Meloxicam 7.5mg Tablets

Document: spc-doc_PL 30464-0103 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Meloxicam 7.5 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 7.5mg meloxicam Excipient(s) with known effect:

Also contains lactose monohydrate.

For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet for oral administration.

Light yellow, round, flat, scored on one side, 7mm diameter tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Meloxicam is indicated for the short term symptomatic treatment of exacerbations of osteoarthrosis, long term symptomatic treatment of rheumatoid arthritis or ankylosing spondylitis.

4.2 Posology and method of administration

Method of administration Oral use

Posology

Meloxicam tablets are for oral administration only. The total daily dose should be taken as a single dose, preferably with water or another liquid, during a meal.

The maximum daily dose is 15mg. Do not exceed this dose.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4). The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

Adult:

Acute exacerbations of osteoarthrosis: The recommended dose is 7.5 mg a day. If necessary, and depending upon the severity of symptoms, dosage may be increased to 15 mg daily.

Rheumatoid arthritis: The recommended dose is 15 mg a day. Patients at increased risk for adverse reactions should initiate therapy at 7.5mg a day.

According to the therapeutic response, the dose may be reduced to 7.5mg/day.

Ankylosing spondylitis: The recommended daily dose is 15mg a day. Patients at increased risk for adverse reactions should initiate therapy at 7.5mg a day.

According to the therapeutic response, the dose may be reduced to 7.5mg/day.

This medicinal product exists in other dosages, which may be more appropriate. Special Populations:

Elderly:

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

In elderly patients being treated for rheumatoid arthritis and ankylosing spondylitis the recommended dose for long term treatment is 7.5mg a day.

Children:

The safety and efficacy of meloxicam have not been established in children under the age of 16 years.

Hepatic impairment (see section 5.2):

Meloxicam is contraindicated in severe hepatic impairment (see Contraindications). Caution should be exercised in patients with lesser degrees of hepatic impairment, and they should be closely monitored. No dose reduction is required in patients with mild to moderate hepatic impairment (see section 4.3 Contraindications).

Renal impairment:

Meloxicam is contraindicated in non-dialysed severe renal failure (see section 4.3). Patients with severe renal failure undergoing dialysis should not exceed a dose of 7.5mg a day. Diuresis and renal function should be carefully monitored during meloxicam therapy (see also special warnings and precautions for use). No dose reduction is required in patients with mild to moderate renal impairment (i.e. patients with a creatinine clearance of greater than 25 ml/min).

4.3 Contraindications

This medicinal product is contra-indicated in the following situations:

Hypersensitivity to meloxicam, or to any of the excipients (see section 6.1) or hypersensitivity to substances with a similar action, e.g. NSAIDs, aspirin.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

Severe heart failure, liver failure and severe non-dialysed kidney failure (see section 4.4). Severely impaired liver function.

During the last trimester of pregnancy (see section 4.6).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Children under 16 years of age

History of cerebrovascular bleeding or other bleeding disorders

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, nor should an additional NSAID be added to the therapy because this may increase the toxicity while therapeutic advantage has not been proven. The use of Meloxicam with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Meloxicam is not appropriate for the treatment of patients requiring relief from acute pain.

In the absence of improvement after several days, the clinical benefit of the treatment should be reassessed.

Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with meloxicam. Attention should routinely be paid to the possible onset of a recurrence in patients treated with meloxicam and with a past history of this type.

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as heparin as curative treatment or given in geriatrics, oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors (SSRIs) or other non steroidal antiinflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (>1g as single intake or > 3g as total daily amount) (see section 4.5).

If GI bleeding or ulceration occurs in patients receiving Meloxicam, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8 -undesirable effects).

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for meloxicam.

Clinical monitoring of blood pressure for patients at risk is recommended at baseline and especially during treatment initiation with meloxicam.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with meloxicam after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Dermatological

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see 4.8). Patients appear to be at highest risk for 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. Meloxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

• Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of meloxicam.

• Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

• If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, meloxicam treatment should be discontinued.

• The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of meloxicam, meloxicam must not be re-started in this patient at any time.

