2.1 Dosage

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.

In patients on hemodialysis, the maximum daily dosage is 5 mg [see Warnings and Precautions (5.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

2.2 Non-Interchangeability with Other Formulations of Meloxicam

VIVLODEX capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, VIVLODEX capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products [see Clinical Pharmacology (12.3)].

5.1 Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of VIVLODEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VIVLODEX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including meloxicam, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with VIVLODEX. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIVLODEX until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)].

5.3 Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIVLODEX immediately, and perform a clinical evaluation of the patient.

5.4 Hypertension

NSAIDs, including VIVLODEX, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

5.5 Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of VIVLODEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIVLODEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6 Renal Toxicity and Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of VIVLODEX in patients with advanced renal disease. The renal effects of VIVLODEX may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating VIVLODEX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIVLODEX [see Drug Interactions (7)]. Avoid the use of VIVLODEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If VIVLODEX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.7 Anaphylactic Reactions

Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4), Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIVLODEX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When VIVLODEX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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 VIVLODEX at the first appearance of skin rash or any other sign of hypersensitivity. VIVLODEX is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as VIVLODEX. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue VIVLODEX and evaluate the patient immediately.

5.11 Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDS, including VIVLODEX, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including VIVLODEX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including VIVLODEX, at about 20 weeks gestation or later in pregnancy may cause 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.

Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit VIVLODEX use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic fluid if VIVLODEX treatment extends beyond 48 hours. Discontinue VIVLODEX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

5.12 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with VIVLODEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including VIVLODEX, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

5.13 Masking of Inflammation and Fever

The pharmacological activity of VIVLODEX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Patients with Osteoarthritis Pain

Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 – 87 years, were enrolled in two Phase 3 clinical trials and received VIVLODEX 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older.

Two hundred sixty-nine (269) patients received VIVLODEX 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1.

Six hundred (600) patients received VIVLODEX 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2.

Additional adverse reactions reported for meloxicam:

8.1 Pregnancy

Risk Summary

Use of NSAIDs, including VIVLODEX, 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 VIVLODEX use between about 20 and 30 weeks of gestation, and avoid VIVLODEX use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

     Premature Closure of Fetal Ductus Arteriosus

     Use of NSAIDs, including VIVLODEX, 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 other 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 1- and 10-times, respectively, the maximum recommended daily dose (MRDD) of VIVLODEX. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre- and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of VIVLODEX. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9- times the MRDD [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. 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.

Clinical Considerations

 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 VIVLODEX, can cause premature closure of the fetal
     ductus arteriosus (see Data).

     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 VIVLODEX
     treatment extends beyond 48 hours, consider monitoring with ultrasound for
     oligohydramnios. If oligohydramnios occurs, discontinue VIVLODEX and follow
     up according to clinical practice (see Data).

Labor or Delivery

     There are no studies on the effects of VIVLODEX 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.

Animal data
     Meloxicam was not teratogenic when administered to pregnant rats during fetal
     organogenesis at oral doses up to 4 mg/kg/day (3.9-times the maximum recommended
     daily dose (MRDD) of 10 mg of VIVLODEX based on body surface area [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 (116-times the MRDD based on BSA comparison). The no
     effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In
     rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day
     and 5 mg/kg/day, respectively (1- and 10-times the MRDD 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 (0.12-times the
     MRDD 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 VIVLODEX and any potential adverse effects on the breastfed infant from the VIVLODEX or from the underlying maternal condition.

Data

Animal data

Meloxicam was excreted 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 VIVLODEX, 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 VIVLODEX, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

The safety and effectiveness of VIVLODEX in pediatric patients has not been established.

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)]. Of the total number of patients in clinical studies of VIVLODEX, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use VIVLODEX in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If VIVLODEX is used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended. In a previous study, the free Cmax plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum VIVLODEX dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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

The mechanism of action of VIVLODEX, 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

The relative bioavailability of VIVLODEX 10 mg capsules compared to meloxicam 15 mg tablets was assessed in 28 healthy subjects under fasted and fed conditions in a single-dose crossover study.

