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AUSTRALIAN PRODUCT INFORMATION - MOBIC®^ (meloxicam) capsule and tablet blister pack 1 NAME OF THE MEDICINE meloxicam 2 QUALITATIVE AND QUANTITATIVE COMPOSITION MOBIC is available as tablets and capsules. Each MOBIC 7.5 mg tablet contains meloxicam 7.5 mg. Each MOBIC 15 mg tablet contains meloxicam 15 mg. Each MOBIC 7.5 mg capsule contains meloxicam 7.5 mg. Each MOBIC 15 mg capsule contains meloxicam 15 mg. Excipients with known effect: Each MOBIC 7.5 mg tablet contains 23.5 mg lactose monohydrate. Each MOBIC 15 mg tablet contains 20 mg lactose monohydrate. Each MOBIC 7.5 mg capsule contains 123 mg lactose monohydrate. Each MOBIC 15 mg capsule contains 112 mg lactose monohydrate. For the full list of excipients, see Section 6.1 List of excipients. 3 PHARMACEUTICAL FORM Tablets 7.5 mg: Pastel-yellow, round tablets, marked 59D on one side with break bar, and company logo on the other. Tablets 15 mg: Pastel-yellow, round tablets, marked 77C on one side with break bar, and company logo on the other. Capsules 7.5 mg: Oblong, hard gelatin capsule with pale green opaque cap and body, containing a fine yellow granulate. Capsules 15 mg: Oblong, hard gelatin capsule with pale green opaque cap and yellow opaque body, containing a fine yellow granulate. 4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS MOBIC tablets and capsules are indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. 4.2 DOSE AND METHOD OF ADMINISTRATION Dosage MOBIC should be used at the lowest dose and for the shortest duration consistent with effective treatment.
The maximum recommended daily dose of MOBIC is 15 mg. A dose of 15 mg/day should not be exceeded. As a dose for children has not been established, use should be restricted to adults (see Section 4.4 Special Warnings and Precautions for Use - Paediatric Use). The dose of MOBIC in patients with end-stage renal failure on haemodialysis should not exceed 7.5 mg/day (see Section 5.2 Pharmacokinetic Properties – Renal Impairment and Haemodialysis). No dose reduction is required in patients with mild or moderate renal impairment (i.e., in patients with a creatinine clearance of greater than 25 mL/min) nor in patients with mild to moderate hepatic impairment. In non-dialysed patients with severe renal impairment MOBIC is contraindicated (see Section 4.3 Contraindications). In patients with increased risks of adverse reactions, e.g. a history of gastrointestinal disease or risk factors for cardiovascular disease, the treatment should be started at a dose of 7.5 mg/day and increased to 15 mg/day only if clinically justified. Patients on long term treatment should be reviewed regularly with regards to efficacy, risk factors and ongoing need for treatment. Osteoarthritis The recommended dose of MOBIC is 7.5 mg once daily, to be swallowed with fluid, in conjunction with food. Depending on the adequacy of response, the severity of the arthritic condition and the patient’s concomitant diseases, the dose may be increased to 15 mg/day. Patients should generally be maintained on the lowest dose consistent with achieving a satisfactory therapeutic response. Rheumatoid Arthritis The recommended dose of MOBIC is 15 mg once daily, to be swallowed with fluid, in conjunction with food. Depending on the adequacy of response and the severity of the condition, the dose may be reduced to 7.5 mg/day. Patients should generally be maintained on the lowest dose consistent with achieving a satisfactory therapeutic response. Pregnancy See Section 4.3 Contraindications and Section 4.6 Fertility, pregnancy and lactation. Method of administration There is insufficient information on the effect of mixing crushed tablets or contents of a capsule with food or fluids. The MOBIC 7.5 mg tablet break mark should not be used to subdivide the tablet into fractions of a full dose e.g. 3.75 mg. MOBIC 7.5 mg tablets can only be subdivided for ease of swallowing. 4.3 CONTRAINDICATIONS
- Peri-operative treatment of pain in patients undergoing coronary artery bypass graft surgery (CABG)
- Known hypersensitivity to meloxicam or any excipients of the product. There is a potential for cross sensitivity to aspirin and other NSAIDs.