Parameters of liver and renal functions

As with most NSAIDs, occasional increases in serum transaminase levels, increases in serum bilirubin or other liver function parameters, as well as increases in serum creatinine and blood urea nitrogen as well as other laboratory disturbances, have been reported. The majority of these instances involved transitory and slight abnormalities. Should any such abnormality prove significant or persistent, the administration of Meloxicam should be stopped and appropriate investigations undertaken.

Functional renal failure

NSAIDs, by inhibiting the vasodilating effect of renal prostaglandins, may induce a functional renal failure by reduction of glomerular filtration. This adverse event is dose-dependant. At the beginning of the treatment, or after dose increase, careful monitoring of diuresis and renal function is recommended in patients with the following risk factors:

Elderly

Concomitant treatments such as ACE inhibitors, angiotensin-II antagonists, sartans, diuretics (see section 4.5. Interaction with other medicinal products and other forms of interaction)

Hypovolemia (whatever the cause) Congestive heart failure Renal failure Nephrotic syndrome Lupus nephropathy

Severe hepatic dysfunction (serum

albumin <25 g/l or Child-Pugh score >10)’

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

No dose reduction is required in patients with mild or moderate renal impairment (i.e. in patients with a creatinine clearance of greater than 25ml/min). (For patients with non-dialysed severe renal failure, see section 4.3)

The dose of meloxicam in patients with end-stage renal failure on haemodialysis should not be higher than 7.5 mg.

Sodium and water retention

Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Furthermore, a decrease of the antihypertensive effect of antihypertensive drugs can occur (see section 4.5). Consequently oedema, cardiac failure or hypertension may be precipitated or exacerbated in susceptible patients as a result. Clinical monitoring is therefore necessary for patients at risk (see sections 4.2 and 4.3).

Hyperkalaemia

Hyperkalaemia can be favoured by diabetes or concomitant treatment known to increase kalaemia (see section 4.5.). Regular monitoring of potassium values should be performed in such cases.

Other warnings and precautions

Adverse reactions are often less well tolerated in elderly, fragile or weakened individuals, who therefore require careful monitoring. As with other NSAIDs, particular caution is required in the elderly, in whom renal, hepatic and cardiac functions are frequently impaired. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Meloxicam, as any other NSAID, may mask symptoms of an underlying infectious disease. SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction Pharmacodynamic Interactions

Other NSAIDs, including salicylates (acetylsalicylic acid > 3 g/d)

Administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect. The concomitant use of meloxicam with other NSAIDs is not recommended (see section 4.4).

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Oral anticoagulants

Increased risk of bleeding, due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4). The concomitant use of NSAIDs and oral anticoagulants is not recommended (see section 4.4).

Careful monitoring of the INR is required if it proves impossible to avoid such combination.

Thrombolytics and antiplatelet drugs

Increased risk of bleeding, via inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4).

Diuretics, ACE inhibitors and Angiotensin-II Antagonists

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administrating of an ACE inhibitor or Angiotensin-II antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter (see also section 4.4).

Other antihypertensive drugs (e.g. Beta-blockers)

As for the latter, a decrease of the antihypertensive effect of beta-blockers (due to

inhibition of prostaglandins with vasodilatory effect) can occur.

Calcineurin inhibitors (e.g. Ciclosporin and Tacrolimus):

Nephrotoxicity of of calcineurin inhibitors may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combined treatment renal function is to be measured. A careful monitoring of the renal function is recommended, especially in the elderly.

Intrauterine devices

NSAIDs have been reported to decrease the efficacy of intrauterine devices.

A decrease of the efficacy of intrauterine devices by NSAIDs has been previously reported but needs further confirmation.

Pharmacokinetic Interactions (Effect of meloxicam on the pharmacokinetics of other drugs)

Lithium

NSAIDs have been reported to increase blood lithium levels (via decreased renal excretion of lithium), which may reach toxic values. The concomitant use of lithium and NSAIDs is not recommended (see section 4.4). If this combination appears necessary, lithium plasma concentrations should be monitored carefully during the initiation, adjustment and withdrawal of meloxicam treatment.

Methotrexate

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 (see section 4.4).