VIVLODEX 10 mg capsules do not result in an equivalent systemic exposure compared to 15 mg meloxicam tablets. When taken under fasted conditions, a 33% lower dose of meloxicam in VIVLODEX 10 mg capsules resulted in a 33% lower overall systemic exposure (AUCinf) and a comparable mean peak plasma concentration (Cmax) to meloxicam 15 mg tablets. The median time to maximum plasma concentration (Tmax) occurred earlier for VIVLODEX capsules (2 hours for both 5 mg and 10 mg) than for meloxicam tablets (4 hours for 15 mg).

Absorption

Single oral doses of VIVLODEX 5 mg and 10 mg were associated with dose-proportional pharmacokinetics. Mean Cmax was achieved within 2 hours post-dose for both VIVLODEX 5 mg and 10 mg capsules when taken under fasted conditions. A second meloxicam concentration peak occurs around 8 hours post-dose.

Taking VIVLODEX with food causes a decrease in the rate but not the overall extent of systemic meloxicam absorption compared with taking VIVLODEX on an empty stomach. VIVLODEX capsules administered under fed conditions results in 22% lower mean Cmax and a 3 hour delay in median Tmax (5 hours for fed versus 2 hours for fasted) compared to the fasted condition. Significant changes in AUCinf were not observed. VIVLODEX can be administered without regard to timing of meals.

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 vitro studies 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 vivo pharmacological 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) for VIVLODEX 5 mg and 10 mg is approximately 22 hours.

Specific Populations

Pediatric: The pharmacokinetics of VIVLODEX have not been investigated in pediatric patients.

Hepatic Impairment: 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 [see Warnings and Precautions (5.3), 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 VIVLODEX in subjects with severe renal impairment is not recommended.

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 Warnings and Precautions (5.6), 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. The clinical significance of this interaction is not known. See Table 3 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 t1/2, 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 tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [see Drug Interactions (7)].

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 tablets 15 mg once per day every day as compared to subjects receiving lithium alone [see Drug Interactions (7)].

Methotrexate: A previous 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 tablets 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 VIVLODEX 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)].

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.8- and 3.9-times, respectively, the maximum recommended daily dose (MRDD) of 10 mg of VIVLODEX based on body surface area (BSA) comparison).

Mutagenesis

Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.

Impairment of Fertility

In previous studies of meloxicam, there was no impairment of male or female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 8.7 and 4.8-times, respectively, the MRDD based on BSA comparison).

14.1 Osteoarthritis Pain

The efficacy of VIVLODEX in the management of osteoarthritis pain was demonstrated in a randomized, double-blind, multicenter, parallel-arm, placebo-controlled study comparing VIVLODEX 5 mg or 10 mg taken once daily and placebo in patients with pain due to osteoarthritis of the knee or hip. The study evaluated 402 patients with a mean age of 61 (range 40 to 87 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain Subscale. The mean baseline WOMAC Pain Subscale Score across treatment groups was 73 mm using a 0 to 100 mm visual analog scale.

The primary efficacy endpoint was the change from baseline to Week 12 in the WOMAC Pain Subscale Score. VIVLODEX 5 mg and 10 mg once daily significantly reduced osteoarthritis pain compared with placebo, as measured by changes in WOMAC Pain Subscale Scores. Although both the 5 mg and 10 mg doses significantly reduced pain compared to placebo, the proportion of responders achieving various percentage reductions in pain intensity from baseline to Week 12 is similar for both the 5 mg and 10 mg once daily doses. The proportion (%) of patients in each group who demonstrated reduction in their pain intensity score from baseline to Week 12 is shown in Figure 1. The figure is cumulative, so patients whose change from baseline is, for example, 30%, are also included in every level of pain reduction below 30%. Patients who did not complete the study were classified as non-responders.

Figure 1 Proportion (%) of Patients Achieving Various Percentage Reductions in Pain Intensity from Baseline to Week 12