Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
History of gastro-intestinal bleeding (melaena, haematemesis), perforation related to previous NSAID therapy or severe gastritis.
Hypersensitivity to tenoxicam or to any of the excipients.
NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (induce symptoms of asthma, rhinitis, angio-oedema or urticaria) in response to salicylates, ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS).
Severe renal, hepatic or heart failure (see section 4.4).
Mobiflex is contraindicated during the last trimester of pregnancy (see section 4.6).
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 use of Mobiflex with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors or 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 should be avoided (see section 4.5).
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 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.
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).
When GI bleeding or ulceration occurs in patients receiving tenoxicam, 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).
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients should be advised of the signs and symptoms and monitored closely for skin reactions. 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. Mobiflex should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
If the patient has developed SJS or TEN with the use of tenoxicam, tenoxicam must not be re-started in this patient at any time.
In rare cases, non-steroidal anti-inflammatory drugs may cause interstitial nephritis, glomerulonephritis, papillary necrosis and the nephrotic syndrome. Such agents inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients, administration of a non-steroidal anti-inflammatory drug may precipitate overt renal decompensation, which returns to the pre-treatment state upon withdrawal of the drug. Patients at greatest risk of such a reaction are those with pre-existing renal disease (including diabetics with impaired renal function), nephrotic syndrome, volume depletion, hepatic disease, congestive cardiac failure, patients receiving concomitant therapy with diuretics or potentially nephrotoxic drugs and the elderly. Such patients should have their renal, hepatic and cardiac functions carefully monitored (see also section 4.3), and the dose should be kept as low as possible in patients with renal, hepatic or cardiac impairment.
Caution is required if administered to patients suffering from, or with a previous history of bronchial asthma since ibuprofen has been reported to cause bronchospasm in such patients.
Occasional elevations of serum transaminases or other indicators 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, Mobiflex should be stopped and follow-up tests carried out. Particular care is required in patients with pre-existing hepatic disease.
Mobiflex reduces platelet aggregation and may prolong bleeding time. This should be borne in mind for patients who undergo major surgery (e.g. joint replacement) and when bleeding time needs to be determined.
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with non-steroidal anti-inflammatory drugs occurred in the elderly and/or debilitated patients.
Particular care should be taken to regularly monitor elderly patients to detect possible interactions with concomitant therapy and to review renal, hepatic and cardiovascular function which may be potentially influenced by non-steroidal anti-inflammatory drugs.
Adverse eye findings have been reported with non-steroidal anti-inflammatory drugs, therefore it is recommended that patients who develop visual disturbances during treatment with Mobiflex have ophthalmic evaluation.
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 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 tenoxicam.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tenoxicam 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).
As known for other anti-inflammatory drugs, Mobiflex may mask the usual signs of infection.
NSAIDs inhibit renal prostaglandin synthesis and consequently may have an undesirable effect on renal haemodynamics and on salt and water balance. It is necessary to adequately monitor the patient with a special emphasis on cardiac and renal function (BUN, creatinine, development of edema, weight gain, etc.) when giving Mobiflex to patients with conditions that could increase their risk of developing renal failure, such as pre-existing renal disease, impaired renal function in diabetics, hepatic cirrhosis, congestive heart failure, volume depletion or concomitant treatment with potentially nephrotoxic drugs, diuretics and corticosteroids. This group of patients is at special risk in peri- and post-operative phases of major surgery due to possibility of serious blood loss. They therefore require close monitoring in the post-operative and recovery periods.
Because of the high plasma protein binding of tenoxicam, caution is required when plasma albumin levels are markedly reduced
Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The use of Mobiflex 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 Mobiflex should be considered.
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4).
Acetylsalicylate and salicylates: Salicylates can displace tenoxicam from protein-binding sites and so increase the clearance and volume of distribution of Mobiflex. Concurrent treatment with salicylates should therefore be avoided because of the increased risk of adverse reactions (particularly gastro-intestinal).
Antacids and H2-receptor antagonists: Antacids may reduce the rate, but not the extent, of absorption of Mobiflex. The differences are not likely to be of clinical significance. No interaction has been found with concomitantly administered cimetidine.
Anticoagulants: Tenoxicam is highly bound to serum albumin, and can, as with all NSAIDs, enhance the effects of anticoagulants such as warfarin (see section 4.4). Close monitoring of the effects of anticoagulants and oral glycaemic agents is advised, especially during the initial stages of treatment with Mobiflex. No interaction with digoxin has been observed. In healthy subjects no clinically relevant interaction between Mobiflex and low molecular weight heparin has been observed.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.
Ciclosporin: As with all NSAIDs caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.
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 of developing convulsions.
Lithium: Non-steroidal anti-inflammatory drugs have been reported to decrease elimination of lithium. If tenoxicam is prescribed for a patient receiving lithium therapy, the frequency of lithium monitoring should be increased, the patient warned to maintain fluid intake and to be aware of symptoms of lithium intoxication.
Diuretics and Antihypertensives: Non-steroidal anti-inflammatory drugs may cause sodium, potassium and fluid retention and may interfere with the natriuretic action of diuretic agents, which can increase the risk of nephrotoxicity of NSAIDs. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for a worsening of those conditions.
No clinically significant interaction between Mobiflex and furosemide was noted, but Tilcotil attenuates the blood pressure lowering effect of hydrochlorothiazide. As known from other NSAIDs, Mobiflex might attenuate the antihypertensive effects of alpha-adrenergic blockers and ACE-inhibitors.
