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UKPAR Meloxicam 7.5mg and 15mg Tablets PL 08215/0082-3

1

MELOXICAM 7.5MG TABLETSPL 08215/0082

MELOXICAM 15MG TABLETS

PL 08215/0083

UKPAR

TABLE OF CONTENTS

Lay Summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 13

Steps taken after authorisation summary Page 14

Summary of Product CharacteristicsPage 15

Product Information Leaflet Page 38

Labelling Page 40

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MELOXICAM 7.5MG TABLETS

PL 08215/0082


PL 08215/0083

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency granted Kent

Pharmaceuticals Limited Marketing Authorisations (licences) for the medicinal

products Meloxicam 7.5mg Tablets (PL 08215/0082) and Meloxicam 15mg Tablets

(PL 08215/0083). These are prescription-only medicines (POM) used to reduceinflammation and pain in the joints and muscles. Meloxicam tablets are for short-

term treatment of acute attacks of osteoarthritis and for long-term treatment of pain

and stiffness in joints (rheumatoid arthritis) or backbone (ankylosing spondylitis).

Meloxicam Tablets contain the active ingredient meloxicam, which belongs to a

group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs).

The test product was considered the same as the original products Mobic 7.5mg and

15mg Tablets (Boehringer Ingelheim) based on the bioequivalence study submitted

and no new safety issues arose as a result of this study. No new or unexpected safety

concerns arose from these applications and it was therefore judged that the benefits oftaking Meloxicam 7.5mg and 15mg Tablets outweigh the risks; hence Marketing

Authorisations have been granted.

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PL 08215/0082


PL 08215/0083

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction Page 4

Pharmaceutical assessment Page 5

Preclinical assessment Page 7

Clinical assessment (including statistical assessment) Page 8

Overall conclusions and risk benefit assessment Page 12

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INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted

marketing authorisations for the medicinal products Meloxicam 7.5 mg Tablets (PL

08215/0082) and Meoxicam 15mg Tablets (PL 08215/0083) on 9th May 2008. The

products are prescription-only medicines.

These are two strengths of Meloxicam, submitted as abridged applications according

to Article 10.1 of Directive 2001/83/EC, and have been shown to be generic medicinal

products of the original, Mobic 7.5 mg Tablets (PL 14598/0002) and Mobic 15 mg

Tablets (PL 14598/0003). The reference products have been have been authorised in

the UK since 21st February 1996 and so the 10-year period of data exclusivity has

expired.

The products contain the active ingredient meloxicam, a non-steroidal anti-

inflammatory drug (NSAIDs), and exhibits anti-inflammatory, analgesic and

antipyretic activities. Its mechanism of action may be related to prostaglandin

sythetase inhibition.

Meloxicam 7.5mg and 15mg Tablets are indicated are indicated for the short term

symptomatic treatment of exacerbations of osteoarthritis, long term symptomatic

treatment of rheumatoid arthritis or ankylosing spondylitis.

These applications were submitted at the same time and both depend on the

bioequivalence study comparing the applicants 15mg product with the reference

product Movatec 15mg Tablets (Boehringer Ingelheim, Germany). Consequently, all

sections of this Scientific Discussion refer to both products.

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PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE

Meloxicam

INN: Meloxicam

Chemical Name: 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-

benzothiazine-3-carboxamide-1-1-dioxide

Molecular formula: C14H13N3O4S2

Molecular weight: 351.4

Physical form: White or almost white fine powder.

Solubility: Practically insoluble in water, soluble in acetone and in methylene chloride,

slightly soluble in alcohol.

An appropriate specification based on the British Pharmacopoeia has been provided.

Analytical methods have been appropriately validated and are satisfactory for ensuring

compliance with the relevant specifications.

Active meloxicam is packed in to transparent double lined polyethylene bags which

are tied and placed in a fibre drum. The fibre drum is closed with a lid, clamped andsealed. The specifications and typical analytical test reports are provided and are

satisfactory.

Batch analysis data are provided and comply with the proposed specification.

Satisfactory certificates of analysis have been provided for working standards used by the

active substance manufacturer and finished product manufacturer during validation studies.

Appropriate stability data have been generated supporting a retest period of 18 months, with

no specific storage instructions.

DRUG PRODUCT

Other ingredients

Other ingredients consist of pharmaceutical excipients, namely sodium citrate dehydrate,

lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, colloidal silicon

dioxide and magnesium stearate. Appropriate justification for the inclusion of each excipient

has been provided.

All excipients used comply with their respective European Pharmacopoeial monograph.

Satisfactory certificates of analysis have been provided for all excipients.

