloxicamin patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6)
  • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.7)
  • Exacerbation of Asthma Related to Aspirin Sensitivity: Meloxicam is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8)
  • Serious Skin Reactions: Discontinue Meloxicam at first appearance of skin rash or other signs of hypersensitivity ( 5.9)
  • Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation ( 5.10, 8.1)
  • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11, 7)

5.9 serious skin reactions

NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Meloxicam at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4)].

6 adverse reactions

  • Most common (5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms ( 6.1)
  • Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA), Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Cardiovascular Thrombotic Events [ see Boxed Warningand Warnings and Precautions ( 5.1)]
  • GI Bleeding, Ulceration, and Perforation [ see Boxed Warningand Warnings and Precautions ( 5.2)]
  • Hepatotoxicity [ see Warnings and Precautions ( 5.3)]
  • Hypertension [ see Warnings and Precautions ( 5.4)]
  • Heart Failure and Edema [ see Warnings and Precautions ( 5.5)]
  • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6)]
  • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7)]
  • Serious Skin Reactions [ see Warnings and Precautions ( 5.9)]
  • Hematologic Toxicity [ see Warnings and Precautions ( 5.11)]

7 drug interactions

  • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking Meloxicam with drugs that interfere with hemostasis. Concomitant use of Meloxicam and analgesic doses of aspirin is not generally recommended ( 7)
  • ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta-Blockers: Concomitant use with Meloxicam may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7)
  • ACE Inhibitors and ARBs: Concomitant use with Meloxicam in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7)
  • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7)

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See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions ( 5.2, 5.6, 5.11) and Clinical Pharmacology ( 12.3).

Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :
Meloxicamandanticoagulantssuchaswarfarinhaveasynergisticeffectonbleeding.Theconcomitantuseofmeloxicamandanticoagulantshaveanincreasedriskofseriousbleedingcomparedtotheuseofeitherdrugalone.
Serotoninreleasebyplateletsplaysanimportantroleinhemostasis.Case-controlandcohortepidemiologicalstudiesshowedthatconcomitantuseofdrugsthatinterferewithserotoninreuptakeandanNSAIDmaypotentiatetheriskofbleedingmorethananNSAIDalone.
Intervention :

MonitorpatientswithconcomitantuseofMeloxicamwithanticoagulants(e.g.,warfarin),antiplateletagents(e.g.,aspirin),selectiveserotoninreuptakeinhibitors(SSRIs),andserotoninnorepinephrinereuptakeinhibitors(SNRIs)forsignsofbleeding[seeWarningsandPrecautions( 5.11)].
Aspirin
Clinical Impact :
ControlledclinicalstudiesshowedthattheconcomitantuseofNSAIDsandanalgesicdosesofaspirindoesnotproduceanygreatertherapeuticeffectthantheuseofNSAIDsalone.Inaclinicalstudy,theconcomitantuseofanNSAIDandaspirinwasassociatedwithasignificantlyincreasedincidenceofGIadversereactionsascomparedtouseoftheNSAIDalone[seeWarningsandPrecautions( 5.2)].
Intervention :

ConcomitantuseofMeloxicamandlowdoseaspirinoranalgesicdosesofaspirinisnotgenerallyrecommendedbecauseoftheincreasedriskofbleeding[seeWarningsandPrecautions( 5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :
NSAIDsmaydiminishtheantihypertensiveeffectofangiotensinconvertingenzyme(ACE)inhibitors,angiotensinreceptorblockers(ARBs),orbeta-blockers(includingpropranolol).
Inpatientswhoareelderly,volume-depleted(includingthoseondiuretictherapy),orhaverenalimpairment,coadministrationofanNSAIDwithACEinhibitorsorARBsmayresultindeteriorationofrenalfunction,includingpossibleacuterenalfailure.Theseeffectsareusuallyreversible.
Intervention :

DuringconcomitantuseofMeloxicamandACEinhibitors,ARBs,orbeta-blockers,monitorbloodpressuretoensurethatthedesiredbloodpressureisobtained. DuringconcomitantuseofMeloxicamandACEinhibitorsorARBsinpatientswhoareelderly,volume-depleted,orhaveimpairedrenalfunction,monitorforsignsofworseningrenalfunction[seeWarningsandPrecautions( 5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :
Clinicalstudies,aswellaspost-marketingobservations,showedthatNSAIDsreducedthenatriureticeffectofloopdiuretics(e.g.,furosemide)andthiazidediureticsinsomepatients.ThiseffecthasbeenattributedtotheNSAIDinhibitionofrenalprostaglandinsynthesis.However,studieswithfurosemideagentsandmeloxicamhavenotdemonstratedareductioninnatriureticeffect.Furosemidesingleandmultipledosepharmacodynamicsandpharmacokineticsarenotaffectedbymultipledosesofmeloxicam.
Intervention :

