MELCAM Tablet Ref.[28248] Active ingredients: Meloxicam

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

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 effects

Gastrointestinal (GI) bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time 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 acetylsalicylic acid, or other medicinal products likely to increase gastrointestinal risk (see below and section 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.

In patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as heparin as curative treatment or given in geriatrics, anticoagulants such as warfarin or other non-steroidal anti-inflammatory drugs or acetylsalicylic acid given at doses (≥500 mg as single intake or ≥3 g as total daily amount the combination with meloxicam is not recommended (see section 4.5).

When 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).

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

Clinical trial and epidemiological data suggest that use of some NSAIDs including meloxicam (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.

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).

Skin reactions

• Life-threatening cutaneous reactions including 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 medicinal product. 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 function

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 and 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 the renal function including the volume of diuresis 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)
• hypovolaemia (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.

The dose of meloxicam in patients with end-stage renal failure on haemodialysis should not exceed 7.5 mg. No dose reduction is required in patients with mild or moderate renal impairment (i.e. in patients with a creatinine clearance of greater than 25 ml/min).

Sodium, potassium 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 medicinal products 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.

Combination with pemetrexed

In patients with mild to moderate renal insufficiency receiving pemetrexed, meloxicam should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).

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.

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 infertility, withdrawal of meloxicam should be considered (see section 4.6).

Melcam contains lactose and sodium

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially ‘sodium-free’.

Risksrelatedtohyperkalaemia

Certain medicinal products or therapeutic groups may promote hyperkalaemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, (low-molecular-weight or unfractionated) heparins, ciclosporin, tacrolimus and trimethoprim. The onset of hyperkalaemia may depend on whether there are associated factors.

This risk is increased when the above-mentioned medicinal products are co-administered with meloxicam.

Pharmacodynamic interactions

Other non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid

Combination (see section 4.4) with other non-steroidal anti-inflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (≥500 mg as single intake or ≥3 g as total daily amount) is not recommended.

Corticosteroids (e.g. glucocorticoids)

The concomitant use with corticosteroids requests caution because of an increased risk of bleeding or gastrointestinal ulceration.

Anticoagulants including heparin

Considerably increased risk of bleeding, via inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anti-coagulants, including coumarins (vitamin K antagonists) such as warfarin (see section 4.4), novel oral anticoagulants (NOACs) and heparin. The concomitant use of NSAIDs and heparin administered in geriatrics or at curative dose, or other anti-coagulants is not recommended (see section 4.4).

In remaining cases (e.g. preventive doses) of heparin use caution is necessary due to an increased bleeding risk. Careful monitoring of the INR is required if it proves impossible to avoid such combination.

Thrombolytics and antiplatelet medicinal products

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.

Diuretics, ACE inhibitors and Angiotensin-II antagonists

NSAIDs may reduce the effect of diuretics and other antihypertensive medicinal products. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration 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 medicinal products (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, tacrolimus)

Nephrotoxicity 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.

Deferasirox

The concomitant administration of meloxicam with deferasirox may increase the risk of gastro-intestinal adverse reactions. Caution should be exercised when combining these medicinal products.

Pharmacokinetic interactions: Effect of meloxicam on the pharmacokinetics of other medicinal products

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 (15 mg/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 NSAIDs (see above) (see section 4.8).

Pemetrexed

For the concomitant use of meloxicam with pemetrexed in patients with creatinine clearance from 45 to 79 ml/min, the administration of meloxicam should be paused for 5 days before, on the day of, and 2 days following pemetrexed administration. If a combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, especially for myelosuppression and gastro-intestinal adverse reactions. In patients with severe renal impairment (creatinine clearance below 45 ml/min) the concomitant administration of meloxicam with pemetrexed is not recommended.

In patients with normal renal function (creatinine clearance ≥80 ml/min), doses of 15 mg meloxicam may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be exercised when administering 15 mg meloxicam concurrently with pemetrexed to patients with normal function (creatinine clearance ≥80 ml/min).

Pharmacokinetic interactions: Effect of other medicinal products 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.

Pharmacokinetic Interactions: Effect of combination of meloxicam and of other drugs on the pharmacokinetics

Oral antidiabetics (sulphonylureas, nateglinide)

Meloxicam is eliminated almost entirely by hepatic metabolism, of which approximately two thirds are mediated by cytochrome (CYP) P450 enzymes (CYP 2C9 major pathway and CYP 3A4 minor pathway) and one-third by other pathways, such as peroxidase oxidation. The potential for a pharmacokinetic interaction should be taken into account when meloxicam and drugs known to inhibit, or to be metabolised by, CYP 2C9 and/or CYP 3A4 are administered concurrently. Interactions via CYP 2C9 can be expected in combination with medicinal products such as oral antidiabetics (sulphonylureas, nateglinide), which may lead to increased plasma levels of these drugs and meloxicam. Patients concomitantly using meloxicam with sulphonylureas or nateglinide should be carefully monitored for hypoglycemia.

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

Paediatric population

Interaction studies have only been performed in adults.

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, at the end of pregnancy, 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 contraindicated during the third trimester of pregnancy.

Breast-feeding

While no specific experience exists for meloxicam in humans, NSAIDs (non-steroidal anti-inflammatory drugs) are known to pass into mother’s milk. Meloxicam has been found in the milk of nursing animals.

A risk cannot be ruled out and administration is not recommended in women who are breast-feeding.

Fertility

The use of meloxicam, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, 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 infertility, withdrawal of meloxicam should be considered.

No specific studies with respect to the effects on the ability to drive and use machinery have been performed. However, on the basis of the pharmacodynamic profile and reported adverse drug reactions, meloxicam is likely to have no or negligible influence on the ability to drive and use machines. However, when visual disturbances, dizziness, vertigo or other central nervous system disturbances occur, it is advisable to refrain from driving and operating machinery.

a) General Description

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) (see section 4.4).

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

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) have been reported following administration. Less frequently, gastritis has been observed. Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

The frequencies of adverse drug reactions given below are based on corresponding occurrences of reported adverse events in 27 clinical trials with a treatment duration of at least 14 days. The information is based on clinical trials involving 15197 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 drug reactions 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 headings of frequency using the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

b) Table of adverse reactions

^* Cardiac failure has been reported in association with NSAID treatment
^** Gastrointestinal haemorrhage, ulceration or perforation may sometimes be severe and potentially fatal, especially in elderly (see section 4.4).

c) Information Characterising Individual Serious and/or Frequently Occurring Adverse Reactions

Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (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: very rare 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 HPRA Pharmacovigilance; website: www.hpra.ie.

Not applicable.