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The only excipients used that contain material of animal or human origin is lactose

monohydrate and magnesium stearate. The applicant has provided a declaration that the milk

used in the production of lactose monohydrate is sourced from healthy animals under the

same conditions as that for human consumption. A satisfactory TSE certificate of suitability

has been provided for the supplier of magnesium stearate.

There were no novel excipients used and no overages.

Dissolution profiles

Dissolution profiles for both strengths of drug product were found to be similar to those for

the reference products.

Manufacture

A description and flow-chart of the manufacturing method has been provided.

In-process controls are appropriate considering the nature of the product and the method of

manufacture. Process validation has been carried out on three commercial-scale batches forthe 7.5 mg product and four commercial scale batches for the 15 mg product with satisfactory

results.

Finished product specification

The finished product specification is satisfactory. Acceptance limits have been justified with

respect to conventional pharmaceutical requirements and, where appropriate, safety. Test

methods have been described and have been adequately validated, as appropriate. Batch data

have been provided and comply with the release specification. Certificates of analysis have

been provided for any working standards used.

Container Closure System

The product is packaged in blisters composed of clear polyvinyl chloride (PVC)/

polyvinylidene chloride (PVdC) and aluminium foil. Specifications and certificates of

analysis for the packaging types used have been provided and are satisfactory. All primary

product packaging complies with EU legislation regarding contact with food. The product is

packaged in pack sizes of 30 tablets.

Stability

Finished product stability studies have been conducted in accordance with current guidelines.

Based on the results, a shelf-life of 24 months has been set, which is satisfactory. Storage

conditions are Do not store above 25 degrees, Do not refrigerate or freeze, Store inoriginal container and Keep the blister in the outer carton.

Conclusion

It is recommended that Marketing Authorisations are granted for these applications.

Meloxicam 7.5mg and 15mg Tablets have been shown to be generic medicinal products of

Mobic 7.5mg and 15mg Tablets. The proposed drug products correspond to the current

EU definition of a generic product as they comply with the criteria of having the same

qualitative and quantitative content of the active substance, pharmaceutical form and

bioequivalence as the reference product.

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PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with these applications and none are

required for an application of this type.

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CLINICAL ASSESSMENT

1.1 CLINICAL BACKGROUNDMeloxicam is a NSAID of the oxicam group with anti-inflammatory, analgesic and

antipyretic properties. It is a COX-2 inhibitor and has been widely used in theproposed indication.

1.2 INDICATIONSMeloxicam is indicated for the short term symptomatic therapy of acute exacerbations

of osteoarthrosis, long term symptomatic treatment of rheumatoid arthritis or

ankylosing spondylitis.

1.3 DOSE AND DOSE REGIMENMeloxicam tablets are for oral administration only. The total daily dose should betaken as a single dose, preferably with or after food..

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. Ifnecessary, 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 increasedrisk 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 atincreased 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 fifteen years.

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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).

1.4 GCP ASPECTSNot applicable as no new data have been submitted.

1.5 ORPHAN MEDICINAL PRODUCTSNot applicable.

1.6 PAEDIATRIC DEVELOPMENT PROGRAMMENot applicable.

1.7 SCIENTIFIC ADVICENot applicable.

1.8 LEGAL STATUSPOM

2 CLINICAL PHARMACOLOGY2.1 PHARMACOKINETICSMeloxicam is well absorbed from the gastrointestinal tract with a high absolutebioavailability of 89% following oral administration. Following single dose

administration of meloxicam, mean maximum plasma concentrations are achieved

within 5-6 hours. With multiple dosing, steady state conditions were reached within 3

to 5 days. Extent of absorption is not altered by concomitant food intake.

Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%).

Meloxicam undergoes extensive hepatic biotransformation. Four different inactive

metabolites of meloxicam were identified in urine. In vitro studies suggest that CYP

2C9 plays an important role with a minor contribution from the CYP 3A4 isoenzyme.

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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.

The mean elimination half-life is about 20 hours.

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

2.2 BIOEQUIVALENCEA single dose, randomised, two-way, crossover study was conducted in healthy

volunteers under fasted conditions.

The reference product Movatec 15mg Tablets was purchased from the Greek market,

but is manufactured in Germany.

The batch of Meloxicam 15mg Tablets (E5C071) used in the study is a commercial

batch size of the proposed commercial formulation.

Samples were taken pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 144and 192 hours. The washout period was 28 days.

The plasma concentrations ranged from 0 to ~1400ng/ml.

Bioequivalence was determined using the 90% confidence interval of the relative

mean Cmax and AUC0-. Cmax was assessed with a bioequivalence range of 0.75 to

1.34 and AUC0- assessed with a bioequivalence range 0.80 to 1.25.

2.3 PHARMACODYNAMICSMeloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam family,with anti-inflammatory, analgesic and antipyretic properties. The anti-inflammatory

activity is due to the inhibition of the biosynthesis of prostaglandins, known

inflammation mediators.

3 CLINICAL EFFICACYNo new efficacy data have been submitted and none are required for this application.

4 CLINICAL SAFETYNo new safety data have been submitted and none are required for this application.

5 EXPERT REPORTSThe expert report is written by a suitably qualified person and is satisfactory.

6 PRODUCT LITERATURE6.1 SPCThis is satisfactory.

6.2 PATIENT INFORMATION LEAFLETThis is satisfactory.

6.3

LABELThis is satisfactory.

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6.4 APPLICATION FORMThis is satisfactory.

7 OVERALL CONCLUSIONThese are abridged applications for Meloxicam 7.5 mg & 15 mg tablets and aregeneric medically products of the originator products, Mobic 7.5 mg & 15 mg tablets,

which have been registered throughout the EU for ten years. The proposed indications

and dosage are identical to the reference product.

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

antipyretic properties. It is a COX-2 inhibitor and has been widely used in the

proposed indication.

The applicant appears to have demonstrated bioequivalence. Marketing authorisations

should be granted for these products.

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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY

The important quality characteristics of Meloxicam 7.5mg and 15mg Tablets are well

defined and controlled. The specifications and batch analytical results indicate

consistency from batch to batch. There are no outstanding quality issues that wouldhave a negative impact on the benefit/risk balance.

PRECLINICAL

No new preclinical data were submitted and none are required for applications of this

type.

EFFICACY

Bioequivalence has been demonstrated between the applicants Meloxicam 15mg

Tablets and Movatec 15mg Tablets (Boehringer Ingelheim, Germany). Given that

linear kinetics apply between the 7.5mg and 15mg tablets, that proportional formulae

for the tablets have been used and that similar dissolution results have been shown forthe two strengths, a separate bioequivalence study using the 7.5mg tablets is not

considered necessary.

No new or unexpected safety concerns arise from these applications.

The SPC, PIL and labelling are satisfactory and consistent with that for Mobic tablets.

RISK BENEFIT ASSESSMENT

The quality of the product is acceptable and no new preclinical or clinical safety

concerns have been identified. The bioequivalence study supports the claim that the

applicants products and the innovator products are interchangeable. Extensive

clinical experience with meloxicam is considered to have demonstrated the

therapeutic value of the compound. The risk benefit is, therefore, considered to be

positive.

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PL 08215/0082


PL 08215/0083

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation applications on 6th April 2005.

2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 14th September 2005.

3 Following assessment of the applications the MHRA requested further and

further information relating to the quality dossiers on 27th September 2005.

4 The applicant responded to the MHRAs requests, providing further information

on 7th July 2006 for the quality sections.

5 The applications were determined on 9th May 2008.

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PL 08215/0082


PL 08215/0083

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date

submitted

Application

type

Scope Outcome

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PL 08215/0082


PL 08215/0083

SUMMARY OF PRODUCT CHARACTERISTICS

The UK Summary of Product Characteristics (SPC) for Meloxicam 7.5 mg and 15 mg

Tablets are as follows:

1 NAME OF THE MEDICINAL PRODUCTMeloxicam 7.5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach tablet contains 7.5mg meloxicam

For excipients see 6.1.

3 PHARMACEUTICAL FORMTablet for oral administration.

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

4 CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONSMeloxicam is indicated for the short term symptomatic treatment of exacerbations of

osteoarthrosis, long term symptomatic treatment of rheumatoid arthritis or ankylosingspondylitis.

4.2 POSOLOGY AND METHOD OF ADMINISTRATIONMeloxicam tablets are for oral administration only. The total daily dose should be taken as a

single dose, preferably with or after food..


Undesirable effects may be minimised by using the lowest effective dose for the shortestduration 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 withosteoarthritis.

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 foradverse reactions should initiate therapy at 7.5mg a day. According to the therapeuticresponse, the dose may be reduced to 7.5mg/day.

Ankylosing spondylitis: The recommended daily dose is 15mg a day. Patients at increased riskfor adverse reactions should initiate therapy at 7.5mg a day. According to the therapeutic

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



Elderly:

The elderly are at increased risk of the serious consequences of adverse reactions. If anNSAID is considered necessary, the lowest effective dose should be used for the shortest

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possible duration. The patient should be monitored regularly for GI bleeding during NSAIDtherapy.