The risk of an interaction between NSAID preparations 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 the 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 (15mg/week) were not relevantly affected by concomitant meloxicam treatment, it should be considered that the haematological toxicity of methotrexate can be amplified by treatment with NSAID drugs (see above). (See section 4.8)

Pharmacokinetic Interactions (Effect of other drugs on the pharmacokinetics of meloxicam)

Cholestyramine

Cholestyramine accelerates the elimination of meloxicam by interrupting the enterohepatic circulation so that clearance for meloxicam increases by 50% and the half-life decreases to 13+3 hrs. This interaction is of clinical significance.

No clinically relevant pharmacokinetic drug-drug interactions were detected with respect to the concomitant administration of antacids, cimetidine and digoxin

4.6 Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, meloxicam should not be given unless clearly necessary. If meloxicam is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)renal dysfunction , which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, meloxicam is contra-indicated during the third trimester of pregnancy. Breast-feeding

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations.

Breast-feeding should be discontinued during treatment with Meloxicam.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

Fertility

The use of meloxicam may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of fertility, withdrawal of meloxicam should be considered Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Cardiovascular and cerebrovascular

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Gastrointestinal

The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:

• non-specific allergic reactions and anaphylaxis

• respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea

• assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

(a) General description

The following adverse events, which may be causally related to the administration of meloxicam, 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 15,197 patients who have been treated with daily oral doses of 7.5 or 15 mg meloxicam tablets or capsules over a period of up to one year.

Adverse events which may be causally related to the administration of meloxicam that have come to light as a result of reports received in relation to administration of the marketed product are included.

Adverse reactions have been ranked under the headings of frequency using the following convention:

Very common (>1/10); common (>1/100, <1/10; uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000) Not known (cannot be estimated from the available data)

(b) Table of adverse reactions

Blood and the lymphatic system disorders Uncommon: Anaemia

Rare: Disturbances of blood count (including differential white cell count);

leucocytopenia; thombocytopenia

Very rare: Agranulocytosis (see section c)

Immune system disorders

Uncommon: Allergic reactions other than anaphylactic or anaphylactoid reactions Not known: Anaphylactic/ anaphylactoid reactions

Psychiatric disorders

Rare: Mood disorders, nightmares

Not known: Confusional state, disorientation

Nervous system disorders Common: headache Uncommon: dizziness, somnolence

Eye disorders

Rare: Visual disturbances including blurred vision, conjunctivitis

Ear and labyrinth disorders Uncommon: Vertigo Rare: Tinnitus

Cardiac disorders Rare: Palpitations

Cardiac failure has been reported in association with NSAID treatment.

Vascular disorders

Uncommon: Increase in blood pressure (see section 4.4), flushes Respiratory, thoracic and mediastinal disorders

Rare: Onset of asthma attacks in certain individuals allergic to aspirin or other NSAIDs Gastrointestinal disorders

Very Common: Dyspepsia, nausea and vomiting symptoms, abdominal pain, constipation, flatulence, diarrhoea

Uncommon: Occult or macroscopic gastrointestinal haemorrhage, stomatitis, gastritis, eructation

Rare: Colitis, gastrointestinal ulcer, oesophagitis Very rare: Gastrointestinal perforation

The peptic ulcers, perforation or gastrointestinal bleeding, that may occur can be sometimes severe and potentially fatal, especially in elderly (see section 4.4).

Hepatobiliary disorders

Uncommon: Transitory disturbance of liver function test (e.g. raised transaminases or bilirubin).

Very rare: Hepatitis.

Skin and subcutaneous tissue disorder Uncommon: Pruritus, rash, angioedema

Rare: Urticaria, Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis,

Very rare: Dermatitis bullous, erythema multiforme Not known: Photosensitivity reactions

Renal and urinary disorders

Uncommon: sodium and water retention, hyperkalaemia (see section 4.4 Special warnings and special precautions for use and section 4.5), renal function test abnormal (eg creatine or urea)

Very rare: Renal failure (see section 4.4)

General disorders and administration site conditions Uncommon: Oedema including oedema of the lower limbs

Isolated cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic drugs (see section 4.5)

(d) Adverse reactions which have not been observed yet in relation to the product, but which are generally accepted as being attributable to other compounds in the class

Organic renal injury probably resulting in acute renal failure: isolated cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the yellow card scheme at www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Symptoms include headache, nausea, lethargy, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning hypertension acute renal failure, liver damage and hepatic dysfunction, respiratory depression, coma and convulsions, cardiovascular collapse and cardiac arrest are possible.

