MELOREX Tablet Ref.[50648] Active ingredients: Meloxicam

Gastrointestinal effects

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 Melorex tablets should be withdrawn if peptic ulceration or gastrointestinal bleeding occurs.

Serious gastrointestinal (GI) toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which may be potentially fatal, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. The consequences of such events are generally more serious in the elderly.

As with other NSAIDs, caution should be exercised in patients receiving treatment with anticoagulants.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1 % of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.

Studies have shown that patients with a prior history of ulcer disease and/or gastrointestinal bleeding and who use NSAIDs have a greater than 10-fold higher risk of developing a gastrointestinal bleed than patients with neither of these factors.

Caution is advised in patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or aspirin concomitantly or patients with a prior history of or recent gastrointestinal disease such as ulceration and gastrointestinal bleeding.

NSAIDs should be prescribed with caution in patients with a prior history of or recent ulcer disease or gastrointestinal bleeding. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Minor upper GI problems, such as dyspepsia, are common and may occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur.

Cardiovascular and cerebrovascular effects

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Use of COX-2 inhibitors (of which meloxicam is one) has been associated with an increased risk of cardiovascular adverse events (myocardial infarction and stroke). This association has been demonstrated with agents of the Coxib class. Adverse cardiovascular events can occur with both short term and long-term use.

Prescribers should inform the individual patient of the (possible or potential) increased risks when prescribing Melorex tablets for patients at high risk of cardiovascular adverse events (including patients with diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension or smokers).

Two large controlled clinical trials of a different COX-2 selective inhibitor for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. In the absence of comparable data with meloxicam, it may be assumed that patients at high risk of cardiovascular disease (including patients with diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension, or smokers) who are undergoing any major surgery may face an increased risk of developing a cardiovascular event. Such patients with significant risk factors for cardiovascular events should only be treated with meloxicam after careful consideration of the patient’s overall risk and the potential risks and benefits of alternative analgesic therapies.

Melorex tablets are not a substitute for cardiovascular prophylaxis and concurrent anti-platelet therapies should not be discontinued. There is no evidence that concurrent use of aspirin decreases the risk of cardiovascular adverse events associated with COX-2 inhibitors, including Melorex tablets.

Concurrent use of aspirin negates most of the gastrointestinal benefit associated with COX-2 inhibitors, including Melorex tablets.

Skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Melorex tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Renal function

As with other NSAIDs, meloxicam inhibits the synthesis of renal prostaglandins which play a supportive role in the maintenance of renal perfusion. In patients whose renal blood flow and blood volume are decreased, administration of an NSAID may precipitate overt renal decompensation which is typically followed by recovery to pre-treatment state upon discontinuation of non-steroidal anti-inflammatory therapy. Patients at greatest risk of such a reaction are elderly individuals, dehydrated patients, those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, those receiving concomitant treatment with a diuretic, ACE inhibitor or angiotensin II receptor antagonist or those having undergone major surgical procedures, which led to hypovolaemia. In such patients, the volume of diuresis and the renal function should be carefully monitored at the beginning of therapy.

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

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

Liver function

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

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

Sodium, potassium and water retention

Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Use of COX-2 inhibitors (of which meloxicam is one) or other NSAIDs may precipitate or exacerbate pre-existing hypertension, cardiac failure or oedema in susceptible patients, and the treatment of these conditions may be compromised. For patients at risk, clinical monitoring is recommended.

Other warnings and precautions

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

Meloxicam, as any other NSAID may mask symptoms of an underlying infectious disease.

The use of Melorex tablets, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of Melorex tablets should be considered.

Meloxicam tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Associations to be taken into account:

