MELOXICAM (Page 3 of 8)

5.10 Premature Closure of Fetal Ductus Arteriosus

Meloxicam may cause 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 Use in Specific Population ( 8.1) ].

5.11 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 on erythropoiesis. If a patient treated with meloxicam has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including meloxicam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), 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) ].

5.12 Masking of Inflammation and Fever

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

5.13 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 ADVERSE REACTIONS

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

  • Cardiovascular Thrombotic Events [ see Boxed Warning and Warnings and Precautions ( 5.1) ]
  • GI Bleeding, Ulceration, and Perforation [ see Boxed Warning and 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) ]

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.

Adults

Osteoarthritis and Rheumatoid Arthritis

The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam 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 2363 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 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 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 with placebo.

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

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

Table 1a: Adverse Events (%) Occurring in ≥ 2% of Meloxicam Patients in a 12-Week Osteoarthritis Placebo- and Active-Controlled Trial

1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined

2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined

Placebo Meloxicam 7 . 5 mg daily Meloxicam 15 mg daily Diclofenac 100 mg daily
No . of Patients 157 154 156 153
Gastrointestinal 17.2 20.1 17.3 28.1
Abdominal pain 2.5 1.9 2.6 1.3
Diarrhea 3.8 7.8 3.2 9.2
Dyspepsia 4.5 4.5 4.5 6.5
Flatulence 4.5 3.2 3.2 3.9
Nausea 3.2 3.9 3.8 7.2
Body as a Whole
Accident household 1.9 4.5 3.2 2.6
Edema 1 2.5 1.9 4.5 3.3
Fall 0.6 2.6 0.0 1.3
Influenza-like symptoms 5.1 4.5 5.8 2.6
Central and Peripheral Nervous System
Dizziness 3.2 2.6 3.8 2.0
Headache 10.2 7.8 8.3 5.9
Respiratory
Pharyngitis 1.3 0.6 3.2 1.3
Upper respiratory tract infection 1.9 3.2 1.9 3.3
Skin
Rash 2 2.5 2.6 0.6 2.0
Table 1b: Adverse Events (%) Occurring in ≥ 2% of Meloxicam Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials

1 MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling)

2 MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS

Placebo Meloxicam Meloxicam
7 . 5 mg daily 15 mg daily
No . of Patients 469 481 477
Gastrointestinal Disorders 14.1 18.9 16.8
Abdominal pain NOS 2 0.6 2.9 2.3
Dyspeptic signs and symptoms 1 3.8 5.8 4.0
Nausea 2 2.6 3.3 3.8
General Disorders and Administration Site Conditions
Influenza-like illness 2 2.1 2.9 2.3
Infection and Infestations
Upper respiratory tract infections-pathogen class unspecified 1 4.1 7.0 6.5
Musculoskeletal and Connective Tissue Disorders
Joint related signs and symptoms 1 1.9 1.5 2.3
Nervous System Disorders
Headaches NOS 2 6.4 6.4 5.5
Skin and Subcutaneous Tissue Disorders
Rash NOS 2 1.7 1.0 2.1

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.

Table 2: Adverse Events (%) Occurring in ≥ 2% of Meloxicam Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials

1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined

2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined

4 to 6 Weeks Controlled Trials 6 Month Controlled Trials
Meloxicam 7 . 5 mg daily Meloxicam 15 mg daily Meloxicam 7 . 5 mg daily Meloxicam 15 mg daily
No . of Patients 8955 256 169 306
Gastrointestinal 11.8 18.0 26.6 24.2
Abdominal pain 2.7 2.3 4.7 2.9
Constipation 0.8 1.2 1.8 2.6
Diarrhea 1.9 2.7 5.9 2.6
Dyspepsia 3.8 7.4 8.9 9.5
Flatulence 0.5 0.4 3.0 2.6
Nausea 2.4 4.7 4.7 7.2
Vomiting 0.6 0.8 1.8 2.6
Body as a Whole
Accident household 0.0 0.0 0.6 2.9
Edema 1 0.6 2.0 2.4 1.6
Pain 0.9 2.0 3.6 5.2
Central and Peripheral Nervous System
Dizziness 1.1 1.6 2.4 2.6
Headache 2.4 2.7 3.6 2.6
Hematologic
Anemia 0.1 0.0 4.1 2.9
Musculoskeletal
Arthralgia 0.5 0.0 5.3 1.3
Back pain 0.5 0.4 3.0 0.7
Psychiatric
Insomnia 0.4 0.0 3.6 1.6
Respiratory
Coughing 0.2 0.8 2.4 1.0
Upper respiratory tract infection 0.2 0.0 8.3 7.5
Skin
Pruritus 0.4 1.2 2.4 0.0
Rash 2 0.3 1.2 3.0 1.3
Urinary
Micturition frequency 0.1 0.4 2.4 1.3
Urinary tract infection 0.3 0.4 4.7 6.9

Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of meloxicam 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 in clinical trials involving approximately 16,200 patients.

Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase
Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis
Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo
Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative
Heart Rate and Rhythm arrhythmia, palpitation, tachycardia
Hematologic leukopenia, purpura, thrombocytopenia
Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis
Metabolic and Nutritional dehydration
Psychiatric abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence
Respiratory asthma, bronchospasm, dyspnea
Skin and Appendages alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria
Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus
Urinary System albuminuria, BUN increased, creatinine increased, hematuria, renal failure

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