DuringconcomitantuseofMeloxicamwithdiuretics,observepatientsforsignsofworseningrenalfunction,inadditiontoassuringdiureticefficacyincludingantihypertensiveeffects[seeWarningsandPrecautions( 5.6)].
Lithium
Clinical Impact :
NSAIDshaveproducedelevationsinplasmalithiumlevelsandreductionsinrenallithiumclearance.Themeanminimumlithiumconcentrationincreased15%,andtherenalclearancedecreasedbyapproximately20%.ThiseffecthasbeenattributedtoNSAIDinhibitionofrenalprostaglandinsynthesis[seeClinicalPharmacology( 12.3)].
Intervention :

DuringconcomitantuseofMeloxicamandlithium,monitorpatientsforsignsoflithiumtoxicity.
Methotrexate
Clinical Impact :
ConcomitantuseofNSAIDsandmethotrexatemayincreasetheriskformethotrexatetoxicity(e.g.,neutropenia,thrombocytopenia,renaldysfunction).
Intervention :

DuringconcomitantuseofMeloxicamandmethotrexate,monitorpatientsformethotrexatetoxicity.
Cyclosporine
Clinical Impact :
ConcomitantuseofMeloxicamandcyclosporinemayincreasecyclosporine'snephrotoxicity.
Intervention :

DuringconcomitantuseofMeloxicamandcyclosporine,monitorpatientsforsignsofworseningrenalfunction.
NSAIDs and Salicylates
Clinical Impact :
ConcomitantuseofmeloxicamwithotherNSAIDsorsalicylates(e.g.,diflunisal,salsalate)increasestheriskofGItoxicity,withlittleornoincreaseinefficacy[seeWarningsandPrecautions( 5.2)].
Intervention :

TheconcomitantuseofmeloxicamwithotherNSAIDsorsalicylatesisnotrecommended.
Pemetrexed
Clinical Impact :
ConcomitantuseofMeloxicamandpemetrexedmayincreasetheriskofpemetrexed-associatedmyelosuppression,renal,andGItoxicity(seethepemetrexedprescribinginformation).
Intervention :

DuringconcomitantuseofMeloxicamandpemetrexed,inpatientswithrenalimpairmentwhosecreatinineclearancerangesfrom45to79mL/min,monitorformyelosuppression,renalandGItoxicity.

Patientstakingmeloxicamshouldinterruptdosingforatleastfivedaysbefore,thedayof,andtwodaysfollowingpemetrexedadministration.

Inpatientswithcreatinineclearancebelow45mL/min,theconcomitantadministrationofmeloxicamwithpemetrexedisnotrecommended.

8 use in specific populations

  • Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation ( 5.10, 8.1)
  • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of Meloxicam in women who have difficulties conceiving ( 8.3)

8.1 pregnancy

Risk Summary

Use of NSAIDs, including Meloxicam, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Meloxicam, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Warnings and Precautions ( 5.10)].

There are no adequate and well-controlled studies of Meloxicam in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.

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 [see Data].

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.

Clinical Considerations

Labor or Delivery

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

Animal Data

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 (0.65and 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).

8.2 lactation

Risk Summary

There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Meloxicam and any potential adverse effects on the breastfed infant from the Meloxicam or from the underlying maternal condition.

Data

Animal Data

Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma.

8.3 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.

8.4 pediatric use

The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [ see Dosage and Administration ( 2.3), Adverse Reactions ( 6.1) and Clinical Studies ( 14.2)].

8.5 geriatric use

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 [ see Warnings and Precautions ( 5.1, 5.2, 5.3, 5.6, 5.13)].

10 overdosage

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Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1, 5.2, 5.4, 5.6)].

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

There is limited experience with meloxicam overdosage. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage.

For additional information about overdosage treatment, call a poison control center (1-800-222-1222).

11 description

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Meloxicam Tablets USP are a nonsteroidal anti-inflammatory drug (NSAID). Each tablet contains 7.5 mg or 15 mg meloxicam for oral administration. Meloxicam is chemically designated as 4-hydroxy-2-methyl- N-(5-methyl-2-thiazolyl)-2 H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C 14H 13N 3O 4S 2and it has the following structural formula:

Chemical Structure
Chemical Structure

Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.

Meloxicam is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam.

The inactive ingredients in Meloxicam tablets USP include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium citrate dihydrate.

12 clinical pharmacology

12.1 mechanism of action

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 vivo effects. 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.

12.3 pharmacokinetics

Absorption

The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.

Meloxicam capsules have been shown to be bioequivalent to Meloxicam tablets.

Table 4 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV).


Steady State
Single Dose
Pharmacokinetic Parameters (% CV )

Healthy male adults ( Fed )
Elderly males ( Fed ) id903_2
Elderly females ( Fed ) id903_2
Renal failure ( Fasted )
Hepatic insufficiency ( Fasted )


7 . 5 mg tablets
15 mg capsules
15 mg capsules
15 mg capsules
15 mg capsules
N

18
5
8
12
12
C m a x
[g/mL]
1.05(20)
2.3(59)
3.2(24)
0.59(36)
0.84(29)
t m a x
[h]
4.9(8)
5(12)
6(27)
4(65)
10(87)
t 1 / 2
[h]
20.1(29)
21(34)
24(34)
18(46)
16(29)
CL/f
[mL/min]
8.8(29)
9.9(76)
5.1(22)
19(43)
11(44)
V z/f
[L]
14.7(32)
15(42)
10(30)
26(44)
14(29)

Food and Antacid Effects

Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, Meloxicam can be administered without regard to timing of meals or concomitant administration of antacids.