In elderly patients being treated for rheumatoid arthritis and ankylosing spondylitis therecommended 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

fifteen years.


Meloxicam is contraindicated in severe hepatic impairment (see Contraindications). Cautionshould be exercised in patients with lesser degrees of hepatic impairment, and they should beclosely monitored. No dose reduction is required in patients with mild to moderate hepaticimpairment (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 alsospecial warnings and precautions for use). No dose reduction is required in patients with mildto moderate renal impairment (i.e. patients with a creatinine clearance of greater than 25ml/min).

4.3 CONTRAINDICATIONSThis medicinal product is contra-indicated in the following situations:

Hypersensitivity to meloxicam, or to any of the excipients (see section 6.1) orhypersensitivity 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 hypersensitivityreactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or

other non-steroidal anti-inflammatory drugs.

Severe heart failure, hepatic failure and severe non-dialysed renal failure (see section 4.4).

During the last trimester of pregnancy (see section 4.6)

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

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

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

In the absence of improvement after several days, the clinical benefit of the treatment shouldbe 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 tothe possible onset of a recurrence in patients treated with meloxicam and with a past historyof this type.

Gastrointestinal bleeding, ulceration and perforation

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

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, inpatients 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 pumpinhibitors) should be considered for these patients, and also for patients requiring concomitantlow 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 unusualabdominal 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 warfarin,selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (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, Crohns 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 especiallygastrointestinal 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 suchpatients.

Cardiovascular, Renal and Hepatic Impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandinformation and precipitate renal failure. Patients at greatest risk of this reaction are those withimpaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and theelderly. Renal function should be monitored in these patients (see also section 4.3).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertensionand/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 highdoses 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 toexclude such a risk for meloxicam.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart

disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated withmeloxicam after careful consideration. Similar consideration should be made before initiatinglonger-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 withthe use of NSAIDSs (see 4.8). Patients appear to be at highest risk for these reactions early inthe 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 skinrash, mucosal lesions, or any other sign of hypersensitivity.

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As with most NSAIDs, occasional increases in serum transaminase levels, increases in serumbilirubin or other liver function parameters, as well as increases in serum creatinine and bloodurea nitrogen as well as other laboratory disturbances, have been reported. The majority of

these instances involved transitory and slight abnormalities. Should any such abnormalityprove significant or persistent, the administration of Meloxicam should be stopped andappropriate investigations undertaken.

Functional renal failure

NSAIDs, by inhibiting the vasodilating effect of renal prostaglandins, may induce a functionalrenal failure by reduction of glomerular filtration. This adverse event is dose-dependant. Atthe beginning of the treatment, or after dose increase, careful monitoring of diuresis and renalfunction 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 formsof interaction)

Hypovolemia (whatever the cause) Congestive heart failure Renal failure Nephrotic syndrome Lupus nephropathy Severe hepatic dysfunction (serum albumin

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The use of meloxicam may impair female fertility and is not recommended in womenattempting to conceive. In women who have difficulties conceiving or who are undergoinginvestigation of fertility, withdrawal of meloxicam should be considered.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption should not take this medicine.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTIONPharmacodynamic Interactions:

Other NSAIDs, including salicylates (acetylsalicylic acid3 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 isnot recommended (see section 4.4).

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase therisk of adverse effects (see section 4.4).

Cardiac glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs canreduce the effect of mifepristone.

Quinolone antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with

quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk ofdeveloping convulsions.

TacrolimusPossible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There isevidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacsreceiving concurrent treatment with zidovudine and ibuprofen.

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 thegastroduodenal 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 thegastroduodenal mucosa.

Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (see section 4.4).

Diuretics, ACE inhibitors and Angiotensin-II Antagonists:

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NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. Diuretics canincrease the risk of nephrotoxicity of NSAIDs. In some patients with compromised renalfunction (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 renalfailure, which is usually reversible. Therefore, the combination should be administered with

caution, especially in the elderly. Patients should be adequately hydrated and considerationshould be given to monitoring of renal function after initiation of concomitant therapy, andperiodically 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 ofprostaglandins with vasodilatory effect) can occur.

Cyclosporin:

Nephrotoxicity of cyclosporin may be enhanced by NSAIDs via renal prostaglandin mediatedeffects. 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 butneeds 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 notrecommended (see section 4.4). If this combination appears necessary, lithium plasmaconcentrations should be monitored carefully during the initiation, adjustment and withdrawalof 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 section4.4).

The risk of an interaction between NSAID preparations and methotrexate, should beconsidered 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 renalfunction should be monitored. Caution should be taken in case both NSAID and methotrexateare given within 3 days, in which case the plasma level of methotrexate may increase andcause increased toxicity.