- Signs/symptoms of asthma, nasal polyps, angioedema or urticaria, following the administration of aspirin or other NSAIDs.
- Active gastrointestinal ulceration / perforation
- Active Inflammatory Bowel Disease (Crohn’s Disease or Ulcerative Colitis)
- Patients with severe hepatic impairment
- Non-dialysed severe renal insufficiency
- Severe uncontrolled heart failure
- Children and adolescents under 18 years of age
- Pregnancy
Co-administration of meloxicam with drugs known to inhibit CYP 3A4 should be undertaken with caution. A combination of meloxicam and substances known to inhibit both CYP 3A4 and CYP 2C9 should be avoided because of the increased risk of toxicity. Cardiovascular effects Long term therapy with some COX-2 selective NSAIDs of the coxib class has been shown to increase the risk of serious cardiovascular thrombotic events. MOBIC is a COX-2 selective NSAID. MOBIC has not been demonstrated to increase the risk of cardiovascular adverse events compared to nonselective NSAIDs in clinical trials. However, long term placebo controlled data to adequately assess any cardiovascular risk are not available for MOBIC. All NSAIDs, both COX-2 selective and nonselective, may cause an increased risk of serious cardiovascular thrombotic events including myocardial infarction and stroke. This may increase with dose and duration of use. Patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. To minimise the potential risk of an adverse cardiovascular event in patients taking MOBIC especially in those with cardiovascular risk factors the lowest effective dose should be used for the shortest possible duration. Physicians and patients should remain alert for such cardiovascular events even in the absence of previous cardiovascular symptoms. Patients should be informed about signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur. Skin reactions Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS) (see Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS)) have been reported very rarely in association with the use of MOBIC. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. MOBIC should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS) DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue the NSAID and evaluate the patient immediately. Renal effects NSAIDs inhibit the synthesis of renal prostaglandins, which play a supportive role in the maintenance of renal perfusion. In patients whose renal blood flow and blood volume are decreased, administration of an NSAID may precipitate overt renal decompensation which is typically followed by recovery to pretreatment state upon discontinuation of nonsteroidal anti-inflammatory therapy.
Patients at greatest risk of such a reaction are elderly individuals, dehydrated patients, those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, those receiving concomitant treatment with a diuretic, ACE inhibitor or angiotensin II receptor antagonist or those having undergone major surgical procedures which led to hypovolaemia. In such patients, the renal function, including volume of diuresis, should be carefully monitored at the beginning of therapy. In rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome. The dose of MOBIC in patients with end-stage renal failure on haemodialysis should not exceed 7.5 mg. No dose reduction is required in patients with mild or moderate renal impairment (i.e., in patients with a creatinine clearance of greater than 25 mL/min). The extent to which metabolites of meloxicam may accumulate in patients with renal failure has not been studied. As some metabolites are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored. Combination use of ACE inhibitors or angiotensin receptor antagonists, anti inflammatory drugs and thiazide diuretics The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti- inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment. Hepatic effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including MOBIC. These laboratory values 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 with NSAIDs. Physicians and patients should remain alert for hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity. Patients with signs and/or symptoms suggesting liver dysfunction (e.g., nausea, fatigue, lethargy, pruritis, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms), 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. eosinophilia, rash, etc), MOBIC should be discontinued. Fluid retention and oedema Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Cardiac failure or hypertension may be precipitated or exacerbated in susceptible patients as a result. For patients at risk, clinical monitoring is recommended. Pre-existing asthma 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
