MOBIC ^®

Meloxicam

Presentation

Tablets 7.5mg: Pale yellow, round uncoated tablets marked 59D on one side with break-bar, and company logo on the other.

Capsules 7.5mg: Green hard gelatine capsules.

Uses

Actions

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, which has shown anti-inflammatory, analgesic and antipyretic properties in animals. Meloxicam showed potent anti-inflammatory activity in all standard models of inflammation. A common mechanism for the above effects may exist in the ability of meloxicam to inhibit the biosynthesis of prostaglandins, known mediators of inflammation.

Comparison of the ulcerogenic dose and the anti-inflammatory effective dose in the rat adjuvant arthritis confirmed a superior therapeutic margin in animals over standard NSAIDs. In vivo, meloxicam inhibited prostaglandin biosynthesis more potently at the site of inflammation than in the gastric mucosa or the kidney.

This improved safety profile is thought to be related to a selective inhibition of COX-2 relative to COX-1. The selective inhibition of COX-2 relative to COX-1 by meloxicam has been demonstrated in vitro on various cell systems: guinea pig macrophages, bovine aortic endothelial cells (for testing COX-1 activity), mouse macrophages (for testing COX-2 activity), and human recombinant enzymes expressed on cos-cells. Evidence is now accumulating that COX-2 inhibition provides the therapeutic effects of NSAIDs whereas inhibition of the constitutive COX-1 is responsible for gastric and renal side effects. Clinical studies demonstrated a lower incidence of gastrointestinal adverse events including perforations, ulcers or bleeds with the recommended doses of meloxicam than standard doses of other NSAIDs.

Pharmacokinetics

MOBIC is well absorbed (89%) following oral and rectal administration. Absorption is not altered by concomitant food intake. Capsules and tablets are bioequivalent. Following oral administration, peak plasma concentrations are obtained between 6 to 9 hours (after a single dose) and 5 to 6 hours (after multiple doses). Steady state conditions are achieved in three to five days. Continuous treatment for periods of more than one year results in similar drug concentrations to those seen where steady state is first achieved. Once daily dosing leads to drug plasma concentrations with a relatively small peak-trough fluctuation in the range of 0.4 - 1.0mcg/mL for 7.5 mg doses or 0.8 - 2.0mcg/mL for 15 mg doses. However, values outside of this range have been encountered.

Meloxicam concentrations rise proportionally to the dose administered. In plasma, more than 99% of the drug is bound to plasma proteins. Meloxicam penetrates well into synovial fluid to give concentrations approximately half those in plasma.

Meloxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the unchanged compound are excreted in urine. The major metabolic pathway is the oxidation of the methyl group of the thiazolyl-moiety of the substance, followed by urinary (50%) or faecal excretion of the metabolites. About half of the substance is excreted in urine, the remainder in the stool. The mean elimination half-life of Meloxicam is 20 hours. Neither hepatic or mild to moderate renal insufficiency substantially affects Meloxicam pharmacokinetics.

Indications

Symptomatic treatment of painful osteoarthritis (arthrosis, degenerative joint disease).
Symptomatic treatment of rheumatoid arthritis.

Dosage and Administration

MOBIC may be administered in a dose of 7.5mg daily. Patients should generally be maintained on the lowest dose consistent with achieving a satisfactory therapeutic response.

Osteoarthritis and Rheumatoid arthritis:

In dialysis patients with severe renal failure:

The dose should not exceed 7.5mg per day.

In patients with mild to moderate renal impairment ( creatinine clearance of greater than 25 mL/min):

The dose should not exceed 7.5 mg per day.

As a dosage for use in children has yet to be established, usage should be restricted to adults.

Tablets and capsules

Tablets and capsules should be swallowed with water and other fluid in conjunction with food.

Contraindications

• Patients with known hypersensitivity to MOBIC or its excipients. There is a potential for cross sensitivity to aspirin and other NSAIDs.
• MOBIC should not be given to patients who have developed signs of asthma, nasal polyps, angioedema or urticaria following the administration of aspirin or other NSAIDs.
• Active peptic ulceration.
• Severe hepatic insufficiency.
• Non-dialysed severe renal insufficiency.
• Children and adolescents aged less than 15 years.
• Pregnancy or lactation.

Warnings and Precautions

As with other NSAIDs caution should be exercised when treating patients with a history of upper gastrointestinal disease and in patients receiving treatment with anticoagulants. Patients with gastrointestinal symptoms should be monitored. MOBIC should be withdrawn if peptic ulceration or gastrointestinal bleeding occurs.

Gastrointestinal bleeding, ulceration or perforation can occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. The consequences of such events are generally more serious in the elderly.

Special attention should be paid in patients reporting mucocutaneous adverse events and consideration given to discontinuing MOBIC.

As with other NSAIDs, MOBIC inhibits 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 pre-treatment state upon discontinuation of non-steroidal anti-inflammatory therapy. Patients at greatest risk of such a reaction are dehydrated patients, those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, those receiving a diuretic or those having undergone major surgical procedures, which led to hypovolaemia. In such patients, the volume of diuresis and the renal function should be carefully monitored at the beginning of therapy.

In rare instances NSAIDs may be the cause of interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome.

The dose of MOBIC in patients with end-stage renal failure on haemodialysis should not be higher than 7.5mg. Patients with mild or moderate renal impairment (i.e. in patients with a creatinine clearance of greater than 25mL/min) may take 7.5mg daily.