Although the pharmacokinetics of methotrexate (15mg/week) were not relevantly affected byconcomitant meloxicam treatment, it should be considered that the haematological toxicity ofmethotrexate 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 enterohepaticcirculation so that clearance for meloxicam increases by 50% and the half-life decreases to13+3 hrs. This interaction is of clinical significance.

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

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4.6 PREGNANCY AND LACTATIONPregnancy

Congenital abnormalities have been reported in association with NSAID administration inman; however these are low in frequency and do not appear to follow any discernible pattern.In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closureof the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of

labour may be delayed and the duration increased with an increased bleeding tendency in bothmother and child (see section 4.3). NSAIDs should not be used during the first two trimesters

of pregnancy or labour unless the potential benefit to the patient outweighs the potential riskto the foetus.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the

embryo/foetal development. Data from epidemiological studies suggest an increased risk ofmiscarriage and of cardiac malformation and gastroschisis after use of a prostaglandinsynthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation wasincreased 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 inhibitorhas 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 theorganogenetic period. During the first and second trimester of pregnancy, meloxicam shouldnot 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 lowand duration of treatment as short as possible.

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

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonaryhypertension)

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 atvery low doses.

inhibition of uterine contractions resulting in delayed or prolonged labour.

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

Lactation

In limited studies so far available, NSAIDs can appear in breast milk in very lowconcentrations. NSAIDs should, if possible, be avoided when breastfeeding.

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

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINESUndesirable 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

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at highdoses and in long term treatment) may be associated with a small increased risk of arterialthrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Cardiovascular and cerebrovascular

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

Gastrointestinal

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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 section4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain,

melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohns disease (seesection 4.4 - Special warnings and precautions for use) have been reported followingadministration. 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 (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivitycomprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skindisorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and morerarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythemamultiforme).

a) General descriptionThe following adverse events, which may be causally related to the administration ofmeloxicam, have been reported. The frequencies given below are based on corresponding

occurrences in clinical trials, regardless of any causal relationship. The information is basedon clinical trials involving 3750 patients who have been treated with daily oral doses of 7.5 or15 mg meloxicam tablets or capsules over a period of 18 months (mean duration of treatment127days).

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

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

Very common (1/10); common (1/100,

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Uncommon: Palpitations

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

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

Uncommon: Gastrointestinal bleeding, peptic ulcers, oesophagitis, stomatitis.

Rare: Gastrointestinal perforation, gastritis, colitis

The peptic ulcers, perforation or gastrointestinal bleeding, that may occur can be sometimessevere, especially in elderly (see section 4.4).

Hepato-biliary disorders

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

Rare: Hepatitis.

Skin and subcutaneous tissue disorder

Common: Pruritus, rash

Uncommon: Urticaria

Rare: Stevens-Johnson syndrome and toxic epidermal necrolysis, angiodema, bullousreactions such as erythema multiforme, photosensitivity reactions

Renal and urinary disorders

Uncommon: Disturbances of laboratory tests investigating renal function (e.g. raisedcreatinine or urea).

Rare: Renal failure (see section 4.4)

General disorders and administration site conditions

Common: Oedema including oedema of the lower limbs

c) Information characterising individual serious and/or frequently occurring adverse reactions

Isolated cases of agranulocytosis have been reported in patients treated with meloxicam and

other potentially myelotoxic drugs (see section 4.5)

Adverse reactions which have not been observed yet in relation to the product, but which aregenerally accepted as being attributable to other compounds in the class

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

4.9 OVERDOSESymptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding,rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting,occasionally convulsions. In cases of significant poisoning acute renal failure and liver

damage are possible.

Therapeutic measure

Patients should be treated symptomatically as required.

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Within one hour of ingestion of a potentially toxic amount, activated charcoal should beconsidered. Alternatively, in adults gastric lavage should be considered within one hour ofingestion 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 convulsionsshould be treated with intravenous diazepam.

Other measures may be indicated by the patients clinical condition.

5 PHARMACOLOGICAL PROPERTIES5.1 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 andantipyretic properties.

The anti-inflammatory activity of meloxicam has been proven in classical models ofinflammation. 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 (includingMeloxicam): inhibition of the biosynthesis of prostaglandins, known inflammation mediators.

5.2 PHARMACOKINETIC PROPERTIESAbsorption

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

Following single dose administration of meloxicam, mean maximum plasma concentrationsare 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 reachedwithin 3 to 5 days. Once daily dosing leads to drug plasma concentrations with a relativelysmall peak-trough fluctuation in the range of 0.4 - 1.0 g/ml for 7.5 mg doses and 0.8 - 2.0g/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 toeight hours for the tablet, capsule and the oral suspension, respectively. Continuous treatmentfor 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 byconcomitant food intake.