Antacids No pharmacokinetic interaction was detected with concomitant administration of antacids. Cimetidine Concomitant administration of 200 mg cimetidine QID did not alter the single dose pharmacokinetics of 30 mg meloxicam. Digoxin 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. Furosemide (Frusemide) Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide (frusemide) and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide (frusemide) agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide (frusemide) single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide (frusemide) and meloxicam, patients should be observed closely for signs of declining renal function (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Diuretics), as well as to assure diuretic efficacy. Cytochrome P450 inhibitors Co-administration of meloxicam with drugs known to inhibit CYP 2C9 is contraindicated. Co- administration of meloxicam with drugs known to inhibit CYP 3A4 should be undertaken with caution (see Section 4.4 Special Warnings and Precautions for Use - Gastrointestinal effects). Other Prostaglandin Synthetase Inhibitors (PSIs) including glucocorticoids and salicylates (acetylsalicylic acid) Co-administration of PSIs may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect, and is not recommended. The concomitant use of meloxicam with other NSAIDs is not recommended. Oral anticoagulants, antiplatelet drugs, systemically administered heparin, thrombolytics and Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of bleeding via inhibition of platelet function, when NSAIDs are co- administered. If such co-prescribing cannot be avoided, close monitoring of their effects on coagulation is required. Lithium NSAIDs have been reported to increase lithium plasma levels (via decreased renal excretion of lithium), which may reach toxic values. The concomitant use of lithium and NSAIDs is not recommended. If this combination appears necessary, lithium plasma concentrations should be monitored carefully during the initiation, adjustment and withdrawal of meloxicam treatment. Methotrexate Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from human serum binding sites. However, as with other NSAIDs, MOBIC may increase the haematologic toxicity of methotrexate. In this situation, strict monitoring of blood cell count is recommended. NSAIDs can reduce the tubular secretion of methotrexate thereby increasing the plasma concentrations of methotrexate. For this reason, for patients on high dosages of methotrexate
(more than 15 mg/week) the concomitant use of NSAIDs is not recommended. The risk of an interaction between NSAIDs and methotrexate should be considered also in patients on low dosage of methotrexate, especially in patients with impaired renal function. In case combination treatment is necessary, blood cell count and renal function should be monitored. Caution should be taken in case both NSAID and methotrexate are given within 3 days, in which case the plasma level of methotrexate may increase and cause increased toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, it should be considered that the haematological toxicity of methotrexate can be amplified by treatment with NSAIDs. Pemetrexed For the concomitant use of meloxicam with pemetrexed in patients with creatinine clearance from 45 to 79 mL/min, the administration of meloxicam should be paused for 5 days before, on the day of, and 2 days following pemetrexed administration. If a combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, especially for myelosuppression and gastro-intestinal adverse reactions. In patients with creatinine clearance below 45 mL/min the concomitant administration of meloxicam with pemetrexed is not recommended. Contraception NSAIDs have been reported to decrease the efficacy of intrauterine devices. Diuretics Treatment with NSAIDs is associated with the potential for acute renal insufficiency in patients who are dehydrated. Patients receiving MOBIC and diuretics should be adequately hydrated and be monitored for renal function prior to initiating treatment. Ciclosporin Nephrotoxicity of ciclosporin may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combined treatment, renal function is to be measured. Antihypertensives (beta-blockers, ACE-inhibitors, vasodilators, diuretics) A reduced effect of the antihypertensive drug by inhibition of vasodilating prostaglandins has been reported during treatment with NSAIDs. Angiotensin-II receptor antagonists NSAIDs and angiotensin-II receptor antagonists as well as ACE inhibitors exert a synergistic effect on the decrease of glomerular filtration. In patients with pre-existing renal impairment this may lead to acute renal failure. Colestyramine Colestyramine binds to meloxicam in the gastrointestinal tract leading to a faster elimination of meloxicam. Oral hypoglycaemics Interactions via CYP 2C9 can be expected in combination with medicinal products such as oral anti-diabetics (sulfonylureas), which may lead to increased plasma levels of these drugs and meloxicam. Patients concomitantly using meloxicam with sulfonylureas should be carefully monitored for hypoglycemia.
