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Prescribing Information
Cardiovascular Risk
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MOBIC® (meloxicam), an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each pastel yellow tablet contains 7.5 mg or 15 mg meloxicam for oral administration. Each bottle of oral suspension contains 7.5 mg meloxicam per 5 mL. Meloxicam is chemically designated as 4-hydroxy-2-methyl- N -(5-methyl-2-thiazolyl)-2 H -1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C 14 H 13 N 3 O 4 S 2 and it has the following structural formula.
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Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P) app = 0.1 in n -octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.
MOBIC is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam, and as an oral suspension containing 7.5 mg meloxicam per 5 mL.
The inactive ingredients in MOBIC tablets include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium citrate dihydrate.
The inactive ingredients in MOBIC oral suspension include colloidal silicon dioxide, hydroxyethylcellulose, sorbitol, glycerol, xylitol, monobasic sodium phosphate (dihydrate), saccharin sodium, sodium benzoate, citric acid (monohydrate), raspberry flavor, and purified water.
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclooxygenase) inhibition.
The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Meloxicam capsules have been shown to be bioequivalent to MOBIC tablets. Following single intravenous doses, dose- proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean C max was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. The rate or extent of absorption was not affected by multiple dose administration, suggesting linear pharmacokinetics. With multiple dosing, steady state conditions were reached by day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting gastrointestinal recirculation.
Meloxicam oral suspension doses of 7.5 mg/5 mL and 15 mg/10 mL have been found to be bioequivalent to meloxicam 7.5 mg and 15 mg capsules, respectively.
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Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., C max ) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (T max ) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the C max values for meloxicam suspension were affected following a similar high fat meal, while mean T max values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, MOBIC can be administered without regard to timing of meals or concomitant administration of antacids.
The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~ 99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~ 99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.
Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.
Meloxicam is almost completely metabolized to four pharmacologically inactive metabolites. The major metabolite, 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism was formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that cytochrome P-450 2C9 plays an important role in this metabolic pathway with a minor contribution of the CYP 3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively.
Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6% and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.
The mean elimination half-life (t 1/2 ) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.
The pharmacokinetics of MOBIC in pediatric patients under 18 years of age have not been investigated.
Elderly males (>/=65 years of age) exhibited meloxicam plasma concentrations and steady state pharmacokinetics similar to young males. Elderly females (>/=65 years of age) had a 47% higher AUC ss and 32% higher C max ss as compared to younger females (</=55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.
Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg MOBIC, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the C max or T max across genders.
Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. No dose adjustment is necessary in mild to moderate hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.
Meloxicam pharmacokinetics have been investigated in subjects with different degrees of renal insufficiency. Total drug plasma concentrations decreased with the degree of renal impairment while free AUC values were similar. Total clearance of meloxicam increased in these patients probably due to the increase in free fraction leading to an increased metabolic clearance. There is no need for dose adjustment in patients with mild to moderate renal failure (CrCL >15 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of MOBIC in subjects with severe renal impairment is not recommended (see WARNINGS , Advanced Renal Disease ).
Following a single dose of meloxicam, the free C max plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
The use of MOBIC for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a double-blind controlled trial in the U.S. involving 464 patients treated with MOBIC for 12 weeks. MOBIC (3.75 mg, 7.5 mg and 15 mg daily) was compared to placebo. The four primary endpoints were investigator's global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function and stiffness). Patients on MOBIC 7.5 mg daily and MOBIC 15 mg daily showed significant improvement in each of these endpoints compared with placebo.
The use of MOBIC for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. in which a total of 9589 patients were treated for 4 weeks to 6 months. In these trials, the efficacy of MOBIC, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial.
The use of MOBIC for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a double-blind, controlled multinational trial involving 1184 patients treated with MOBIC for 12 weeks. MOBIC (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory and functional measures of RA response. Patients receiving MOBIC 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose.
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.
Carefully consider the potential benefits and risks of MOBIC and other treatment options before deciding to use MOBIC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
MOBIC is indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
MOBIC is contraindicated in patients with known hypersensitivity to meloxicam.
MOBIC should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS , Anaphylactoid Reactions , and PRECAUTIONS , Pre-existing Asthma ).
MOBIC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS , Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation ).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS ).
NSAIDs, including MOBIC, can lead to onset of new hypertension or worsening of pre-xisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including MOBIC, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Fluid retention and edema have been observed in some patients taking NSAIDs. MOBIC should be used with caution in patients with fluid retention, hypertension, or heart failure.
