WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS

6 ADVERSE REACTIONS

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.

The following serious adverse reactions are discussed elsewhere in the labeling:

•Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.1)]

•Gastrointestinal effects – risk of GI ulceration, bleeding and perforation [see Boxed Warning and Warnings and Precautions (5.2)]

•Hepatic effects [see Warnings and Precautions (5.3)]

•Hypertension [see Warnings and Precautions (5.4)]

•Congestive heart failure and edema [see Warnings and Precautions (5.5)]

•Renal effects [see Warnings and Precautions (5.6)]

•Anaphylactoid reactions [see Warnings and Precautions (5.7)]

•Adverse skin reactions [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Adults

Osteoarthritis and Rheumatoid Arthritis

The Meloxicam Tablets USP Phase 2/3 clinical trial database includes 10,122 OA patients and 1,012 RA patients treated with Meloxicam Tablets USP 7.5 mg/day, 3,505 OA patients and 1,351 RA patients treated with Meloxicam Tablets USP 15 mg/day. Meloxicam Tablets USP at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2,363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across Meloxicam Tablets USP trials.

A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of Meloxicam Tablets USP with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of Meloxicam Tablets USP with placebo.

Table 1a depicts adverse events that occurred in ≥ 2% of the Meloxicam Tablets USP treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial.

Table 1b depicts adverse events that occurred in ≥ 2% of the Meloxicam Tablets USP treatment groups in two 12-week placebo-controlled rheumatoid arthritis trials.

The adverse events that occurred with meloxicam in ≥ 2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2.

Higher doses of Meloxicam Tablets USP (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of Meloxicam Tablets USP should not exceed 15 mg.

Pediatrics

Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis

(JRA)

Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to meloxicam with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with meloxicam were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (< 2%) patients receiving meloxicam. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect.

The following is a list of adverse drug reactions occurring in < 2% of patients receiving Meloxicam Tablets USP in clinical trials involving approximately 16,200 patients.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Meloxicam Tablets USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post- marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson Syndrome and toxic epidermal necrolysis.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

7.5 mg: pastel yellow, round, uncoated, debossed tablets with ‘B404’ on one side and plain on the other side.

15 mg: pastel yellow, capsule-shaped, uncoated, debossed tablets with‘B419’ on one side and plain on the other side.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C; Category D Starting 30 Weeks Gestation

There are no adequate and well controlled studies in pregnant women. Meloxicam crosses the placental barrier. Prior to 30 weeks gestation, use Meloxicam Tablets USP during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, avoid meloxicam and other NSAIDs, in pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, inform the patient of the potential hazard to a fetus [see Warnings and Precautions (5.9) and Patient Counseling Information (17.8)].

Teratogenic Effects

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 maximum recommended human daily dose [MRHD] 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. The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).

Nonteratogenic Effects

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.

8.2 Labor and Delivery

The effects of Meloxicam Tablets USP on labor and delivery of pregnant women are unknown. 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 (at least 12.5 times lower than the maximum recommended human daily dose based on body surface area comparison).

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk; however, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Meloxicam Tablets USP, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

As with any NSAID, caution should be exercised in treating the elderly (65 years and older).

Of the total number of subjects in clinical studies, 5,157 were age 65 and over (4,044 in OA studies and 1,113 in RA studies). 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. Since meloxicam is significantly metabolized in the liver; the use of meloxicam in these patients should be done with caution [see Warnings and Precautions (5.3) and 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 Meloxicam Tablets USP 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). Therefore, it is recommended that meloxicam dosage in this population not exceed 7.5 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 Dosage and Administration (2.1), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

8.8 Females of Reproductive Potential

Data from several small studies in humans and from studies in animals indicate that NSAIDs, including Meloxicam Tablets USP, may be associated with a reversible delay in ovulation. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, use of meloxicam is not recommended.

10 OVERDOSAGE

There is limited experience with meloxicam overdose. Four cases have taken 6 to 11 times the highest recommended dose; all recovered. Cholestyramine is known to accelerate the clearance of meloxicam.

Symptoms following acute NSAID overdose include lethargy, drowsiness, nausea, vomiting and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed with symptomatic and supportive care following an NSAID overdose. Administration of activated charcoal is recommended for patients who present 1 to 2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given 3 times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdose. Forced diuresis, alkalinization of urine, hemodialysis or hemoperfusion may not be useful due to high protein binding.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Meloxicam Tablets USP are available as 7.5 mg pastel yellow, round, uncoated, debossed tablets with ‘B404’ on one side and plain on the other side, and as 15 mg pastel yellow, capsule-shaped, uncoated, debossed tablets with‘B419’ on one side and plain on the other side.

Meloxicam Tablets USP 7.5 mg:
NDC 62250-675-30; Bottles of 30
NDC 62250-675-10; Bottles of 100
NDC 62250-675-03; Bottles of 1000

Meloxicam Tablets USP 15 mg:
NDC 62250-676-30; Bottles of 30
NDC 62250-676-10; Bottles of 100
NDC 62250-676-03; Bottles of 1000

Storage
Store at 25°C (77°F); excursions permitted to 15°C -30°C (59°F -86°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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

**Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. **

17.1 Medication Guide

Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using Meloxicam Tablets USP.

17.1 Medication Guide

Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using Meloxicam Tablets USP.

17.2 Cardiovascular Effects

NSAIDs including Meloxicam Tablets USP may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1)].

17.3 Gastrointestinal Effects

NSAIDs including Meloxicam Tablets USP, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena and hematemesis. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.2)].

17.4 Hepatotoxicity

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

17.5 Adverse Skin Reactions

NSAIDs including Meloxicam Tablets USP, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible [see Warnings and Precautions (5.8)].

17.6 Weight Gain and Edema

Advise patients to promptly report signs or symptoms of unexplained weight gain or edema to their physicians [see Warnings and Precautions (5.5)].

17.7 Anaphylactoid Reactions

Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients seek immediate emergency help [see Warnings and Precautions (5.7)].

17.8 Effects During Pregnancy

Starting at 30 weeks gestation, Meloxicam Tablets USP should be avoided as premature closure of the ductus arteriosus in the fetus may occur [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)].

17.9 Effects On Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Meloxicam Tablets USP, may be associated with a reversible delay in ovulation For women who have difficulties conceiving, or who are undergoing investigation of infertility, use of meloxicam is not recommended [see Use in Specific Populations 8.8)].

Please address medical inquiries to 1-727-471-0850.
Manufactured by:
CSPC OUYI PHARMACEUTICAL CO., LTD.
Shijiazhuang Hebei, China.
Distributed by:
Belcher Pharmaceuticals, LLC
Largo, FL 33777, USA