receiving oral doses > 0.125 mg/kg/day (less than 0.1 times the human dose based on BSA) during late gestation and the lactation period. Meloxicam crosses the placental barrier. There are no adequate, well-controlled studies in pregnant women. Oligohydramnios and Neonatal Renal Impairment: Use of NSAIDs from about 20 weeks gestation 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 post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Use in Lactation Studies of meloxicam excretion in human milk have not been conducted. However, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. The safety of meloxicam in humans during lactation has not been established and therefore, the drug should not be used during lactation. 4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES There are no specific studies about effects on the ability to drive vehicles and to use machinery. Patients who experience visual disturbances, drowsiness or other central nervous system disturbances should refrain from these activities. 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS) Reporting suspected adverse effects Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems. The MOBIC phase II/III safety database includes 10,122 osteoarthritis patients and 1012 rheumatoid arthritis patients treated with MOBIC 7.5 mg/day and 3,505 osteoarthritis patients and 1351 rheumatoid arthritis patients treated with MOBIC 15 mg/day. MOBIC at these doses was administered to 661 patients for at least six 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 2362 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, multicentre, double-blind, randomised 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. Table 2 presents the adverse events that occurred in 1% of the MOBIC treatment groups.
Table 2 : Adverse events (%) occurring in ≥ 1% 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 Ear and labyrinth disorders Ear disorder 0 0 1.3 0. Vertigo 0 0.6 1.3 0. Eye disorders Cataract 0 0 1.3 1. Gastrointestinal Abdominal pain 2.5 1.9 2.6 1. Constipation 1.9 1.9 0.6 3. Diarrhoea 3.8 7.8 3.2 9. Dyspepsia 4.5 4.5 4.5 6. Eructation 0 0 1.3 0 Flatulence 4.5 3.2 3.2 3. Gastro-oesophageal reflux disease 0 0.6 1.9 1. Nausea 3.2 3.9 3.8 7. Vomiting 1.9 1.3 1.3 2. General disorders and administration site conditions Fatigue 1.9 1.9 1.3 1. Gravitational oedema 0.6 1.3 1.9 3. Influenza like illness 5.1 4.5 5.8 2. Oedema peripheral 1.3 0.6 3.2 0 Immune system disorders Hypersensitivity 1.9 1.9 0.6 1. Infections and infestations Pharyngitis 1.3 0.6 3.2 1. Sinusitis 5.1 1.3 1.9 5. Upper respiratory tract infection 1.9 3.2 1.9 5. Injury, poisoning and procedural complications Accident at home 1.9 4.5 3.2 2. Fall 0.6 2.6 0 1. Metabolism and nutrition disorders Dehydration 0 1.3 0 0 Increased appetite 0.6 0 1.3 0
Table 3 : Adverse Events (%) occurring in ≥ 1% of MOBIC patients in two 12-week rheumatoid arthritis placebo- and active controlled trials. Placebo MOBIC 7.5 mg daily MOBIC 15 mg daily Diclofenac 150mg daily No. of Patients 470 482 478 182 Gastrointestinal disorders Abdominal pain 0.6 3.1 2.3 4. Abdominal pain upper 0.9 1.9 1.0 0 Constipation 0.9 1.5 1.7 3. Diarrhoea 5.3 5.2 3.3 6. Dyspepsia 3.6 5.6 3.6 7. Flatulence 1.1 1.2 1.5 5. Nausea 2.6 3.3 3.8 7. Vomiting 2.3 0.8 1.3 1. General disorders and administration site conditions Influenza like illness 2.1 2.3 2.3 5. Immune system disorders Hypersensitivity 0.4 1.2 0.2 0 Infection and infestations Bronchitis 0.2 0.6 1.3 0. Nasopharyngitis 0.6 1.7 1.9 0 Pharyngitis 0.6 0.8 1.0 1. Rhinitis 0.4 0.6 1.0 1. Sinusitis 1.3 1.7 1.5 1. Upper respiratory tract infection 2.1 4.1 4.0 2. Urinary tract infection 1.3 1.2 1.3 1. Injury, poisoning and procedural complications Fall 0.2 0.6 1.0 0. Musculoskeletal and connective tissue disorders Arthralgia 1.9 1.0 1.7 2. Back pain 2.3 1.5 1.9 2. Myalgia 0.2 1.0 0.6 0. Rheumatoid arthritis 2.3 1.9 1.5 1. Nervous system disorders Dizziness 3.0 2.3 0.6 3. Headache 6.6 6.6 5.4 9. Psychiatric disorders Insomnia 0.6 1.0 0.6 1.