Distribution

Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%). Meloxicampenetrates 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 ofmeloxicam were identified in urine, which are all pharmacodynamically inactive. The majormetabolite, 5-carboxymeloxicam (60% of dose), is formed by oxidation of an intermediatemetabolite 5- hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% ofdose). In vitro studies suggest that CYP 2C9 plays an important role in this metabolicpathway, with a minor contribution from the CYP 3A4 isoenzyme. The patients peroxidaseactivity is probably responsible for the other two metabolites, which account for 16% and 4%

of the administered dose respectively.

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Elimination

Meloxicam is excreted predominantly in the form of metabolites and occurs to equal extents inurine and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while onlytraces of the parent compound are excreted in urine. The mean elimination half-life is about 20hours. 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 to15 mg following per oral or intramuscular administration.

Special populations

Hepatic/renal Insufficiency:

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

Elderly

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

5.3 PRECLINICAL SAFETY DATAThe 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 highdoses 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 at1 mg/kg and higher. 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 usedclinically.

6 PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTSSodium citrate dihydrateLactose monhydrateMicrocrystaline cellulosePovidone

CrospovidoneColloidal anhydrous silicaMagnesium stearate

6.2 INCOMPATIBILITIESNot applicable

6.3 SHELF LIFE24 months

6.4 SPECIAL PRECAUTIONS FOR STORAGEDo not store above 25

oC. Do not refrigerate or freeze. Store in the original package. Keep the

blister in the outer carton.

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6.5 NATURE AND CONTENTS OF CONTAINERPVC/ PVDC- Aluminium blisters in packs of 30 tablets

6.6 SPECIAL PRECAUTIONS FOR DISPOSALNo special requirements

7 MARKETING AUTHORISATION HOLDERKent Pharmaceuticals Ltd.,Wotton Road,Ashford,Kent TN23 6LL,

UK.

8 MARKETING AUTHORISATION NUMBER(S)PL08215/0082

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION09/05/2008

10 DATE OF REVISION OF THE TEXT

09/05/2008

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF

APPLICABLE)

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1 NAME OF THE MEDICINAL PRODUCTMeloxicam 15mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach tablet contains 15mg meloxicam

For excipients see 6.1.

3 PHARMACEUTICAL FORMTablet for oral administration.

Light yellow, round, flat, scored on one side, 10.5mm diameter tablets.

4 CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONSMeloxicam is indicated for the short term symptomatic treatment of exacerbations ofosteoarthrosis, long term symptomatic treatment of rheumatoid arthritis or ankylosingspondylitis.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

Meloxicam tablets are for oral administration only. The total daily dose should be taken as asingle dose, preferably with or after food..


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 symptomaticrelief and response to therapy should be re-evaluated periodically, especially in patients withosteoarthritis.

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 foradverse reactions should initiate therapy at 7.5mg a day. According to the therapeuticresponse, the dose may be reduced to 7.5mg/day.

Ankylosing spondylitis: The recommended daily dose is 15mg a day. Patients at increased riskfor adverse reactions should initiate therapy at 7.5mg a day. According to the therapeuticresponse, the dose may be reduced to 7.5mg/day.



Elderly:

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

therapy.

In elderly patients being treated for rheumatoid arthritis and ankylosing spondylitis, therecommended 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

fifteen years.


Meloxicam is contraindicated in severe hepatic impairment (see Contraindications). Cautionshould 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 hepaticimpairment ( see section 4.3 Contraindications).

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Renal impairment:

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

4.3 CONTRAINDICATIONSThis medicinal product is contra-indicated in the following situations:

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

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

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions

(e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

Severe heart failure, hepatic failure and severe non-dialysed renal failure (see section 4.4).

During the last trimester of pregnancy (see section 4.6)

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USEUndesirable effects may be minimised by using the lowest effective dose for the shortestduration 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 insufficienttherapeutic 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 Meloxicamwith concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided

(see section 4.5).

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

Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensuretheir total cure before starting treatment with meloxicam. Attention should routinely be paid tothe 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 ofserious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, inpatients 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 lowestdose available. Combination therapy with protective agents (e.g. misoprostol or proton pump

inhibitors) should be considered for these patients, and also for patients requiring concomitantlow 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 unusualabdominal 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 warfarin,selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

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

NSAIDs should be given with care to patients with a history of gastrointestinal disease(ulcerative colitis, Crohns 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 especiallygastrointestinal 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 suchpatients.

