MELOXICAM (Page 3 of 8)

​ 5.11 Fetal Toxicity

​ Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including meloxicam, in pregnant women at about 30 weeks gestation and later. NSAIDs, including meloxicam, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including meloxicam, 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 meloxicam use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam treatment extends beyond 48 hours. Discontinue meloxicam 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 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) ].

5.13 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.

5.14 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 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) ]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10) ]
• Fetal Toxicity [see Warnings and Precautions (5.11) ]
• Hematologic Toxicity [see Warnings and Precautions (5.12) ]

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
Edema1	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
Rash2	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 NOS2	0.6	2.9	2.3
Dyspeptic signs and symptoms1	3.8	5.8	4.0
Nausea2	2.6	3.3	3.8
General Disorders and Administration Site Conditions
Influenza-like illness2	2.1	2.9	2.3
Infection and Infestations
Upper respiratory tract infections-pathogen class unspecified1	4.1	7.0	6.5
Musculoskeletal and Connective Tissue Disorders
Joint related signs and symptoms1	1.9	1.5	2.3
Nervous System Disorders
Headaches NOS2	6.4	6.4	5.5
Skin and Subcutaneous Tissue Disorders
Rash NOS2	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
Edema1	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
Rash2	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