Placebo MOBIC 7.5 mg daily MOBIC 15 mg daily Diclofenac 150mg daily Respiratory, thoracic and mediastinal disorders Cough 1.5 0.8 1.5 2. Skin and subcutaneous tissue disorders Pruritus 1.3 0.6 1.0 1. Purpura 0.2 0.2 1.0 0 Rash 1.7 1.0 2.3 3. Vascular disorders Hypertension 0.9 1.5 1.0 2. 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 events occurring in <1% of patients, which may be causally related to the administration of MOBIC. The information is based on clinical trials involving patients who have been treated with daily oral doses of 7.5 or 15 mg MOBIC tablets or capsules over a period of up to 18 months (mean duration of treatment 127 days). Blood and lymphatic system disorders: blood count abnormal (including differential white cell count), leukopenia, thrombocytopenia, anaemia Concomitant administration of a potentially myelotoxic drug, in particular methotrexate, appears to be a predisposing factor to the onset of a cytopenia. Cardiac disorders: palpitations Ear and labyrinth disorders: tinnitus Gastrointestinal disorders: gastrointestinal perforation, occult or macroscopic gastrointestinal haemorrhage, gastroduodenal ulcer, colitis , oesophagitis, stomatitis Gastro-intestinal haemorrhage, ulceration or perforation may potentially be fatal. Hepatobiliary disorders: transitory abnormalities of liver function parameters (e.g. raised transaminases or bilirubin) Nervous system disorders: somnolence Renal and urinary disorders: renal function test abnormal (increased serum creatinine and/or serum urea) Respiratory, thoracic and mediastinal disorders: onset of asthma attacks in individuals allergic to aspirin or other NSAIDs Skin and subcutaneous tissue disorders: urticaria, photosensitivity reaction Vascular disorders: flushing Post-Market Adverse Drug Reactions Additional reports of adverse events which may be causally associated to the administration of MOBIC during worldwide post-marketing experience are included below. General disorders and administration site conditions: In rare cases, other drugs of this class are reported to cause meningitis Eye disorders: visual disturbance including blurred vision, conjunctivitis Gastrointestinal disorders: gastritis
effect on prostaglandin biosynthesis at the site of inflammation than in the gastric mucosa or the kidney. Selective inhibition of the cyclooxygenase-2 (COX-2) isoenzyme, relative to COX-1, by meloxicam has been demonstrated in vitro on various cell systems: guinea pig macrophages, bovine aortic endothelial cells (for testing of COX-1 activity), mouse macrophages (for testing for COX-2 activity), and human recombinant enzymes expressed in cos-cells and in human whole blood. Clinical trials The efficacy of meloxicam in treating the symptoms of osteoarthritis and rheumatoid arthritis has been confirmed in several clinical studies. Osteoarthritis Trials Two clinical studies of 6 months duration were performed in patients with osteoarthritis of the hip or knee. In the first study, the efficacy of meloxicam 15 mg (n=306) and piroxicam 20 mg (n=149) were found to be comparable, using as efficacy endpoints improvement in overall pain, pain on movement, global efficacy, change in duration of inactivity and change in quality of life score. In the second study, the efficacy of meloxicam 7.5 mg (n=169) was found to be comparable to that of diclofenac 100 mg SR (n=167) using similar endpoints. Once daily dosing of meloxicam 7.5 mg (n=153) and 15 mg (n=156) showed a consistently more efficacious response than placebo (n=155) in a 12 week trial in patients with osteoarthritis of the knee or hip. Efficacy was measured by global assessment of disease activity, global assessment of pain and arthritic condition, as measured by the WOMAC (Western Ontario and McMaster University) Osteoarthritis Index. Both doses of meloxicam were also shown to be comparable to diclofenac 50 mg BID (n=152) with regard to efficacy, with a lower incidence of GI adverse events when compared to diclofenac. Two large scale, randomised, active-controlled clinical studies of 4 weeks duration were conducted in patients with osteoarthritis of the hand, hip, knee or spine. In the first study (MELISSA), the effects of meloxicam 7.5 mg (n=4635) were compared against the effects of diclofenac 100 mg SR (n=4688). In the second study (SELECT), the effects of meloxicam 7. mg (n=4320) were compared against the effects of piroxicam 20 mg (n=4336). The results from both studies indicated that meloxicam 7.5 mg was as efficacious as diclofenac 100 mg SR and piroxicam 20 mg, in the treatment of symptomatic osteoarthritis. Rheumatoid arthritis trials The use of MOBIC for the symptomatic treatment of rheumatoid arthritis was evaluated in a double-blind controlled trial involving 894 patients treated for 12 weeks. Meloxicam (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo, with diclofenac (75 mg twice daily) compared to placebo to establish trial sensitivity. The primary endpoints were number of painful or tender joints; number of swollen joints; investigator’s global assessment of disease activity; patients global assessment of disease activity and patient’s assessment of pain. For all 5 primary endpoints, the meloxicam 7.5 mg group was significantly better than placebo for both mean on trial and last observation. The meloxicam 15 mg group was significantly better for 3 of 5 primary endpoints, excluding painful and swollen joints. In patients who had flared at baseline tender joints, the meloxicam 15 mg group differed almost significantly from the placebo group (p<0.05 not met due to the lower number of patients). A second trial also investigated the use of MOBIC for the symptomatic treatment of rheumatoid arthritis. This double-blind placebo controlled trial used three doses of meloxicam (7.5 mg, 15 mg and 22.5 mg daily), in patients with rheumatoid arthritis over a 12 week period. A total of 898 patients were treated with meloxicam. The primary endpoint in this study was the American College of Rheumatology (20%) response criterion (ACR20) response rate, a composite measure of clinical, laboratory and functional measures of rheumatoid arthritis response. For this parameter, all three doses of meloxicam were more effective than placebo for the duration of the study. For the endpoints that comprised the ACR20 criteria, each of the meloxicam groups was superior to placebo at all visits except for C-Reactive Protein. Efficacy reached a
plateau at the meloxicam 15 mg dose (Table 4 ). The overall incidence and severity of adverse events was similar among all three meloxicam groups. Table 4 : Analysis of ACR20 Response Rate for Evaluable Patients at 12 weeks P-value# Study phase Treatment Total Responder^1 * N (%) Placebo Meloxicam 7.5 mg Meloxicam 15 mg Week 12 Placebo 292 97 (33.2) Meloxicam 7.5 mg 306 138 (45.1) 0. Meloxicam 15 mg 293 158 (53.9) 0.0000 0. (^1) The primary efficacy end-point was the ACR20. A responder was a patient with a response defined as: ≥20% improvement in both tender joint count and swollen joint count, and at least three of the following: ≥20% improvement in: patient pain assessment; patient global (overall) assessment; physician global (overall) assessment; the modified health assessment questionnaire; C-Reactive protein. *Early terminations were considered as non-responders from the termination date. #Obtained from Cochran-Mantel-Haenszel test stratified by centre. The data from both studies indicate that meloxicam is effective and safe for the treatment of patients with rheumatoid arthritis. 5.2 PHARMACOKINETIC PROPERTIES Absorption Meloxicam is well absorbed from the gastrointestinal tract following oral administration (absolute bioavailability 89%). MOBIC tablets are bioequivalent to MOBIC capsules. Once daily dosing leads to mean drug plasma concentrations with a relatively narrow Cmaxss - Cminss window in the range of 0.3-1.0 g/mL for 7.5 mg doses or 0.7-1.9 g/mL for 15 mg doses. However, values outside of this range have been encountered (Cmin and Cmax at steady state, respectively). The absorption is not altered by concomitant food intake. However, food shortens the tmax of the capsules by approximately 2.5 hours and marginally increases the Cmax of the capsules, whereas maximum plasma concentrations were regularly achieved between 5 - 6 hours following tablet administration, irrespective of concomitant food consumption. Drug concentrations are dose-proportional for oral 7.5 mg and 15 mg doses, respectively. Steady state conditions are achieved in three to five days. Distribution Volume of distribution is low (on average, 16L). The volume of distribution following administration of multiple oral doses of meloxicam (7.5 to 15 mg) ranged from 10.1L - 17.0L (%CV 24.6% - 39.9%). In plasma, more than 99% is bound to plasma proteins. Meloxicam penetrates well into synovial fluid to give concentrations approximately half those in plasma. Metabolism Meloxicam is eliminated almost entirely by hepatic metabolism: two thirds by cytochrome (CYP) P450 enzymes (CYP 2C9 two thirds and CYP 3A4 one third) and one third by other pathways, such as peroxidase oxidation. Meloxicam is almost completely metabolised to four pharmacologically inactive metabolites. The major metabolite, 5’-carboxymeloxicam (60% of dose), from CYP 2C9 mediated metabolism, is formed by oxidation of an intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays an important role in this metabolic pathway, with a minor contribution from the CYP 3A4 isoenzyme. The patient’s peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose respectively.