• Other Prostaglandin Synthetase Inhibitors (PSI) including glucocorticoids and salicylates: (acetylsalicylic acid): Co-administration of PSIs may increase the risk of gastrointestinal ulcers and bleeding via a synergistic effect and is not recommended. The concomitant use of meloxicam with other NSAIDs is not recommended. Concomitant administration of aspirin (1000 mg tid) to healthy volunteers tended to increase the AUC (10%) and C_max (24%) of meloxicam. The clinical significance of this interaction is not known.
• Oral anticoagulants, antiplatelet drugs, systemically administered heparin, thrombolytics and Selective Seratonin Reuptake Inhibitors (SSRIs): increased risk of bleeding via inhibition of platelet function. If such co-prescribing cannot be avoided, close monitoring is required.
• Lithium: NSAIDs have been reported to increase lithium plasma levels.
• 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. 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 NSAID drugs.
• Contraception: A decrease of the efficacy of intrauterine devices by NSAIDs has been previously reported but needs further confirmation.
• Diuretics: Treatment with NSAIDs is associated with the potential for acute renal insufficiency in patients who are dehydrated. Patients receiving meloxicam and diuretics should be adequately hydrated and be monitored for renal function prior to initiating treatment.
• Antihypertensives (e.g. beta-blockers, ACE-inhibitors, vasodilators, diuretics): A reduced effect of the antihypertensive drug by inhibition of vasodilating prostaglandins has been reported during treatment with NSAIDs.
• NSAIDs and angiotensin-II receptor antagonists as well as ACE inhibitors exert a synergistic effect on the decrease of glomerular filtration. In patients with pre-existing renal impairment this may lead to acute renal failure.
• Cholestyramine binds meloxicam in the gastrointestinal tract leading to a faster elimination of meloxicam.
• Nephrotoxicity of cyclosporin may be enhanced by NSAID’s via renal prostaglandin mediated effects. During combined treatment renal function is to be measured.
• Interactions with oral antidiabetics cannot be excluded.
• 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 two days following pemetrexed administration. If a combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, especially for myelosuppression and gastrointestinal adverse reactions. In patients with creatinine clearance below 45 mL/min the concomitant administration of meloxicam with pemetrexed is not recommended.
• Antiplatelet drugs and Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of bleeding via inhibition of platelet function.

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 hypoglycaemia.

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

Pregnancy

Meloxicam is contraindicated in the 3^rd trimester of pregnancy.

Inhibition of prostaglandin-synthesis may adversely affect pregnancy and/or the embryo-foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation and gastrochisis 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 increase 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.

Meloxicam should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. If there is a compelling need for NSAID treatment during the first or second trimester, limit use to the lowest effective dose and shortest duration possible.

Data from epidemiological studies suggest an increased risk of miscarriage and congenital malformation associated with NSAID use in early pregnancy.

Use of NSAIDs in the second or third trimester may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Oligohydramnios is generally seen after days to weeks of treatment, although it has been reported as soon as 48 hours after NSAID initiation. Oligohydramnios is usually, but not always, reversible after treatment discontinuation. Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with [NSAID] if oligohydramnios occurs.

NSAID use during the 3rd trimester may cause premature closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation, and may delay labour and birth. NSAID use in the 3rd trimester of pregnancy is therefore contraindicated.

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

Breast feeding

While no specific experience exists for Meloxicam tablets, NSAIDs are known to pass into mother’s milk. Administration therefore, is contraindicated in women who are breastfeeding.

Fertility

The use of meloxicam, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Meloxicam may delay ovulation. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of meloxicam should be considered.

There are no specific studies about the effects on the ability to drive vehicles and to use machinery. Patients who experience visual disturbances, drowsiness or other central nervous system disturbances should refrain from these activities.

The meloxicam phase II/III safety database includes 10,122 osteoarthritis patients and 1012 rheumatoid arthritis patients treated with meloxicam 7.5 mg/day and 3,505 osteoarthritis patients and 1351 rheumatoid arthritis patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least six months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo and or active-controlled osteoarthritis trials and 2362 of these patients were treated in ten placebo and or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials.

Gastrointestinal disorders

Adverse events occurring in ≥2% of meloxicam patients in a 12-week osteoarthritis placeboand active-controlled trial: abdominal pain, diarrhea, dyspepsia, flatulence, nausea.

The adverse events that occurred with meloxicam in ≥2% of patients treated short-term (4-6 weeks) and long-term (6 months) in active controlled osteoarthritis trials: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea, vomiting.

The adverse events that occurred in <2% of patients, treated with daily oral doses of 7.5 or 15 mg meloxicam tablets or capsules over a period of up to 18 months: oesophagitis, gastroduodenal ulcer, occult or macroscopic gastrointestinal haemorrhage, gastrointestinal perforation, colitis, gastritis.

b. Tabulated list of adverse reactions

The following adverse drug reactions, which may be causally related to the administration of meloxicam, have been reported.

Adverse drug reactions that have come to light as a result of reports received in relation to administration of the marketed product are included.

The following terms are used to rank the adverse drug reactions by frequency: 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).

Table 1. Summary of adverse drug reactions per frequency category:

¹ Concomitant administration of a potentially myelotoxic drug, in particular methotrexate, appears to be a predisposing factor to the onset of cytopenia.
² Frequency not known, no adverse drug reactions observed in 15,197 patients in clinical trials.
³ Gastrointestinal haemorrhage, ulceration or perforation may potentially be fatal.
⁴ Frequency not known, no adverse drug reactions observed in 286 female patients with an age ≤50 years in clinical trials which are a subpopulation of the 15,197 patients in clinical trials with an observation period of at least 90 days.

Post-marketing experience

Oligohydramnios, neonatal renal impairment

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

Not applicable.