Cardiovascular, Renal and Hepatic Impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin

formation and precipitate renal failure. Patients at greatest risk of this reaction are those with

impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and theelderly. Renal function should be monitored in these patients (see also section 4.3).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertensionand/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 highdoses 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 toexclude such a risk for meloxicam.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart

disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated withmeloxicam after careful consideration. Similar consideration should be made before initiatinglonger-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 withthe 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 thefirst month of treatment. Meloxicam should be discontinued at the first appearance of skinrash, mucosal lesions, or any other sign of hypersensitivity.

As with most NSAIDs, occasional increases in serum transaminase levels, increases in serumbilirubin or other liver function parameters, as well as increases in serum creatinine and bloodurea nitrogen as well as other laboratory disturbances, have been reported. The majority ofthese instances involved transitory and slight abnormalities. Should any such abnormality

prove significant or persistent, the administration of Meloxicam should be stopped andappropriate investigations undertaken.

Functional renal failure

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

Elderly

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

Hypovolemia (whatever the cause) Congestive heart failure Renal failure Nephrotic syndrome Lupus nephropathy Severe hepatic dysfunction (serum albumin

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Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase therisk of adverse effects (see section 4.4).

Cardiac glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs canreduce the effect of mifepristone.

Quinolone antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated withquinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of

developing convulsions.

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There isevidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacsreceiving concurrent treatment with zidovudine and ibuprofen.

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 thegastroduodenal 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.

Anti-platelet agents and 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 canincrease the risk of nephrotoxicity of NSAIDs. In some patients with compromised renalfunction (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 renalfailure, which is usually reversible. Therefore, the combination should be administered withcaution, especially in the elderly. Patients should be adequately hydrated and considerationshould be given to monitoring of renal function after initiation of concomitant therapy, andperiodically 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 ofprostaglandins with vasodilatory effect) can occur.

Cyclosporin:

Nephrotoxicity of cyclosporin may be enhanced by NSAIDs via renal prostaglandin mediated

effects. During combined treatment renal function is to be measured. A careful monitoring ofthe renal function is recommended, especially in the elderly.

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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 notrecommended (see section 4.4). If this combination appears necessary, lithium plasmaconcentrations should be monitored carefully during the initiation, adjustment and withdrawalof meloxicam treatment.

Methotrexate:

NSAIDs can reduce the tubular secretion of methotrexate thereby increasing the plasmaconcentrations 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 impairedrenal function. In case combination treatment is necessary blood cell count and the renalfunction should be monitored. Caution should be taken in case both NSAID and methotrexateare given within 3 days, in which case the plasma level of methotrexate may increase andcause increased toxicity.

Although the pharmacokinetics of methotrexate (15mg/week) were not relevantly affected byconcomitant meloxicam treatment, it should be considered that the haematological toxicity ofmethotrexate 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 enterohepaticcirculation 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 tothe concomitant administration of antacids, cimetidine and digoxin.

4.6 PREGNANCY AND LACTATIONPregnancy

Congenital abnormalities have been reported in association with NSAID administration inman; however these are low in frequency and do not appear to follow any discernible pattern.

In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closureof the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset oflabour may be delayed and the duration increased with an increased bleeding tendency in both

mother and child (see section 4.3). NSAIDs should not be used during the first two trimestersof pregnancy or labour unless the potential benefit to the patient outweighs the potential riskto the foetus.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or theembryo/foetal development. Data from epidemiological studies suggest an increased risk ofmiscarriage and of cardiac malformation and gastroschisis after use of a prostaglandinsynthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation wasincreased from less than 1%, up to approximately 1.5 %. The risk is believed to increase withdose 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-foetallethality. In addition, increased incidences of various malformations, including cardiovascular,have been reported in animals given a prostaglandin synthesis inhibitor during the

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organogenetic period. During the first and second trimester of pregnancy, meloxicam shouldnot be given unless clearly necessary. If meloxicam is used by a woman attempting toconceive, 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 thefoetus to:

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonaryhypertension)

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 atvery low doses.

inhibition of uterine contractions resulting in delayed or prolonged labour.

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

Lactation

In limited studies so far available, NSAIDs can appear in breast milk in very lowconcentrations. NSAIDs should, if possible, be avoided when breastfeeding.

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

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

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

4.8 UNDESIRABLE EFFECTSClinical 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) (see section 4.4).

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 section4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain,melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohns disease (seesection 4.4 - Special warnings and precautions for use) have been reported followingadministration. Less frequently, gastritis has been observed. Pancreatitis has been reported

very rarely.