NSAIDs, including MOBIC, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs, occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of MOBIC in patients with advanced renal disease. Therefore, treatment with MOBIC is not recommended in these patients with advanced renal disease. If MOBIC therapy must be initiated, close monitoring of the patient's renal function is advisable.
As with other NSAIDS, anaphylactoid reactions may occur in patients without known prior exposure to MOBIC. MOBIC should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS , Pre-existing Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
NSAIDs, including MOBIC, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, MOBIC should be avoided because it may cause premature closure of the ductus arteriosus.
MOBIC cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of MOBIC in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including MOBIC. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with MOBIC. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosin-ophilia, rash, etc.), MOBIC should be discontinued.
Caution should be used when initiating treatment with MOBIC in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with MOBIC. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS , Renal Effects and Advanced Renal Disease ).
The extent to which metabolites may accumulate in patients with renal failure has not been studied with MOBIC. Because some MOBIC metabolites are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.
Anemia is sometimes seen in patients receiving NSAIDs, including MOBIC. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including MOBIC, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
Drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving MOBIC who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, MOBIC should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, MOBIC should be discontinued.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
When MOBIC is administered with aspirin (1000 mg TID) to healthy volunteers it tended to increase the AUC (10%) and C max (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects.
Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis.
Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.
Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam.
Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after (beta)-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.
Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. 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. Nevertheless, during concomitant therapy with MOBIC, patients should be observed closely for signs of declining renal failure (see WARNINGS , Renal Effects ), as well as to assure diuretic efficacy.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced, adjusted, or withdrawn.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
No carcinogenic effect of meloxicam was observed in rats given oral doses up to 0.8 mg/kg/day (approximately 0.4-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) for 104 weeks or in mice given oral doses up to 8.0 mg/kg/day (approximately 2.2-fold the human dose, as noted above) for 99 weeks.
Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
Meloxicam did not impair male and female fertility in rats at oral doses up to 9 and 5 mg/kg/day, respectively (4.9-fold and 2.5-fold the human dose, as noted above). However, an increased incidence of embryolethality at oral doses >/=1 mg/kg/day (0.5-fold the human dose, as noted above) was observed in rats when dams were given meloxicam 2 weeks prior to mating and during early embryonic development.
Meloxicam caused an increased incidence of septal defect of the heart, a rare event, at an oral dose of 60 mg/kg/day (64.5-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) and embryolethality at oral doses >/=5 mg/kg/day (5.4-fold the human dose, as noted above) when rabbits were treated throughout organogenesis. Meloxicam was not teratogenic in rats up to an oral dose of 4 mg/kg/day (approximately 2.2-fold the human dose, as noted above) throughout organogenesis. An increased incidence of stillbirths was observed when rats were given oral doses >/=1 mg/kg/day throughout organogenesis. Meloxicam crosses the placental barrier.
However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. MOBIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Meloxicam caused a reduction in birth index, live births, and neonatal survival at oral doses >/=0.125 mg/kg/day (approximately 0.07-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) when rats were treated during the late gestation and lactation period. No studies have been conducted to evaluate the effect of meloxicam on the closure of the ductus arteriosus in humans; use of meloxicam during the third trimester of pregnancy should be avoided.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred.
Studies in rats with meloxicam showed an increased incidence of stillbirths, prolonged delivery, and delayed parturition at oral dosages >/=1 mg/kg/day (approximately 0.5-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion), and decreased pup survival at an oral dose of 4 mg/kg/day (approximately 2.1-fold the human dose, as noted above) throughout organogenesis. Similar findings were observed in rats receiving oral dosages >/=0.125 mg/kg/day (approximately 0.07-fold the human dose, as noted above) during late gestation and the lactation period.
The effects of MOBIC on labor and delivery in pregnant women are unknown.
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 MOBIC, 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.
Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
As with any NSAIDs caution should be exercised in treating the elderly (65 years and older).
The MOBIC phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with MOBIC 7.5 mg/day, 3,505 OA patients and 1351 RA patients 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. 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 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 with rheumatoid arthritis to compare the efficacy and safety of MOBIC with placebo.
Table 2a depicts adverse events that occurred in >/=2% of the MOBIC treatment groups in a 12-week placebo and active-controlled osteoarthritis trial.
