Meloxicam: Package Insert and Label Information (Page 2 of 4)

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 meloxicam capsules have any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including meloxicam, 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 meloxicam capsules 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 Warnings and Precautions (5.1) ]

• GI Bleeding, Ulceration and Perforation [see 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.

Adverse Reactions in Patients with Osteoarthritis Pain

Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 to 87 years, were enrolled in two Phase 3 clinical trials and received meloxicam capsules 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 meloxicam capsules 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.

Table 1 Summary of Adverse Reactions (≥2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain

Adverse Reactions	Meloxicam Capsules 5 mg or 10 mg N=269	Placebo N=133
Diarrhea	3%	1%
Nausea	2%	0
Abdominal Discomfort	2%	0

Six hundred (600) patients received meloxicam capsules 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.

Table 2 Summary of Adverse Reactions (≥2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain

Adverse Reactions	Meloxicam Capsules 10 mg N=600
Arthralgia	6%
Urinary Tract Infection	6%
Osteoarthritis	5%
Hypertension	4%
Diarrhea	4%
Headache	4%
Upper Respiratory Tract Infection	4%
Back Pain	4%
Nasopharyngitis	4%
Bronchitis	3%
Sinusitis	3%
Constipation	3%
Dyspepsia	3%
Nausea	2%
Edema Peripheral	2%
Pain in Extremity	2%
Additional adverse reactions reported for meloxicam:
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	agranulocytosis, leukopenia, purpura, thrombocytopenia
Immune System	anaphylactoid reactions (including shock)
Liver and Biliary System	ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure
Metabolic and Nutritional	dehydration
Psychiatric	abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence,
Respiratory	asthma, bronchospasm, dyspnea
Skin and Appendages	alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticaria
Special Senses	abnormal vision, conjunctivitis, taste perversion, tinnitus
Urinary System	albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure,

7 DRUG INTERACTIONS

See Table 3 for clinically significant drug interactions with meloxicam.

Table 3 Clinically Significant Drug Interactions with meloxicam

Drugs That Interfere with Hemostasis
Clinical Impact			Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:			Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:		Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.
Intervention:		Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact:		NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention		During concomitant use of meloxicam and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Digoxin
Clinical Impact	The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention	During concomitant use of meloxicam and digoxin, monitor serum digoxin levels
Methotrexate
Clinical Impact	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:		Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention		During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.