Side Effects of Mobic (meloxicam)

Mobic(meloxicam) is anonsteroidal anti-inflammatory drug(NSAID) used to treat tenderness, swelling, andpaincaused by the inflammation ofosteoarthritis,rheumatoid arthritis, andjuvenile rheumatoid arthritisin patients 2 years of age or older.

Prostaglandins are chemicals that contribute to inflammation especially within joints, and it is the inflammation that leads to the common symptoms ofpain, tenderness, and swelling associated witharthritis.

Mobic blocks the enzymes that make prostaglandins (cyclooxygenase 1 and 2) and reduces the levels of prostaglandins. As a result, inflammation and its accompanying symptoms are reduced.

Common side effects of Mobic include

• stomach pain,
• nausea,
• vomiting,
• heartburn,
• diarrhea,
• constipation,
• gas,
• dizziness, and
• coldorflu symptoms.

Serious side effects of Mobic include

• skinrash,
• shortness of breath(even with mild exertion),
• swelling or rapidweight gain,
• stomach bleeding (bloody ortarry stools,coughing up bloodor vomit that looks like coffee grounds),
• liverproblems (nausea, upper stomach pain,itching, tired feeling,flu-like symptoms,loss of appetite,dark urine, clay-colored stools,jaundice(yellowing of the skin or eyes),
• lowred blood cells(pale skin, unusualtiredness,lightheadedness,cold handsandfeet), and
• kidney problems (little or no urination, swelling in your feet or ankles, feeling tired or short of breath).

Drug interactionsof Mobic includelithium, because Mobic may increase the blood levels of lithium by reducing the excretion of lithium by the kidneys, which may lead to lithium toxicity.

• Mobic may reduce the官网地址bwin-lowering effects ofdrugsgiven to reduce blood pressure.
• When Mobic is used in combination withmethotrexateor aminoglycosides the blood levels of the Mobic or aminoglycoside may increase, presumably because their elimination from the body is reduced.
• This may lead to more Mobic or aminoglycoside-related side effects. Mobic increases the negative effect ofcyclosporineon kidney function and reduces the effect offurosemideandthiazide diureticsbecause of prostaglandin inhibition. Individuals taking oral blood thinners, for example,warfarin, should avoid Mobic because Mobic also thins the blood, and excessive blood thinning may lead to bleeding.
• Mobic should be avoided by patients with a history ofasthmaattacks,hives, or otherallergicreactions toaspirinor otherNSAIDs.
• If aspirin is taken with Mobic there may be an increased risk for developing a gastrointestinal ulcer.
• Persons who have more than three alcoholicbeveragesper day may be at increased risk of developing stomach ulcers when taking Mobic or other NSAIDs.
• Cholestyramine,colestipol, andcolesevelammay decrease the effectiveness of Mobic by preventing its absorption from the intestine. There have been no studies of Mobic in preg

Because Mobic may cause a fetal birth defect called ductus arteriosus (early closure of two major blood vessels of theheartand lung) it should be avoided duringpregnancy.

It is unknown if Mobic is excreted inbreast milk. Consult your doctor beforebreastfeeding.

WARNING

• Individuals who are allergic to NSAIDs may experience shortness of breath when given an NSAID. People withasthmaalso are at a higher risk for experiencing seriousallergic reactionto NSAIDs. Individuals with a seriousallergyto one NSAID are likely to experience a similar reaction to a different NSAID.
• New onset or worsening ofhigh blood pressure(hypertension) may occur. Blood pressure should be monitored closely during treatment.
• Meloxicam may cause fluid retention and swelling (edema). It should be used cautiously in people withheart failure.
• Meloxicam may reduce kidney function. Therefore, it should not be used in people with severekidney failure. It should be used cautiously in the elderly, people with heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists.
• Serious skin reactions such as exfoliativedermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis (TEN) may occur without warning.
• NSAIDs (except low dose aspirin) may increase the risk of potentially fatalheart attacks,stroke, and related conditions in people with or withoutheart diseaseor risk factors forheart disease. The increased risk ofheart attackorstrokemay occur as early as the first week of use and the risk may increase with longer use and is higher in patients who have underlying risk factors for heart and blood vessel disease. Therefore, NSAIDs should not be used for the treatment of pain resulting fromcoronary artery bypass graft(CABG) surgery.
• Central nervous system effects including drowsiness,dizziness, andblurred visionmay occur in patients who are taking an NSAIDs.