As with most other NSAIDs, occasional elevations of serum transaminases or other parameters of liver function have been reported. In most cases, these have been small and transient increases above the normal range. If the abnormality is significant or persistent, MOBIC should be stopped and follow up tests carried out.

No dose reduction is required in patients with clinically stable liver cirrhosis.

Frail or debilitated patients may be less tolerant to side effects and such patients should be carefully supervised. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.

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.

There are no specific studies about the 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.

Use in Pregnancy

Although no teratogenic effects were seen in animal testing, the use of MOBIC during pregnancy has not been established (see Contraindications).

Meloxicam is a NSAID which owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible.

Use in Lactation

Although no teratogenic effects were seen in animal testing, the use of MOBIC during lactation has not been established (see Contraindications).

Adverse Effects

The following adverse events, which may be causally related with the administration of MOBIC, have been reported. The frequencies given below are based on corresponding occurrences in clinical trials, regardless of any causal relationship. The information is based on clinical trials involving 3750 patients who have been treated with daily oral doses of 7.5mg or 15mg MOBIC tablets or capsules over a period of 18 months (mean duration of treatment 127 days).

Gastrointestinal:

More frequent than 1%: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhoea.

Between 0.1 and 1%: transitory abnormalities of liver function parameters (e.g. raised transaminases or bilirubin) eructation, oesophagitis, gastroduodenal ulcer, occult or macroscopic gastrointestinal bleeding.

Less frequent than 0.1%: gastrointestinal perforation, colitis, hepatitis and gastritis.

Haematological:

More frequent than 1%: anaemia

Between 0.1 and 1%: disturbances of blood count, including differential white cell count, leukopaenia and thrombocytopaenia. Concomitant administration of a potentially myelotoxic drug, in particular methotrexate, appears to be a predisposing factor to the onset of cytopaenia.

Dermatological:

More frequent than 1%: pruritus, skin rash.

Between 0.1 and 1%: stomatitis, urticaria.

Less frequent than 0.1%: photosensitization. On rare occasions bullous reactions, erythema multiforme, Stevens Johnson Syndrome,or Toxic Epidermal Necrolysis may develop.

Respiratory:

Less frequent than 1%: onset of acute asthma has been reported in certain individuals following the administration of aspirin or other NSAIDs, incl., MOBIC.

Central Nervous System:

More frequent than 1%: light-headedness, headache

Between 0.1 and 1%: vertigo, tinnitus, drowsiness.

Less frequent than 0.1%: confusion and disorientation.

Cardiovascular:

More frequent than 1%: oedema.

Between 0.1 and 1%: increase of blood pressure, palpitations, flushes.

Genitourinary:

Between 0.1 and 1%: abnormal renal function parameters (increased serum creatinine and/or serum urea).

Less frequent than 0.1%: acute renal failure.

Vision disorders:

Less frequent than 0.1%: conjunctivitis, visual disturbances including blurred vision.

Hypersensitivity reactions:

Less frequent than 0.1%: angio-oedema and immediate hypersensitivity reactions, including anaphylactoid / anaphylactic reactions.

Results of post- marketing surveillance

The following have been reported rarely:

• Bullous reactions, erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis.
• Acute renal failure
• Hepatitis
• Increase in blood pressure
• Angio-oedema and hypersensitivity reactions, including anaphylactic/anaphylactoid reactions.

Interactions

No relevant pharmacokinetic drug-drug interactions were detected with respect to the concomitant administration of antacid, cimetidine, digoxin and frusemide.

Associations to be taken into account:

• Other NSAIDs including salicylates in high doses: Concomitant administration of more than one NSAID may increase the risk of gastrointestinal ulceration and bleeding through synergistic action.
• Oral anticoagulants, ticlopidine, systemically administered heparin, thrombolytics: increased risk of bleeding. If such co-prescribing cannot be avoided, close monitoring of the effects of anticoagulants is required.
• Lithium: NSAIDs have been reported to increase lithium plasma levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing MOBIC.
• Methotrexate: As other NSAIDs MOBIC may increase the haematologic toxicity of methotrexate. In this situation, strict monitoring of blood cell count is 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.
• Antihypertensives (e.g. 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.
• Cholestyramine binds Meloxicam in the gastrointestinal tract leading to a faster elimination of Meloxicam.
• Nephrotoxicity of cyclosporin may be enhanced by NSAID's via renal prostaglandin mediated effects. During combined treatment renal function is to be measured.
• Interactions with oral antidiabetics cannot be excluded.

Overdosage

In case of overdose the standard measures of gastric evacuation and general supportive measures should be used, as there is no known antidote. It has been shown in a clinical trial that cholestyramine accelerates the elimination of meloxicam.

Pharmaceutical Precautions

Capsules and Tablets: Store below 25°C (blister pack)
Store below 30°C (glass / polypropylene tube)
Store in a safe place out of the reach of children

Medicine Classification

Prescription Medicine

Package Quantities

Tablets 7.5mg :10 and 30.
Capsules 7.5mg :10 and 30

Further Information

MOBIC(r) is a registered Trademark

Excipients:

Tablets: sodium citrate, lactose, microcrystalline cellulose, polyvidone, anhydrous colloidal silica, crospolyvidone, magnesium stearate

Capsules: sodium citrate, lactose, corn starch, cellulose, magnesium stearate, Capsule envelope: gelatine, indigotine, yellow iron oxide, titanium dioxide