Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Alpex Pharma (UK) Limited, Warren Plantation Church End, Haynes, Bedford, MK45 3RJ, UK Contact address: PO BOX 849, Bedford, MK45 9EG
This medicinal product is contra-indicated in the following situations:
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).
The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, nor should an additional NSAID be added to the therapy because this may increase the toxicity while therapeutic advantage has not been proven. The use of Meloxicam Orodispersible Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Meloxicam Orodispersible Tablets 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.
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5).
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution is advised 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, including acetylsalicylic acid given at antiinflammatory doses (≥1g as single intake or ≥3g as total daily amount) (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving Meloxicam orodispersible tablets the treatment should be withdrawn.
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 Orodispersible Tablets.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for meloxicam.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with meloxicam orodispersible tablets 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).
Serious skin reactions, some of them fatal, including exfoliative dermatitis, StevensJohnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: The onset of the reaction occurring in the majority of cases within the first month of treatment. Meloxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
As with most NSAIDs, occasional increases in serum transaminase levels, increases in serum bilirubin or other liver function parameters, as well as increases in serum creatinine and blood urea nitrogen as well as other laboratory disturbances, have been reported. The majority of these instances involved transitory and slight abnormalities. Should any such abnormality prove significant or persistent, the administration of Meloxicam should be stopped and appropriate investigations undertaken.
NSAIDs, by inhibiting the vasodilating effect of renal prostaglandins, may induce a functional renal failure by reduction of glomerular filtration. This adverse event is dose-dependant. At the beginning of the treatment, or after dose increase, careful monitoring of diuresis and renal function is recommended in patients with the following risk factors:
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 be higher than 7.5 mg. No dose reduction is required in patients with mild or moderate renal impairment (i.e. patients with a creatinine clearance of greater than 25 ml/min).
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 (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 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.
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 orodispersible tablet, as any other NSAID may mask symptoms of an underlying infectious disease.
The use of meloxicam orodispersible tablet, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair 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.
Meloxicam orodispersible tablet contains a source of phenylalanine: Aspartame (E951) and may be harmful for people with phenylketonuria.
Meloxicam orodispersible tablet contains Sorbitol (E420): Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Interaction studies have only been performed in adults.
Meloxicam is metabolised in liver, mostly by CYP 2C9 and CYP 3A4. Possibility of pharmacokinetic interactions between meloxicam and drugs inhibiting or being metabolised by CYP 2C9 and CYP 3A4 has to be considered.
combination (see section 4.4) 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.
The concomitant use with corticosteroids requests caution because of an increased risk of bleeding or gastrointestinal ulceration.
Anticoagulant or heparin administered in geriatrics or at curative doses:
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 (see section 4.4). The concomitant use of NSAIDs and anticoagulants or heparin administered in geriatrics or at curative dose is not recommended (see section 4.4).
In remaining 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.
Increased risk of bleeding, via inhibition of platelet function and damage to the gastroduodenal mucosa.
Increased risk of gastrointestinal bleeding (see section 4.4).
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 (see also section 4.4).
As for the latter, a decrease of the antihypertensive effect of beta-blockers (due to inhibition of prostaglandins with vasodilatory effect) can occur.
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.
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.
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.
NSAIDs can reduce the tubular secretion of methotrexate thereby increasing the plasma concentrations of methotrexate. For this reason, for patients on high dosages of methotrexate (more than 15 mg/week) the concomitant use of NSAIDs is not recommended (see section 4.4).
The risk of an interaction between NSAID preparations and methotrexate, should be considered also in patients on low dosage of methotrexate, especially in patients with impaired renal function. In case combination treatment is necessary blood cell count and the renal function should be monitored. Caution should be taken in case both NSAID and methotrexate are given within 3 days, in which case the plasma level of methotrexate may increase and cause increased toxicity.
Although the pharmacokinetics of methotrexate (15mg/week) were not relevantly affected by concomitant meloxicam treatment, it should be considered that the haematological toxicity of methotrexate can be amplified by treatment with NSAID drugs (see above). (See section 4.8)
Cholestyramine accelerates the elimination of meloxicam by interrupting the enterohepatic circulation so that clearance for meloxicam increases by 50% and the half-life decreases to 13 + 3 hrs. This interaction is of clinical significance.
No clinically relevant pharmacokinetic drug-drug interactions were detected with respect to the concomitant administration of antacids, cimetidine and digoxin.
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:
the mother and the neonate, at the end of pregnancy, to:
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.
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 – Special warnings and precautions for use) 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)
Uncommon: Anaemia
Rare: Blood count abnormal (including differential white cell count), leukopenia, thrombocytopenia
Very rare cases of agranulocytosis have been reported (see section c).
Uncommon: Hypersensitivity, allergic reactions other than anaphylactic or anaphylactoid reactions
Not known: Anaphylactic reaction, anaphylactoid reaction
Rare: Mood altered, nightmares
Not known: Confusional state, disorientation
Common: Headache
Uncommon: Dizziness, somnolence
Rare: Visual disturbance including vision blurred; conjunctivitis
Uncommon: Vertigo
Rare: Tinnitus
Rare: Palpitations
Cardiac failure has been reported in association with NSAID treatment.
Uncommon: Blood pressure increased (see section 4.4), flushing
Rare: Asthma in individuals allergic to aspirin or other NSAIDs
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 (see section 4.4).
Uncommon: Liver function disorder (e.g. raised transaminases or bilirubin)
Very rare: Hepatitis
Uncommon: Angioedema, pruritus, rash
Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Very rare: Dermatitis bullous, erythema multiforme
Not known: Photosensitivity reaction
Uncommon: Sodium and water retention, hyperkalaemia (see section 4.4. Special warnings and special precautions for use and section 4.5.), renal function test abnormal (increased serum creatinine and/or serum urea)
Very rare: Acute renal failure in particular in patients with risk factors (see section 4.4.)
Uncommon: Oedema including oedema of the lower limbs.
Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic drugs (see section 4.5).
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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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