Hypersensitivity

Hypersensitivity reactions have been reported following treatment with NSAIDs. These mayconsist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivitycomprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skindisorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and more

rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythemamultiforme).

b) General descriptionThe following adverse events, which may be casually related to the administraion of

meloxicam, have been reported. The frequencies given below are based on correspondingoccurances in clinical trials, regardless of any casual relationship. The information is based on

clinical trials involving 3750 patients who have been treated with daily oral doses of 7.5 or 15

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mg meloxicam tablets or capsules over a period of 18 months (mean duration of treatment127days).

Adverse events which may be casually related to the administration of meloxicam that havecome to light as a result of reports received in relation to administraion of the marketedproduct are included.

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

Very common (1/10); common (1/100,

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Rare: Hepatitis.

Skin and subcutaneous tissue disorder

Common: Pruritus, rash

Uncommon: Urticaria

Rare: Stevens-Johnson syndrome and toxic epidermal necrolysis, angiodema, bullousreactions such as erythema multiforme, photosensitivity reactions

Renal and urinary disorders

Uncommon: Disturbances of laboratory tests investigating renal function (e.g. raisedcreatinine or urea).

Rare: Renal failure (see section 4.4)

General disorders and administration site conditions

Common: Oedema including oedema of the lower limbs

c) Information characterising individual serious and/or frequently occurring adverse reactions

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

Adverse reactions which have not been observed yet in relation to the product, but which aregenerally accepted as being attributable to other compounds in the class

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

4.9 OVERDOSESymptoms:

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding,rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting,

occasionally convulsions. In cases of significant poisoning acute renal failure and liverdamage are possible.

Therapeutic measure

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should beconsidered. Alternatively, in adults gastric lavage should be considered within one hour ofingestion 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 leastfour hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions

should be treated with intravenous diazepam.Other measures may be indicated by the patients clinical condition.

5 PHARMACOLOGICAL PROPERTIES5.1 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 andantipyretic properties.

The anti-inflammatory activity of meloxicam has been proven in classical models ofinflammation. 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 (includingMeloxicam): inhibition of the biosynthesis of prostaglandins, known inflammation mediators.

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5.2 PHARMACOKINETIC PROPERTIESAbsorption

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

Following single dose administration of meloxicam, mean maximum plasma concentrationsare achieved within 2 hours for the suspension and within 7-8 hours with solid oral dosageforms (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 relativelysmall peak-trough fluctuation in the range of 0.4 - 1.0 g/ml for 7.5 mg doses and 0.8 - 2.0

g/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 toeight 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 oncesteady 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%). Meloxicampenetrates 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 majormetabolite, 5-carboxymeloxicam (60% of dose), is formed by oxidation of an intermediate

metabolite 5- hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% ofdose). 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 patients peroxidaseactivity 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 inurine 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 20hours. 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 meloxicampharmacokinetics. 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 beexceeded (see section 4.2).

Elderly

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

5.3 PRECLINICAL SAFETY DATAThe toxicological profile of Meloxicam has been found in preclinical studies to be identical tothat 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 ofimplantations and embryotoxic effects (increase of resorptions) at maternotoxic dose levels at

1 mg/kg and higher. These dose levels exceeded the clinical dose (7.5-15 mg) by a factor of 10to 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. Nocarcinogenic risk has been found in the rat and mouse at doses far higher than those used

clinically.

6 PHARMACEUTICAL PARTICULARS6.1 LIST OF EXCIPIENTS

Sodium citrate dihydrateLactose monhydrateMicrocrystaline cellulosePovidoneCrospovidoneColloidal anhydrous silica

Magnesium stearate

6.2 INCOMPATIBILITIESNot applicable

6.3 SHELF LIFE24 months

6.4 SPECIAL PRECAUTIONS FOR STORAGEDo 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 CONTAINERPVC/ PVDC- Aluminium blisters in packs of 30 tablets.

6.6 SPECIAL PRECAUTIONS FOR DISPOSALNo special requirements.

7 MARKETING AUTHORISATION HOLDERKent Pharmaceuticals Ltd.,Wotton Road,Ashford,

Kent TN23 6LL,UK.

8 MARKETING AUTHORISATION NUMBER(S)Meloxicam 15mg Tablets PL08215/0083

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/05/2008

10 DATE OF REVISION OF THE TEXT

09/05/2008

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF

APPLICABLE)

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PL 08215/0082


PL 08215/0083

PATIENT INFORMATION LEAFLET

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PL 08215/0082


PL 08215/0083

LABELLING

Carton-Meloxicam 7.5mg Tablets

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Carton-Meloxicam 15mg Tablets

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