No interactions have been reported between Mobiflex and centrally acting alpha agonists or calcium channel blockers.
There was no clinically relevant interaction when Mobiflex was administered together with atenolol. During clinical trials no interaction was reported for patients treated concomitantly with digitalis products. Thus concurrent dosing of Mobiflex and digoxin appears to be without major risk.
Methotrexate: Caution is advised where methotrexate is given concurrently because of possible enhancement of its toxicity, since NSAIDs have been reported to decrease elimination of methotrexate.
Oral Antidiabetics: The clinical effect of the oral antidiabetic drugs glibornuride, glibenclamide, tolbutamide, was likewise not modified by Mobiflex. Nevertheless, as for other NSAIDs, careful monitoring is recommended when patients concomitantly receive oral antidiabetic drugs.
Colestyramine: Colestyramine may increase the clearance and reduce the half-life of tenoxicam.
Dextromethorphan: The concomitant administration of tenoxicam and dextromethorphan may increase the analgesic effect compared to monotherapy.
Food: The extent of absorption of tenoxicam is not influenced by food, but the rate of absorption (Cmax) may be slower than in fasting state.
Others: Co-administration of probenecid and tenoxicam treatment may increase plasma concentration of tenoxicam. The clinical significance of this observation has not been established.
Mifepristone: NSAIDs should not be used for 8–12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.
Corticosteroids: As with all NSAIDs, caution should be taken when co-administering cortico-steroids because of the increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): There is an increased risk of gastrointestinal bleeding (see section 4.4) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
Tacrolimus: There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: There is an increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Gold/penicillamine: No clinically relevant interaction was found in small numbers of patients receiving treatment with penicillamine or parenteral gold.
The use of tenoxicam, 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 difficulty conceiving or are undergoing investigation of infertility, withdrawal of tenoxicam should be considered. (See section 4.4).
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 sysnthesis 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, tenoxicam should not be given unless clearly necessary. If tenoxicam 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, tenoxicam is contraindicated during the third trimester of pregnancy.
In the limited studies available so far, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
Based on findings from single dose administration, a very small amount (mean value less than 0.3% of the dose) of tenoxicam passes into breast milk (see section 5.2 Pharmacokinetic properties). There is no evidence of adverse reactions in breast-fed infants of mothers taking Mobiflex. Nevertheless, infants should be weaned or the drug discontinued.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
Usually the undesirable effects reported were mild and transient. In a small proportion of patients the interruption of treatment due to undesirable effects was necessary.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories:
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)
Frequency not known: agranulocytosis, anemia, aplastic anemia, haemolytic anemia, leucopenia, thrombocytopenia, non-thrombocytopenic purpura, eosinophilia
Frequency not known: hypersensitivity reactions such as asthma, anaphylactic reactions, angioedema
Common: anorexia
Rare: Metabolic abnormalities (like: hyperglycaemia, weight increased/decreased)
Rare: sleep disorder (e.g. insomnia), depression, nervousness, dream abnormalities
Frequency not known: confusional state, hallucinations
Common: dizziness, headache
Frequency not known: Somnolence, paraesthesia
Frequency not known: visual disturbances (such as visual impairment and vision blurred), swollen eyes, eye irritation
Rare: vertigo
Frequency not known: tinnitus
Rare: palpitations
Frequency not known: cardiac failure
The possibility of precipitating congestive cardiac failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.
Rare: Thrombotic events (e.g. myocardial infarction or stroke)
Frequency not known: vasculitis, hypertension
Clinical trial and epidemiological data suggest that use of selective Cyclooxygenase 2 inhibitors (COX2 inhibitors) and 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). Also tenoxicam has not shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk with tenoxicam.
Rare: bronchospasm, aggravated asthma, dyspnoea
Frequency not known: epistaxis
Bronchospasm and aggravated asthma have been reported following treatment with NSAIDs.
Very Common: gastric, epigastric and abdominal pain and discomfort, dyspepsia, nausea, vomiting, flatulence, constipation, diarrhea, indigestion, epigastric distress, stomatitis
Common: gastrointestinal haemorrhage, gastrointestinal perforation, gastrointestinal ulcers, peptic ulcer, sometimes fatal, particularly in the elderly, haematemesis, melena, constipation, diarrhoea, mouth ulceration, gastritis, dry mouth, exacerbation of colitis and Crohn’s disease (see section 4.4 Special warning and precautions for use).
Very rare: pancreatitis
Uncommon: increased hepatic enzymes
Frequency not known: hepatitis, jaundice
Uncommon: pruritus, erythema, exanthema, rash, urticaria
Rare: vesiculo-bullous reactions.
Very rare: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome, toxic epidermal necrolysis (see section 4.4)
Frequency not known: photosensitivity reaction.
Nail disorders and, photosensitivity reaction and alopecia have been reported rarely following treatment with NSAIDs.
Uncommon: increased blood urea or creatinine
Frequency not known: nephrotoxicity (e.g. renal failure, interstitial nephritis, nephrotic syndrome, increased blood urea or creatinine).
Isolated cases of female infertility have been reported with drugs known to inhibit cyclooxygenase/prostaglandin synthesis including tenoxicam.
Uncommon: fatigue, oedema -
Frequency not known: Malaise
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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