Trepoxicam-7.5 (Page 3 of 5)

7.1 ACE-inhibitors 7.2 Aspirin 7.4 Lithium 7.5 Methotrexate 7.7 Warfarin

7 DRUG INTERACTIONS See also Clinical Pharmacology ( 12.3).

7.1 ACE-inhibitors NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking MOBIC concomitantly with ACE-inhibitors.

7.2 Aspirin When MOBIC is administered with aspirin (1000 mg three times daily) to healthy volunteers, an increase in the AUC (10%) and Cmax (24%) of meloxicam was noted. 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.

7.3 Diuretics 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. 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. Nevertheless, during concomitant therapy with MOBIC, patients should be observed closely for signs of renal failure [see Warnings and Precautions (5.6)], as well as to ensure diuretic efficacy.

7.4 Lithium 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 twice daily with meloxicam 15 mg every day as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Closely monitor patients on lithium treatment for signs of lithium toxicity when MOBIC is introduced, adjusted, or withdrawn.

7.5 Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Therefore, NSAIDs may reduce the elimination of methotrexate, thereby enhancing the toxicity of methotrexate. Use caution when MOBIC is administered concomitantly with methotrexate [see Clinical Pharmacology (12.3)].

7.6 Cyclosporine MOBIC, like other NSAIDs, may affect renal prostaglandins, thereby altering the renal toxicity of certain drugs. Therefore, concomitant therapy with MOBIC may increase cyclosporine’s nephrotoxicity. Use caution when MOBIC is administered concomitantly with cyclosporine.

7.7 Warfarin 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. Monitor anticoagulant activity, 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 than with the use of either drug alone. Use caution 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 [see Clinical Pharmacology (12.3)].

8.1 Pregnancy 8.7 Renal Impairment

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Pregnancy Category C; Category D starting 30 weeks gestation There are no adequate and well-controlled studies in pregnant women. Meloxicam crosses the placental barrier. Prior to 30 weeks gestation, use MOBIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, avoid MOBIC and other NSAIDs, in pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, inform the patient of the potential hazard to a fetus [see Warnings and Precautions (5.9) and Patient Counseling Information (17.8)]. Teratogenic Effects Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the maximum recommended human daily dose [MRHD] based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day. The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion) . Nonteratogenic Effects In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65- and 6.5- fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis.

8.2 Labor and Delivery The effects of MOBIC on labor and delivery of pregnant women are unknown. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (at least 12.5 times lower than the maximum recommended human daily dose based on body surface area comparison).

8.3 Nursing Mothers

8.3 Nursing Mothers 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.

8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Studies (14.2)].

8.6 Hepatic Impairment 8.7 Renal Impairment

8.5 Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older). Of the total number of subjects in clinical studies, 5157 were age 65 and over (4044 in OA studies and 1113 in RA studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver; the use of meloxicam in these patients should be done with caution [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of MOBIC in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, it is recommended that meloxicam dosage in this population not exceed 7.5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Dosage and Administration (2.1), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

10 OVERDOSAGE 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 include 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. Administration of activated charcoal is recommended for patients who present 1 to 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. For additional information about overdose treatment, call a poison control center (1-800-222-1222).

11 DESCRIPTION Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each pastel yellow MOBIC tablet contains 7.5 mg or 15 mg meloxicam for oral administration. Each bottle of MOBIC oral suspension contains 7.5 mg meloxicam per 5 mL. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula:

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.

12.2 Pharmacodynamics Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic activities.