little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or tmax across genders. 5.3 PRECLINICAL SAFETY DATA Genotoxicity Meloxicam did not demonstrate genotoxic potential in assays for gene mutation in vitro and chromosomal damage in vitro and in vivo. Carcinogenicity Two year dietary studies showed no evidence for carcinogenic activity at meloxicam doses up to 0.8 mg/kg/day (approximately half of the highest human dose at 15 mg/day for a 50 kg person based on body-surface-area [BSA]) in rats and up to 8 mg/kg/day (2.2 times the highest human dose based on BSA) in mice. In rats, the highest dose used was nephrotoxic, while the highest dose used in mice was subtoxic. 6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS The list of excipients for each dosage form is provided below: Tablets (7.5 mg and 15 mg): sodium citrate dihydrate, lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, colloidal anhydrous silica, magnesium stearate. Capsules (7.5 mg and 15 mg): sodium citrate dihydrate, lactose monohydrate, maize starch, magnesium stearate, gelatin, indigo carmine CI73015, iron oxide yellow CI77492, titanium dioxide, purified water. 6.2 INCOMPATIBILITIES Incompatibilities were either not assessed or not identified as part of the registration of this medicine. 6.3 SHELF LIFE In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging. 6.4 SPECIAL PRECAUTIONS FOR STORAGE Tablets and Capsules: Store below 25°C. Protect from direct sunlight. 6.5 NATURE AND CONTENTS OF CONTAINER Tablets 7.5 mg: PVC/PVDC/Al Blister packs: 10, 20, 30, 60, 100 tablets. Tablets 15 mg: PVC/PVDC/Al Blister packs: 10 , 20, 30, 60, 100 tablets. Capsules 7.5 mg: PA/Al/PVC/Al Blister packs: 10, 20, 30, 100* capsules. Capsules 15 mg: PA/Al/PVC/Al Blister packs: 10, 20, 30, 100* capsules. *not currently distributed in Australia
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy. 6.7 PHYSICOCHEMICAL PROPERTIES Meloxicam is a pastel yellow solid with pKa values of 1.09 and 4.18 and a melting point of about 256C. The substance is practically insoluble in water, soluble in dimethylformamide, slightly soluble in chloroform and acetone, and very slightly soluble in methanol. There are no chiral centres and no polymorphs are formed under normal conditions. MOBIC is available as tablets and capsules. Chemical structure Chemical names: 4 - hydroxy- 2 - methyl-N-(5-methyl- 2 - thiazolyl)-2H-1,2-benzothiazine- 3 - carboxamide-1,1-dioxide and 2H-1,2-benzothiazine- 3 - carboxamide,4- hydroxy- 2 - methy-N-(5-methyl- 2 - thiazolyl)-,1,1-dioxide Molecular formula: C 14 H 13 N 3 O 4 S 2 Molecular weight: 35 1. Structural formula: CAS number 71125 - 38 - 7 7 MEDICINE SCHEDULE (POISONS STANDARD) S4 – Prescription Only Medicine 8 SPONSOR Boehringer Ingelheim Pty Limited ABN 52 000 452 308 78 Waterloo Road North Ryde NSW 2113 www.boehringer-ingelheim.com.au 9 DATE OF FIRST APPROVAL 23 February 2001