Table 2b depicts adverse events that occurred in >/=2% of the MOBIC treatment groups in two 12-week placebo controlled rheumatoid arthritis trials.
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The adverse events that occurred with MOBIC in >/=2% of patients treated short-term (4-6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 3.
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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.
The following is a list of adverse drug reactions occurring in <2% of patients receiving MOBIC in clinical trials involving approximately 16,200 patients. Adverse reactions reported only in worldwide post-marketing experience or the literature are shown in italics and are considered rare (<0.1%).
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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 are usually limited to 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. In cases of acute overdose, gastric lavage followed by activated charcoal is recommended. Gastric lavage performed more than one hour after overdose has little benefit in the treatment of overdose. Administration of activated charcoal is recommended for patients who present 1-2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of meloxicam by 4 gm oral doses of cholestyramine given three 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.
Carefully consider the potential benefits and risks of MOBIC and other treatment options before deciding to use MOBIC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
After observing the response to initial therapy with MOBIC, the dose should be adjusted to suit an individual patient's needs.
For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of MOBIC is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of MOBIC is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. The maximum recommended daily oral dose of MOBIC is 15 mg regardless of formulation.
MOBIC oral suspension 7.5 mg/5 mL or 15 mg/10 mL may be substituted for MOBIC tablets 7.5 mg or 15 mg, respectively.
Shake the oral suspension gently before using.
MOBIC may be taken without regard to timing of meals.
MOBIC is available as a pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg or as a pastel yellow, oblong, biconvex, uncoated tablet containing meloxicam 15 mg. The 7.5 mg tablet is impressed with the Boehringer Ingelheim logo on one side, and on the other side, the letter "M". The 15 mg tablet is impressed with the tablet code "15" on one side and the letter "M" on the other. MOBIC is also available as a yellowish green tinged viscous oral suspension containing 7.5 mg meloxicam in 5 mL.
MOBIC Tablets 7.5 mg is available as follows:
NDC 0597-0029-01; Bottles of 100
MOBIC Tablets 15 mg is available as follows:
NDC 0597-0030-01; Bottles of 100
MOBIC Oral Suspension 7.5mg/5mL is available as follows:
NDC 0597-0034-01; Bottles of 100 mL
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Keep MOBIC tablets in a dry place.
Dispense tablets in a tight container. Keep oral suspension container tightly closed.
Keep this and all medications out of the reach of children.
Mobic Tablets 7.5 mg and 15 mg are manufactured by:
Boehringer Ingelheim Pharma GmbH & Co. KG
Ingelheim, Germany
and
Boehringer Ingelheim Promeco
S.A. de C.V., Mexico City, Mexico
Mobic Oral Suspension 7.5 mg/5mL is manufactured by:
Boehringer Ingelheim Roxane, Inc.
Columbus, OH 43216 USA
Marketed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
©Copyright Boehringer Ingelheim International GmbH
2005, ALL RIGHTS RESERVED
U.S. Patent No. 6,184,220 covers the Meloxicam Oral Suspension product.
Revised July15, 2005
OT1400
ATTENTION DISPENSER:
Accompanying Medication Guide must be dispensed with this product.
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MOBIC® (mo'-bik) Tablets
MOBIC® Oral Suspension
Generic name: meloxicam tablets and oral suspension
Medication Guide for Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines).
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:
NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:
NSAID medicines should only be used:
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
Do not take an NSAID medicine:
Tell your healthcare provider:
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These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
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All registered trademarks in this document are the property of their respective owners.
Please address medical inquiries to http://us.boehringer-ingelheim.com , (800) 542-6257 or (800) 459-9906 TTY.
Mobic Tablets 7.5 mg and 15 mg are manufactured by:
Boehringer Ingelheim Pharma GmbH & Co. KG
Ingelheim, Germany
and
Boehringer Ingelheim Promeco
S.A. de C.V., Mexico City, Mexico
Mobic Oral Suspension 7.5 mg/5mL is manufactured by:
Boehringer Ingelheim Roxane, Inc.
Columbus, OH 43216 USA
Marketed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
©Copyright Boehringer Ingelheim Pharmaceuticals, Inc.
2005, ALL RIGHTS RESERVED
U.S. Patent No. 6,184,220 covers the Meloxicam Oral Suspension product.
Revised: July 15, 2005
OT1400
This Medication Guide has been approved by the US Food and Drug Administration