Meloxicam

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

The concomitant use of meloxicam with selective serotonin reuptake inhibitors (SSRIs) requests caution because of increased risk of gastrointestinal bleeding.

Considerably increased risk of bleeding, via inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anti-coagulants, such as warfarin. The concomitant use of NSAIDs and anticoagulants or heparin administered in geriatrics or at curative dose is not recommended.

In cases 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.

The concomitant use of meloxicam with thrombolytics, antiplatelet drugs requests caution because of increased risk of bleeding, via inhibition of platelet function and damage to the gastroduodenal mucosa.

In concomitant use of meloxicam with beta-blockers, a decrease of the antihypertensive effect of beta-blockers (due to inhibition of prostaglandins with vasodilatory effect) can occur.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. 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.

Combination of meloxicam with other non steroidal anti-inflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (≥1g as single intake or ≥3g as total daily amount) is not recommended.

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.

Nephrotoxicity of calcineurin inhibitors (cyclosporin) 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.

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. If this combination appears necessary, lithium plasma concentrations should be monitored carefully during the initiation, adjustment and withdrawal of meloxicam treatment.

NSAIDs can reduce the tubular secretion of methotrexate thereby increasing the plasma concentrations of methotrexate. For this reason, for patients on high dosages of methotrexate (more than 15 mg/week) the concomitant use of NSAIDs is not recommended.

The risk of an interaction between NSAID preparations and methotrexate, should be considered also in patients on low dosage of methotrexate, especially in patients with impaired renal function. In case combination treatment is necessary blood cell count and the renal function should be monitored. Caution should be taken in case both NSAID and methotrexate are given within 3 days, in which case the plasma level of methotrexate may increase and cause increased toxicity.

Although the pharmacokinetics of methotrexate (15mg/week) were not relevantly affected by concomitant meloxicam treatment, it should be considered that the haematological toxicity of methotrexate can be amplified by treatment with NSAID drugs (see above).

Nephrotoxicity of calcineurin inhibitors (tacrolimus) 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.

Co-administration of telmisartan with meloxicam may increase the risk of acute renal failure and hyperkalaemia.

Meloxicam may antagonize the antihypertensive effect of timolol.

Meloxicam may antagonize the antihypertensive effect of trandolapril.

When treprostinil is co-administered with meloxicam, the risk of bleeding may be increased.

Voriconazole can increase the concentration of meloxicam in the serum, reducing its metabolism.

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.

In dialysis patients with severe renal failure, the dose should not exceed 7.5 mg per day.

Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Furthermore, a decrease of the antyhypertensive effect of antyhypertensive drugs can occur. 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.

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 oligohydroamniosis;

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.

While no specific experience exists for meloxicam, NSAIDs are known to pass into mother’s milk. Administration therefore is not recommended in women who are breastfeeding.

There are no specific studies on the ability to drive and use machinery. However, on the basis of the pharmacodynamic profile and reported adverse drug reactions, meloxicam is likely to have no or negligible influence on these abilities. However, when visual disturbances or drowsiness, 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).

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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.

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, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000).

b) List of adverse reactions

Blood and lymphatic system disorders

Uncommon: Anaemia

Rare: Blood count abnormal (including differential white cell count), leukopenia, thrombocytopenia

Very rare cases of agranulocytosis have been reported (see section c).

Immune system disorders

Uncommon: Hypersensitivity, allergic reactions other than anaphylactic or anaphylactoid reactions

Not known: Anaphylactic reaction, anaphylactoid reaction

Psychiatric disorders

Rare: Mood altered, nightmares

Not known: Confusional state, disorientation

Nervous system disorders

Common: Headache

Uncommon: Dizziness, somnolence

Eye disorders

Rare: Visual disturbance including vision blurred; conjunctivitis

Ear and labyrinth disorders

Uncommon: Vertigo

Rare: Tinnitus

Cardiac disorders

Rare: Palpitations

Cardiac failure has been reported in association with NSAID treatment.

Vascular disorders

Uncommon: Blood pressure increased, flushing

Respiratory, thoracic and mediastinal disorders

Rare: Asthma in individuals allergic to aspirin or other NSAIDs

Gastrointestinal disorders

Very common: Dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhoea

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

Rare: Colitis, gastroduodenal ulcer, oesophagitis

Very rare: Gastrointestinal perforation

Not known: Pancreatitis

Gastrointestinal haemorrhage, ulceration or perforation may sometimes be severe and potentially fatal, especially in elderly.

Hepatobiliary disorders

Uncommon: Liver function disorder (e.g. raised transaminases or bilirubin)

Very rare: Hepatitis

Skin and subcutaneous tissue disorders

Uncommon: Angioedema, pruritus, rash

Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Very rare: Dermatitis bullous, erythema multiforme

Not known: Photosensitivity reaction

Renal and urinary disorders

Uncommon: Sodium and water retention, hyperkalaemia, renal function test abnormal (increased serum creatinine and/or serum urea)

Very rare: Acute renal failure in particular in patients with risk factors

General disorders and administration site conditions

Uncommon: Oedema including oedema of the lower limbs.

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 drugs.

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.