Distribution

The mean volume of distribution (Vss) of meloxicam is approximately 10 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.

Elimination

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. All 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 (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.

Specific Populations

Pediatric

After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg [ see Dosage and Administration ( 2.4)]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively.

In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients.

The pharmacokinetics of Meloxicam in pediatric patients under 2 years of age have not been investigated.

Geriatric

Elderly males (65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.

Sex

Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg Meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.

Hepatic Impairment

Following a single 15 mg dose of meloxicam 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 [ see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.6)].

Renal Impairment

Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of Meloxicam in subjects with severe renal impairment is not recommended [ see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.6) and Use in Specific Populations ( 8.7)].

Hemodialysis

Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Dosage and Administration ( 2.1) and Use in Specific Populations ( 8.7)].

Drug Interaction Studies

Aspirin:When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. When Meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7)].

Cholestyramine:Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.

Cimetidine:Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam.

Digoxin:Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after -acetyldigoxin administration for 7 days at clinical doses. In vitrotesting found no protein binding drug interaction between digoxin and meloxicam.

Lithium:In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7)].

Methotrexate:A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7)].

Warfarin:The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering Meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [ see Drug Interactions ( 7)].

13 nonclinical toxicology

14 clinical studies

16 how supplied/storage and handling

Product: 63629-7966

NDC: 63629-7966-1 20 TABLET in a BOTTLE

NDC: 63629-7966-2 30 TABLET in a BOTTLE

NDC: 63629-7966-3 90 TABLET in a BOTTLE

17 patient counseling information

Spl unclassified section

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed.

Additional Medication Guides can be obtained by calling Unichem at 1-866-562-4616.

Inform patients, families or their caregivers of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [see Warnings and Precautions ( 5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.2)].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop Meloxicam tablets and seek immediate medical therapy [ see Warnings and Precautions ( 5.3)].

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5)].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4) and Warnings and Precautions ( 5.7)].

Serious Skin Reactions

Advise patients to stop Meloxicam tablets immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Meloxicam tablets, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3)].

Fetal Toxicity

Inform pregnant women to avoid use of Meloxicam tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [ see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of Meloxicam tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2) and Drug Interactions ( 7)]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

Use of NSAIDs and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Meloxicam tablets until they talk to their healthcare provider [ see Drug Interactions ( 7)].

For current prescribing information, call Unichem at 1-866-562-4616.

Manufactured by:

UNICHEM LABORATORIES LTD.

Pilerne Ind. Estate,

Pilerne, Bardez, Goa 403511, India

Manufactured for:

Unichem Logo
Unichem Logo

Hasbrouck Heights, NJ 07604

07-R-09/2017

13009858

Spl medguide

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs"
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?"
new or worse high blood pressure
heart failure
liver problems including liver failure
kidney problems including kidney failure
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include:stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat

Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:
Nausea
more tired or weaker than usual
diarrhea
itching
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms, legs, hands and feet

If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs:
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.
Additional Medication Guides can be obtained by calling Unichem at 1-866-562-4616.
The other trademarks referenced are owned by third parties not affiliated with Unichem Laboratories Limited
Manufactured by:
UNICHEM LABORATORIES LTD.
Pilerne Ind. Estate,
Pilerne, Bardez, Goa 403511, India
Manufactured for:
meloxicam
Hasbrouck Heights, NJ 07604
06-R-09/2017
13009858

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: September 2017

Ingredients and appearance - Product information

Meloxicam tablet- Meloxicam

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 63629-7966
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Meloxicam ( UNII: VG2QF83CGL)( Meloxicam - UNII: VG2QF83CGL ) 15 mgin 1

Inactive Ingredients

Ingredient Name Code
Microcrystalline cellulose ( UNII: OP1R32D61U)
Crospovidone, unspecified ( UNII: 2S7830E561)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Povidone k30 ( UNII: U725QWY32X)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Trisodium citrate dihydrate ( UNII: B22547B95K)

Product Characteristics

Color YELLOW Shape OVAL
Size 12 mm Score 1
Imprint Code U;L;15

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 63629-7966-1 20 in 1 BOTTLE 2019/03/13
2 NDC: 63629-7966-2 30 in 1 BOTTLE 2019/03/13
3 NDC: 63629-7966-3 90 in 1 BOTTLE 2019/03/13

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA077927 USA 2019/03/13

Labeler - Bryant Ranch Prepack( 171714327)

Establishment

Name ID/FEI Business Operations
Bryant Ranch Prepack 171714327 REPACK( 63629-7966), RELABEL( 63629-7966)

Meloxicam 15mg tablet

The parameter values in the table are from various studies
not under high fat conditions
Meloxicam tablets
VZ/f =Dose/(AUCKel)