Therapeutic measure

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition. Accelerated removal of meloxicam by 4g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : Non steroidal anti-inflammatory drug (NSAID), Oxicams

ATC Code: M01AC06

Meloxicam is a NSAID of the oxicam group, with anti-inflammatory, analgesic and antipyretic properties.

The anti-inflammatory activity of meloxicam has been proven in classical models of inflammation. As with other NSAIDs, its precise mechanism of action remains unknown. However, there is at least one common mode of action shared by all NSAIDs (including Meloxicam): inhibition of the biosynthesis of prostaglandins, known inflammation mediators.

5.2 Pharmacokinetic properties

Absorption

Meloxicam is well absorbed from the gastrointestinal tract, which is reflected by a high absolute bioavailability of 89% following oral administration (capsule). Tablets, oral suspension and capsules were shown to be bioequivalent.

Following single dose administration of meloxicam, mean maximum plasma concentrations are achieved within 2 hours for the suspension and within 7-8 hours with solid oral dosage forms (capsules and tablets). With multiple dosing, steady state conditions were reached within 3 to 5 days. Once daily dosing leads to drug plasma concentrations with a relatively small peak-trough fluctuation in the range of 0.4 - 1.0 pg/ml for 7.5 mg doses and 0.8 - 2.0 pg/ml for 15 mg doses, respectively (Cmin and Cmax at steady state, respectively).

Maximum plasma concentrations of meloxicam, at steady state, are achieved within seven to eight hours for the tablet, capsule and the oral suspension, respectively. Continuous treatment for periods of more than one year results in similar drug concentrations to those seen once steady state is first achieved.

Extent of absorption for meloxicam following oral administration is not altered by concomitant food intake.

Distribution

Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%). Meloxicam penetrates into synovial fluid to give concentrations approximately half of those in plasma. Volume of distribution is low, on average 11 L. Inter-individual variation is the order of 30-40%.

Biotransformation

Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 5’-carboxymeloxicam (60% of dose), 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.

Elimination

Meloxicam is excreted predominantly in the form of metabolites and occurs to equal extents in urine and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the parent compound are excreted in urine. The mean elimination half-life is about 20 hours. Total plasma clearance amounts on average 8 ml/min.

Linearity/non-linearity

Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg to 15 mg following per oral or intramuscular administration.

Special populations

Hepatic/renal Insufficiency:

Neither hepatic, mild nor moderate renal insufficiency have a substantial effect on meloxicam pharmacokinetics. In terminal renal failure, the increase in the volume of distribution may result in higher free meloxicam concentrations, and a daily dose of 7.5 mg must not be exceeded (see section 4.2).

Elderly

Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.

5.3 Preclinical safety data

The toxicological profile of Meloxicam has been found in preclinical studies to be identical to that of other NSAIDs: gastrointestinal ulcers and erosions; renal papillary necrosis at high doses during chronic administration in two animal species.

Oral reproductive studies in the rat have shown a decrease of ovulations and inhibition of implantations and embryotoxic effects (increase of resorptions) at maternotoxic dose levels at 1 mg/kg and higher. Studies of toxicity on reproduction in rats and rabbits did not reveal teratogenicity up to oral doses of 4mg/kg in rats and 80mg/kg in rabbits. These dose levels exceeded the clinical dose (7.5-15 mg) by a factor of 10 to 5-fold on a mg/kg dose basis (75kg person). Fetotoxic effects at the end of gestation, shared by all prostaglandin synthesis inhibitors, have been described.

No evidence has been found of any mutagenic effect, either in vitro or in vivo. No carcinogenic risk has been found in the rat and mouse at doses far higher than those used clinically.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium citrate dihydrate

Lactose monhydrate Microcrystaline cellulose Povidone Crospovidone Colloidal anhydrous silica Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Do not store above 25^oC. Do not refrigerate or freeze. Store in the original package. Keep the blister in the outer carton.

6.5 Nature and contents of container

PVC/ PVDC- Aluminium blisters in packs of 30 tablets

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Athlone Pharmaceuticals Limited Ballymurray,

Co.Roscommon,

Ireland.

8 MARKETING AUTHORISATION NUMBER(S)

PL 30464/0103

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/05/2008

10 DATE OF REVISION OF THE TEXT

11/02/2014