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

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration, and Perforation
• Hepatotoxicity
• Hypertension
• 心Failure and Edema
• Renal Toxicity andHyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Clinical Trials Experience

Becauseclinical trials在不同条件下进行,阿erse 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 Mobic Phase 2/3 clinical trial database includes 10,122 OA patients and 1012RApatients treated with Mobic 7.5 mg/day, 3505 OA patients and 1351RApatients treated with Mobic 15 mg/day. Mobic at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year.

大约10500个patients were treated in ten placebo- and/or activecontrolledosteoarthritistrials and 2363 of these patients were treated in ten placebo- and/or activecontrolledrheumatoid arthritistrials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across Mobic 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 Mobic with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients withrheumatoid arthritisto compare the efficacy and safety of Mobic with placebo.

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

Table 1b depicts adverse events that occurred in ≥ 2% of the Mobic treatment groups in two 12-week placebo-controlledrheumatoid arthritistrials.

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

	Placebo	Mobic 7.5 mg daily	Mobic 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
1WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2WHO preferred terms rash, rash erythematous, and rash maculo-papular combined

Table 1b : Adverse Events (%) Occurring in ≥ 2% of Mobic Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials

	Placebo	Mobic 7.5 mg daily	Mobic 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
1MedDRA 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) 2MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS

The adverse events that occurred with Mobic 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 Mobic Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials

	4 to 6 Weeks Controlled Trials		6 Month Controlled Trials
	Mobic 7.5 mg daily	Mobic 15 mg daily	Mobic 7.5 mg daily	Mobic 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
背部疼痛	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
Pruritiis	0.4	1.2	2.4	0.0
Rash2	0.3	1.2	3.0	1.3
Urinary
Mictiirition frequency	0.1	0.4	2.4	1.3
Urinary tract infection	0.3	0.4	4.7	6.9
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
背部疼痛	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
Pruritiis	0.4	1.2	2.4	0.0
Rash2	0.3	1.2	3.0	1.3
Urinary
Mictiirition frequency	0.1	0.4	2.4	1.3
Urinary tract infection	0.3	0.4	4.7	6.9
1WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2WHO preferred terms rash, rash erythematous, and rash maculo-papular combined

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

Pediatrics

Pauciarticular And Polyarticular Course Juvenile Rheumatoid Arthritis (JRA)

Three hundred and eighty-seven patients with pauciarticular and polyarticular courseJRAwere exposed to Mobic 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 Mobic 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.

Rashwas reported in seven ( < 2%) patients receiving Mobic. 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 Mobic 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
心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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Mobic. 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:

• acuteurinary retention;
• agranulocytosis;
• alterations in mood (such as mood elevation);
• anaphylactoid reactions includingshock;
• erythema multiforme;
• exfoliative dermatitis;
• interstitial nephritis;
• jaundice;
• liver failure;
• Stevens-Johnson syndrome;
• toxic epidermal necrolysis, and
• infertilityfemale.

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 Mobic 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.
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.
Intervention:	Concomitant use of Mobic and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding. Mobic is not a substitute for low dose aspirin for cardiovascular protection
ACE Inhibitors, Angiotensin Receptor Blockers, or 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 Mobic and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Mobic and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
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. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam
Intervention:	During concomitant use of Mobic with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of Mobic and lithium, monitor patients for signs of lithium to xicity.
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 Mobic and methotrexate, monitor patients for methotrexate to xicity.
Cyclosporine
Clinical Impact:	Concomitant use of Mobic and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of Mobic 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.
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of Mobic and pemetrexed may increase the risk of pemetrexed-associated myelosuppression renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of Mobic and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.